The Cancer Market - UBS - Nov00

bcdC.J. Sylvester

212-713-1419

Jeffrey Chaffkin

212-713-2432

Stacy Parker, Dale Shivnarain

Associate Analysts Pharmaceuticals

Health Care Group

Disease Dynamics:The Cancer Market

November 8, 2000

Significant Opportunities Remain

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Industry Outlook

Disease Dynamics: The Cancer Market November 8, 2000 UBS Warburg LLC

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UBS Warburg LLC Disease Dynamics: The Cancer Market November 8, 2000

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Significant Opportunities Remain

�There are several reasons for writing this report:

� Continued limited success with current cancer therapies.

� Tremendous R&D activity in this specific therapeutic market.

� Cancer is a clear beneficiary of the knowledge that is being developed out ofthe analysis of the human genome.

�This report provides an in-depth review of current trends in the cancer marketfrom three perspectives: scientific, medical/treatment and investment. The reportculminates in an analysis of the various companies and their positions in thisgrowing market.

�We have attempted to provide a review of the recent scientific advances on suchtopics as oncogenes, multidrug resistance and biologic therapies.

�Using a patient database of approximately 10,000 individuals, we have provided ananalysis of the utilization trends in the U.S. cancer market, which provides detailedinsight into what regimens are being used for the various types of cancer.

�We have also reviewed the most recent treatment literature and summarized currenttreatment trends for the major cancers in the United States.


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Table of Contents

Introduction.................................................................................................................... 5Cancer Overview ................................................................................................................. 8Key Concepts: Cell Biology............................................................................................... 10Key Concepts: Molecular Biology .................................................................................... 11Key Concepts: Oncogenes................................................................................................. 15Treatment .......................................................................................................................... 18Key Concepts: Immunotherapy ....................................................................................... 27Key Concepts: Drug Resistance ........................................................................................ 31The Next Wave of Agents ................................................................................................. 33How Cancer Is Staged ....................................................................................................... 37

The Individual Cancer Markets .............................................................................39

Introduction ...................................................................................................................... 40

Breast Cancer..................................................................................................................... 43

Lung Cancer ...................................................................................................................... 52

Colorectal Cancer.............................................................................................................. 60

Non-Hodgkin’s Lymphoma............................................................................................. 63

Ovarian Cancer ................................................................................................................. 69

Bladder Cancer .................................................................................................................. 73

Pancreatic Cancer.............................................................................................................. 77

Prostate Cancer ................................................................................................................. 80

Company Cancer Portfolios ....................................................................................85Introduction ...................................................................................................................... 86Alza .................................................................................................................................... 86American Home Products ................................................................................................ 88Amgen................................................................................................................................ 89AstraZeneca ....................................................................................................................... 90Aventis ............................................................................................................................... 92Bayer AG............................................................................................................................ 95Bristol-Myers Squibb ........................................................................................................ 95Eli Lilly ............................................................................................................................. 102Genentech........................................................................................................................ 105IDEC Pharmaceuticals .................................................................................................... 107Merck & Co. .................................................................................................................... 108Novartis ........................................................................................................................... 108Pfizer ................................................................................................................................ 111Pharmacia Corp. ............................................................................................................. 112Roche ............................................................................................................................... 117Schering-Plough.............................................................................................................. 118SmithKline Beecham....................................................................................................... 122

Cancer Terms.............................................................................................................. 125


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IntroductionThis report is designed to provide a detailed overview of the cancer market, which webelieve remains one of the largest untapped disease markets in the world and whichconsequently presents a large opportunity for the pharmaceutical industry. In 1999,cancer and cancer-related therapies generated approximately $9.5 billion worldwide;this was up 29% over 1998. It is estimated that cancer results in health care expendi-tures of more than $110 billion annually worldwide.

Exhibit 1: Worldwide Major Oncology Drug RevenuesDollars in millions

Oncology Market Revenues(Worldwide Revenues in Millions)

Product Class Company 1998 1999 GrowthTaxol taxane Bristol-Myers Squibb 1,206.0$ 1,481.0$ 22.8%Lupron GnRH analog TAP 750.0$ 730.0$ -2.7%Zoladex GnRH analog AstraZeneca 624.8$ 686.0$ 9.8%Paraplatin alkylating agent Bristol-Myers Squibb 525.0$ 600.0$ 14.3%Aredia bisphosphonate Novartis 390.9$ 588.0$ 50.4%Nolvadex nonsteroidal antiestrogen AstraZeneca 523.7$ 573.0$ 9.4%Taxotere taxane Aventis 380.4$ 514.0$ 35.1%Gemzar nucleoside analog Eli Lilly 306.8$ 455.8$ 48.6%Sandostatin somatostatin Novartis 310.9$ 360.7$ 16.0%Casodex nonsteroidal antiestrogen AstraZeneca 243.6$ 340.0$ 39.6%Intron A** interferon Schering-Plough 620.0$ 650.0$ 4.8%Leuplin GnRH analog Takeda 271.0$ 298.0$ 10.0%Camptosar topoisomerase I inhibitor Pharmacia 193.7$ 293.4$ 51.5%Rituxan monoclonal antibody Genentech/Idec 162.6$ 279.4$ 71.8%Ellence anthracycline Pharmacia 177.3$ 210.0$ 18.4%Herceptin antibody Genentech N/A 188.4$ N/AHycamtin topoisomerase I inhibitor SmithKline Beecham 117.7$ 151.2$ 28.5%Arimidex aromatase inhibitor AstraZeneca 103.1$ 140.0$ 35.7%Platinol-AQ platinum derivative Bristol-Myers Squibb 132.0$ 136.0$ 3.0%Furtulon antineoplastic Roche 149.5$ 131.6$ -11.9%Eulexin nonsteroidal antiestrogen Schering-Plough 171.0$ 130.0$ -24.0%Proleukin recombinant IL-2 Chiron 93.0$ 112.0$ 20.4%Ethyol cytoprotective Roche/ALZA 35.0$ 101.3$ 189.4%Fludara antineoplastic Schering AG N/A 94.0$ N/ACampto topoisomerase I inhibitor Aventis N/A 92.6$ N/AEloxatine platinum derivative Sanofi N/A 83.1$ N/ANilandron antiandrogenic agent Aventis 45.5$ 83.0$ 82.6%Oncoseed radionuclide Nycomed N/A 82.2$ N/AVePesid antineoplastic Bristol-Myers Squibb 84.0$ 80.0$ -4.8%Ifex antineoplastic Bristol-Myers Squibb N/A 79.0$ N/AFemara aromatase inhibitor Novartis 103.1$ 70.7$ -31.5%Navelbine vinca alkaloid GlaxoWellcome 63.0$ 70.0$ 11.1%Leukine GCSF Immunex N/A 69.1$ N/ABondronat bisphosphonate Roche 55.2$ 68.0$ 23.3%Adriamycin PFS anthracycline Pharmacia 67.0$ 61.0$ -9.0%Leustatin antineoplastic Johnson&Johnson 53.0$ 56.0$ 5.7%

Total Cancer and Cancer-Related Therapies 7,958.7$ 10,138.5$ 27.4%

Source: MedAdNews.

**Please note: Schering-Plough’s Intron A is used for oncology and hepatitis; approximately 50% of its sales are in cancer-related indications; full-year revenue is reflective of all indications.

In 1999, cancer andcancer-relatedtherapiesgeneratedapproximately $9.5billion worldwide;this was up 29%over 1998.


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We believe there are three key reasons why the cancer market could offer tremendousgrowth opportunities in the future. First, the macro trends clearly indicate growth.Through 2020, the older segments of the population, which are the segments mostlikely to develop cancer, will continue to expand to unprecedented levels (see Exhibit 2).

Exhibit 2: Worldwide Demographic Trends, 2000-20

-40%

-20%

0%

20%

40%

60%

80%

100%

120%

Age Group

Per

cent

Cha

nge

Total Europe Japan U.S. Totals

0-44

45-64

64-79

80+

Source: United Nations.

Second, we have seen a steady increase in the amount of research and development(R&D) activity associated with developing cancer therapies. Prior to the end of the20th century, there were only a handful of companies with a presence in the oncologymarket. Now, it appears as though every major pharmaceutical company is vying forposition in this potentially lucrative market. Fortunately, advances in molecular biolo-gy have furthered the understanding of the disease and cancer is no longer a “blackbox.” This increase in understanding has facilitated the drug development process andlowered the risk profile of cancer therapies. In a PhRMA annual survey from 1999,there were 354 drugs in development for cancer. This number was greater than thenumber of drugs in development for heart disease, stroke, AIDS, rheumatoid arthritis,diabetes and Alzheimer’s disease combined. Consequently, a majority of pharmaceuti-cal companies are now looking to this market for future growth.

Third, the margin for improvement over current therapies remains large. There con-tinues to be a relative inadequacy of current cancer therapies when compared to otherdiseases. Current therapies, for the most part, have limited success with no real signifi-cant improvements in survival being seen in the past several years. Physicians continueto measure improvement in patient survival in months rather than years when lookingat new therapies. Interestingly, it is estimated that the typical cancer drug works in30-40% of the population. It remains unclear as to why one individual responds to acertain therapy while others with the same diagnosis do not. Additionally, currenttherapies are difficult to administer with minimal availability of oral agents (most


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current therapies require multi-hour infusion regimens) and the majority of agentshaving severe side-effect profiles. Additionally, there are some experts who believe that,in the future, cancer could possibly be treated in a similar fashion to HIV. Perhaps inthe future patients would initially be treated to stop the spread of the disease and thentake a certain therapy chronically in an effort to keep the disease at bay. Currently,patients cycle off and on cancer therapies in monthly shifts (e.g., a three-monthchemotherapy cycle). In this new paradigm, once patients go into remission, theyremain on therapy indefinitely.

In the U.S., cancer is the second-leading cause of death behind cardiovascular disease.But it is likely, in the next few years, that cancer will become the number one cause ofdeath. The reasons behind this appear to be twofold. First, deaths due to cardiovasculardisease are decreasing because of more effective therapies resulting from a greater un-derstanding of the molecular components involved in cardiovascular disease. Second,people are living longer; consequently, since cancer tends to be caused by an accumu-lation of genetic mutations, the longer individuals live, the greater the likelihood thatthey will develop cancer. However, the underlying molecular mechanisms of cancer arejust being unearthed and the relative understanding of them is still developing.Currently, although unfortunate, mortality from cancer remains very high. The onlycurative therapies for cancer, surgery and radiation, are usually only effective if the dis-ease is found early. For the most part, current chemotherapies are palliative in effectand rarely offer a long-term cure.

Recently, most of the popular press has focused on the next wave of new medicinesthat will result from the entire human genome being known. Although we believe theactual completion of the Human Genome Project is somewhat of an arbitrary land-mark with regard to drug discovery, it does highlight the large potential opportunityfor the industry. Approximately 20 years ago, the first oncogene defects were discov-ered. Since that time, the number of drug targets has risen dramatically. But as the sci-entific understanding of cancer has grown, so, too, has the rate of discovery of drugtargets. We believe we are at the early stages of drug development for cancer. Forexample, it took approximately 40 years to understand hypertension and to developdrugs such as the ACE inhibitors and the ARBs; consequently, the opportunities incancer remain quite impressive, in our opinion.

In the U.S., canceris the second-leading cause ofdeath behindcardiovasculardisease. But it islikely, in the nextfew years, that itmay become thenumber one causeof death.

We are at the earlystages of drugdevelopment forcancer. . . it tookapproximately 40years to under-stand hypertensionand to developdrugs to treat it.Consequently, theopportunities incancer remainquite impressive.


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Cancer OverviewThe term “cancer” is used to describe a group of diseases that are characterized by un-controlled cell growth, cell differentiation and the spreading of cells throughout thebody. Approximately 1.22 million new cancer cases are expected to be diagnosed in theU.S. this year. It is estimated that in the U.S., over 563,000 deaths can be attributed tocancer annually. That makes cancer the second-leading cause of death, behind heartdisease. Current statistics suggest that approximately 30% of Americans will developcancer in their lifetime and roughly two-thirds of these individuals will die from theirdisease. The following two charts indicate the historical relative incidence rates of vari-ous cancers in women and men, respectively.

Exhibit 3: Age-Adjusted Female Cancer Death Rates by Site1979-1997

-

10,000

20,000

30,000

40,000

50,000

60,000

70,000

1979

1980

1981

1982

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

LUNG BREAST COLORECTAL UTERINE OVARIAN PANCREAS BLADDER

Source: CDC Mortality Data.

Statistics suggestthat approximately30% of Americans

will develop cancerin their lifetime

and roughly two-thirds will die of

the disease.


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Exhibit 4: Age-Adjusted Male Cancer Death Rates by Site1979-1997

-

10,000

20,000

30,000

40,000

50,000

60,000

70,000

80,000

90,000

100,00019

79

1980

1981

1982

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

LUNG COLORECTAL PROSTATE ESOPHAGUS BLADDER

PANCREAS LIVER STOMACH

Source: CDC Mortality Data.

Cancer is caused by both environmental and genetic factors, which can sometimeswork in concert to promote the disease. Factors such as inherited traits, hormones,viruses, chemicals or radiation can produce or stimulate cancer cells. In men, the mostprevalent sites for cancer are the prostate gland and the lung; the most common sites inwomen are the breast and the lung.

Virtually every tissue in the human body can spawn malignancies, with some tissuesbeing able to produce several different types of cancer. A malignancy occurs after anaccumulation of genetic mutations in a particular cell. Researchers are currently awareof a basic set of rules that governs the development of a malignancy. Cells of a tumordescend from a common ancestral cell that, at some point, usually decades before atumor is detected, began a process of inappropriate cellular reproduction. It is likelythat the malignant transformation of the particular cell came about through the accu-mulation of mutations in specific classes of genes within the cell. Current theories sug-gest that anywhere between five and 15 cumulative mutations are required to cause amalignancy.

Although each cancer has a unique profile, the basic processes that produce tumorstend to be quite similar. Normally, cells divide to produce more cells only when thebody needs them. However, if cells continue dividing when new cells are not needed, amass of tissue forms. This mass of tissue is referred to as a tumor. Tumors can bedivided into two categories, benign or malignant. Benign tumors are rarely life-threatening and, in most cases, can be surgically removed without any future compli-cations. Malignant tumors are cancer. Importantly, malignancies possess an insidiousproperty, the ability to migrate from the site where they originated. Malignancies caninvade and damage nearby tissues and organs. Often, cancer cells from a malignanttumor enter the bloodstream and cause tumors to develop in other regions of the body.This process is referred to as metastasis.

Malignanciespossess an insidi-ous property, theability to migratefrom the site wherethey originated.They can invadeand damagenearby tissues andorgans, through aprocess known asmetastasis.


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Key Concepts: Cell BiologyThe cell is the basic unit of all animals and plants. Cells are endowed with the uniqueability to replicate and differentiate themselves, two qualities that are central to anydiscussion of cancer. They have clearly defined morphology (structure) and physiology(function). All cells have the potential to assume any morphology and to have anyphysiological characteristic through differentiation, a developmental process that re-sults in structural and functional distinction between tissues. Cells differentiate frompluripotential (developmentally plastic) stem cells. Once differentiated into a particulartype of cell, for example a liver cell, that cell has the ability to replicate itself throughcellular division, producing more differentiated cells.

To facilitate further discussion, we are providing a brief review of cell structure. Thecentral core of the cell, the nucleus, houses the cell’s genome (its complete set of DNA)and is the primary site of cancerous development. Protein synthesis takes place in theendoplasmic reticulum and the Golgi apparatus found in the cytoplasm, while the mi-tochondria are the fuel-processing centers of the cell. Receptors are located on both thecell membrane and the nuclear membrane and are the site of interaction between theextracellular environment and the cell, as well as the means through which the genomeand the cytoplasmic infrastructure communicate. The centrioles play an important rolein cell division while the lysomes are acid-filled vesicles that are important to the de-struction of cellular debris and the cell itself.

Cancerous cells can be distinguished from normal cells through microscopic examina-tion. Changes in the phenotype, or physical appearance and function, of a cell can helpto determine its normalcy. In a tumor, for example, the cells will typically have a highernucleus-to-cytoplasm ratio, prominent nucleoli and few specialized structures, all typi-cal of actively dividing cells. In addition to changes in the degree of cell division, can-cerous cells also exhibit alterations in their ability to produce certain types andamounts of proteins, including enzymes and hormones.

Protein synthesis is an essential function of all cells. The process begins in the nucleus,where strands of DNA arranged into unique units called genes provide the template forall the proteins a cell produces. The genes themselves are arranged into series known asgene families, which, in turn, are arranged into chromosomes. The DNA strands of agiven gene are transcribed into a special type of RNA called messenger RNA (mRNA)through a process known as “transcription,” signaling the beginning of protein syn-thesis, which takes place in the cell nucleus. There are several proteins and enzymesthat facilitate this process, including RNA polymerase and transcription factors. Oncethe DNA is transcribed into RNA, the mRNA travels to the cytoplasm and inserts itselfinto the rough endoplasmic reticulum, where the second step in protein synthesis, aprocess known as translation, takes place. During translation, the code written in thelanguage of ribonucleic acids is translated into the language of amino acids, which arethe basic units of proteins. We discuss deoxyribonucleic acid (DNA), ribonucleic acid(RNA) and amino acids (proteins) in greater detail below.


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Exhibit 5: The Cell

Source: MS Encarta Encyclopedia.

Key Concepts: Molecular BiologyTo fully understand how cancer develops and how drugs combat cancer, it is necessaryto understand some basic concepts in molecular biology and genetics. In each of ourseveral trillion cells, there is a nucleus. This nucleus houses 23 pairs of chromosomes.Chromosomes are packets of compressed and entwined DNA. DNA is the famousdouble helix; conceptually, think of a ladder that is twisted. Each rung of the ladder ismade up of a base pair. Notably, approximately 3 billion base pairs make up our entiregenome (a genome is an organism’s complete set of genetic information). The intrinsicelegance of our complexity is the simplicity of our genetic code. Specifically, there areonly four types of bases in every piece of DNA. The bases are denoted by “A” adenine,“C” cytosine, “G” guanine and “T” thymine in every organism. Interestingly, the dif-ferences between the human genome and the mouse genome are relatively small. Fur-thermore, we share about 99.9% of our genome with chimps. Clearly, the variationbetween our species is due to a very small number of genes. A key to understandinghow DNA is our genetic code lies in the simplicity of its design. These bases come incomplementary pairs so that “A” always pairs with “T” and “C” always pairs with “G.”


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Exhibit 6: Gene Microstructure

Source: Primer on Molecular Genetics, DOE.

Therefore, conceptually, one side of the DNA ladder is the exact complement of theother. Consider, if we designate one side A and the other side A’, strand A can serve asa template for making a new strand A’, whereas A’ can serve to make a new strand of A.Therefore, genetic information can be copied through a method that separates A fromA’, and each separated strand then serves as a template for the production of a newcomplementary partner strand. Therefore, as a direct consequence of the base pairing,it becomes clear that DNA carries information by means of the linear sequence of thebases. Each nucleotide (a base attached to the sugar-phosphate backbone or “rail of theladder”)—A, C, T or G can each be considered a letter in a four-letter alphabet that isused to write out biological messages.


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Exhibit 7: The Process of DNA Replication

Source: DOE.

Although the principle of gene “replication” or reproduction is simple and elegant, theactual process is extremely complex and will not be discussed further in this report.

Genes are made up of DNA. Importantly, in most cases, a single gene will encode for aspecific protein, although in some instances, different genes can synthesize the sameproteins. It is important to note that our bodies are composed of roughly 100,000 dif-ferent types of proteins. Proteins are made up of building blocks called amino acids.There are 20 essential amino acids found in humans and these are linked up to formthe various proteins that are in our body.

The rules by which the nucleotide sequence of a gene is translated into the amino acidsequence of a protein, the genetic code, has been known for 40 years. The sequence ofnucleotides in messenger RNA (mRNA), which acts as the intermediate between DNAand protein, was found to be read in a serial order in groups of three (see Exhibit 8).Each triplet (or codon) specifies one amino acid. Theoretically, there are 64 (43) possi-ble amino acids. The following exhibit illustrates this concept. The unbolded itemsrefer to abbreviations for amino acids. For instance, if your three base pairs are CTT,then the amino acid produced would be leucine. Interestingly, if the three bases areTAA, TAG or TGA, no amino acid is produced; these three codons, known as “stopcodons,” specify the termination of the protein chain that is being produced.


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Exhibit 8: The Genetic Code for Proteins

SECOND BASET C A G

T Phe Ser Tyr Cys TPhe Ser Tyr Cys CLeu Ser STOP STOP A

F Leu Ser STOP Trp G TI C Leu Pro His Arg T HR Leu Pro His Arg C IS Leu Pro Gln Arg A RT Leu Pro Gln Arg G D

A Ile Thr Asn Ser TB Ile Thr Asn Ser C BA Ile Thr Lys Arg A AS Met Thr Lys Arg G SE G Val Ala Asp Gly T E

Val Ala Asp Gly CVal Ala Glu Gly AVal Ala Glu Gly G

Source: UBS Warburg LLC.

To review, a gene is the blueprint for an inherited trait. A gene specifies a sequence ofamino acids that must be linked together to make a particular protein. It is this proteinthat will carry out the work of the gene. When a gene is properly stimulated, the cellusually responds by synthesizing the specific protein. Proteins are responsible for eve-rything your body does, and can even regulate when genes are “turned on” or “turnedoff.” Consequently, malfunctioning genes are intrinsically involved in most diseases.When a gene is active or “expressed,” the sequence of bases in its DNA is used as ablueprint to produce a specific protein. Knowing which genes are expressed in healthyand diseased tissues allows the identification of proteins required for normal func-tioning of the body and the identification of genes that may cause disease.

A gene specifies asequence of aminoacids that must be

linked to make aparticular protein.

It is this proteinthat will carry out

the work of thegene. Proteins are

responsible foreverything your

body does.


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Key Concepts: OncogenesOver the past 15 years, a considerable amount of attention has been given to the par-ticular genes that control cell proliferation and cell death. It is thought that a disrup-tion or mutation in these genes could be one of the underlying causes of cancer. Somemutations may occur in cells of the reproductive organs, which may explain the highincidence of cancer in some families. Other mutations may be due to exposure to envi-ronmental carcinogens or viruses. However, for cancer to occur, it must be the result ofmore than one mutation in the DNA that make up a gene. As mentioned previously, itappears that several distinct changes in a gene or gene family are necessary for full ex-pression of a cancer cell.

Research involving cancer and DNA has focused on two elements of the human ge-nome: the oncogenes and the tumor suppressor genes. Proto-oncogenes are normallyoccurring genes that are the progenitors of oncogenes. They become oncogenicthrough mutations or level of expression. Some oncoproteins are mutant forms of theregular proteins, while others are the same as the normal protein but may be expressedwhen they should not be or may be expressed at an abnormal level. The proto-oncogene and oncogene are identified by an italicized, three-letter code, such as “src”(v-src indicates a viral oncogene while c-src would indicate a cellular oncogene). Theoncoprotein is designated by the same three-letter code with the first letter capitalizedand without the italics (e.g., “Src.”) Tumor suppressor genes are also prevalent in everycell and act to control normal cell proliferation. Oncogenes and tumor suppressorgenes have five general categories of gene products, including: growth factors; recep-tors, both cell surface and intracellular; intracellular transducers, including protein-tyrosine kinases; nuclear transcription factors; and cell-cycle control proteins, such asp53, which fall into the tumor suppressor category. In general, oncogenes encouragecell growth, whereas tumor suppressor genes inhibit it. It appears as though a disrup-tion between the activity of oncogenes and the inactivity of tumor suppressor genes is acrucial factor in carcinogenesis.

Approximately 20 proto-oncogenes have been identified and their protein products arelocated throughout the cell. Examples of these products include tyrosine kinases andgrowth factors; in the following tables, we identify genes that are currently associatedwith various cancers.


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Exhibit 9: OncogenesONCOGENES

Genes for growth factors or their receptors

v-sis/PDGF Codes for platelet-derived growth factor. Involved in brain cancer

erb-B Codes for the receptor for epidermal growth factor. Involved in brain and breast cancer

erb-B2 (HER-2 or neu) Codes for a growth factor receptor. Involved in breast, ovarian and salivary gland cancers

RET Codes for a growth factor receptor. Involved in thyroid cancer

Genes for stimulatory signals

K-ras Involved in lung, ovarian, colon and pancreatic cancers

N-ras Involved in leukemias

Genes for transcription factors that activate growth-promoting genes

c-myc Involved in leukemias and breast, stomach and lung cancers

N-myc Involved in brain and nerve cell cancers

L-myc Involved in lung cancer

Genes for other kinds of compounds

Bcl-2 Codes for a protein that normally blocks cell suicide. Involved in follicular B cell lymphoma

Bcl-1 (PRAD1) Codes for cyclin D1, a stimulatory component of the cell's clock. Involved in breast, head and neck cancers

MDM2 Codes for the antagonist of the p53 tumor suppressor protein. Involved in connective tissue cancers

Source: Scientific American.

Exhibit 10: Tumor Suppressor GenesTUMOR SUPPRESSOR GENES

Genes for proteins in the cytoplasmAPC Involved in colon and stomach cancersDPC4 Codes for a relay molecule in a signaling pathway that inhibits cell division. Involved in pancreatic cancer

NF-1 Codes for a protein that inhibits a stimulatory (Ras) protein. Involved in myeloid leukemiaNF-2 Involved in brain cancer and other cancers of the nervous system

Genes for proteins in the cell nucleusMTS1 Codes for p16 protein, a braking mechanism in the cell cycle clock. Involved in numerous cancersRB Codes for the pRB protein, a master brake of the cell cycle clock. Involved in retinoblastoma and bone, bladder,

small cell lung and breast cancer

p53 Codes for the p53 protein which can halt cell division and induce abnormal cells to commit suicide. Involved in awide range of cancers

Genes for proteins whose cellular location is unclearBRCA1 Involved in breast and ovarian cancersBRCA2 Involved in breast cancerVHL Involved in kidney cancer



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Possibilities for Gene Therapy?Abnormalities in the p53 tumor suppressor gene are prevalent in a wide variety oftumors; its restoration could perhaps be used as a cancer therapy. Two companies areinvolved in the development of p53 gene therapy, Schering-Plough and Aventis.Schering is currently in Phase II and earlier studies with its p53 tumor suppressor genetherapy for treating various solid tumors. Schering has a number of agreements thatcontinue to advance this therapeutic platform. Currently, Schering has a collaborationwith Gene Logic, Inc. to help identify patients with a missing or defective p53 gene intheir tumors.

Aventis, in collaboration with Introgen, is also developing cancer gene therapies. Itslead product, INGN 201, combines the p53 gene with a gene delivery system the com-pany has developed. The gene delivery system uses a modified adenovirus, a commoncold virus, to deliver the p53 gene to cancer cells. The two companies have commencedPhase III trials in head and neck cancers. Phase II trials are ongoing in non-small-celllung cancer.

In Phase II trials, 112 patients with either recurrent or refractory head and neck cancerwere treated with INGN 201. A preliminary analysis showed that when investigatorsadministered INGN 201 locally, tumors shrank or stopped growing in 25% of patientstreated.

During the first half of 2000, gene therapy received a great deal of scrutiny due to someadverse events and the death of a young man enrolled in a University of Pennsylvaniastudy. However, now that additional safeguards have been established and imple-mented, it appears as though gene therapy is beginning to gain momentum. On April28, reports of the first unequivocal success for gene therapy were issued. Several in-fants, who likely would otherwise have died of a severe immune disorder known assevere combined immune deficiency (SCID), were treated effectively with gene therapyto repair a genetic flaw in their immune systems. The gene therapy was effective at tenmonths when the story was reported. This experiment marked a tremendous step for-ward for the gene therapy community because this was the first real instance wherediseased children were effectively cured of disease.


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TreatmentThe evolution of cancer treatment modalities remains very dynamic. The roles of sur-gery, radiation and chemotherapy tend to be specific for each type of cancer and evenmore specific for the individual patient. Cancer treatment and therapy often involvetwo forms of treatment; one form is intended to eliminate the tumor itself and anyfurther spread (i.e., chemotherapy); the second form is intended to make the patientmore durable to future therapies (i.e., blood factor stimulants). Aggressive initialcombined-modality treatments increase the likelihood of a potential cure and increasesurvival times. Importantly, it is necessary to consider the aggressiveness of the treat-ment and its associated toxicity, mortality and the cost/benefit relationship of thetreatment. There is a current emphasis on using chemotherapy as an adjuvant to sur-gery or radiation therapy, but this type of treatment must be properly sequenced be-cause certain toxicities are associated with improper sequencing of agents.

SurgerySurgery continues to play the key role in oncology. Surgery is needed for biopsies andis usually the definitive treatment for most individuals with cancer. However, sinceits relative importance to pharmaceutical companies is minimal, we will not go intofurther detail on cancer surgery in this report.

RadiationRadiation plays an integral role in both the primary and the palliative treatment of can-cer. There are currently two types of radiation therapies: 1) electromagnetic radiationsuch as X-rays, and 2) subatomic particle radiation, which consists of alpha particles,electrons, protons, etc. X-rays are most commonly used to treat malignant tumors;however, gamma rays, which are similar to X-rays, except that they are emitted byradioactive isotopes of radium or cobalt, are also used. Radiation therapy damages cellsby transferring energy to tissues in the form of photons. Photons damage both malig-nant and healthy tissues by producing ionization within cells. The toxicities associatedwith radiation therapy can be divided into two groups, early and late radiation effects.Early radiation effects are often referred to as acute toxicity and include erythema(redness of the skin), desquamation (peeling of the skin in scales), nausea, alopecia(baldness) and bone marrow suppression. The late radiation effects usually determinethe limiting toxicity of the therapy and include tissue necrosis (death) and tissue fibro-sis. Advances in imaging such as CT scanning have improved the radiation oncologists’ability to visualize tumors and limit the impact of the radiation on surrounding healthytissues. Additionally, advances in areas such as photodynamic therapy, which employsa systemically delivered tissue sensitizer, have been used to treat malignancies involvingthe skin, esophagus, bladder and brain.

ChemotherapyChemotherapy is the use of chemical agents to destroy malignant tissue. Over theyears, clinical trials have indicated that chemotherapeutic agents used in combinationproduce higher rates of objective responses and longer survival rates when compared

Aggressive initialcombined-

modalitytreatments areincreasing thelikelihood of a

potential cure andincreasing survival

times.


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to single agents used alone. To understand the impact and efficacy of chemotherapy, itis necessary to understand the cell life cycle. Cells reproduce by duplicating their con-tents and then dividing into two; this is commonly referred to as the cell division cycle.Many rounds of cellular division are required to create a new individual, but cell divi-sion is required in the adult body as well, to replace cells that are lost by wear and tearor through apoptosis (programmed cell death). There are four divisions in the cellcycle, which are depicted in the diagram below (S, G

2, M and G

1). DNA is replicated

during the S phase. The cell cycle usually lasts between 24 and 48 hours in normalhuman cells; however, in malignant cells, the cell cycle can be as long as 120 hours, butthese cycle times are not fixed. They can be increased or decreased depending on avariety of factors. Although it is poorly understood, the growth rate of tumors de-creases as the tumor increases in size. Two factors appear to account for this, a decreasein the fraction of tumor cells that are dividing and an increase in the rate of apoptosis(or cell death). As cells accumulate, whether it be in normal or cancerous tissue, thereis a decrease in the frequency with which they initiate new rounds of DNA synthesisand thereby produce new cells.

Exhibit 11: Interactions of Chemotherapeutic Agents in the Cell Cycle

Antibiotics

Antimetabolites

S(2-6h)

G2

(2-32h)

M(0.5-2h)

Alkylating agents

G0

Vinca alkaloids

Mitotic inhibitors

Taxoids

G1

(2-?h)


Ideally, cancer treatment should be performed on a tumor whose cells are rapidlydividing or “cycling.” Tumors with a high mitotic rate are thought to be more respon-sive to chemotherapy than those with a smaller fraction of dividing cells. Therefore, thestrategy behind cancer therapy is to get noncycling cells to begin to cycle again. This isachieved by using a combination of initial surgery to reduce the tumor’s size, followedby chemotherapy. By reducing the tumor’s size, surgery effectively gets a greater por-tion of cells cycling again. After the primary tumor is removed, microscopic metastasesmay remain at distant sites, but because of their small size, they are by definition com-posed primarily of cycling cells.


20

Nearly all chemotherapeutic agents interfere with DNA synthesis, with precursors ofDNA or with mitosis. In general, chemotherapeutic agents that induce DNA damageare administered by short-term infusions. Nucleotide analogs (nucleotide analogs re-semble the building blocks of DNA) such as antimetabolites are only thought to beeffective during S phase and, consequently, are given by continuous infusion to maxi-mize the potential exposure of cycling tumor cells. However, many agents, particularlythe alkylating agents (more on the different classes of agents below) can kill cells thatare not cycling and are therefore sometimes referred to as “non-cell proliferation-dependent” drugs. Drug classes like the antimetabolites and antibiotics are termed “cellproliferation-dependent” drugs because they are most active in cells during S phase.

Finally, several factors are considered when developing a chemotherapeutic regimen,including combinations of drugs based on pharmacological properties, drug sensitivityof the tumor, and any overlapping toxicities.

Classes of Chemotherapeutic Agents

Alkylating Agents

Alkylating agents were the first anticancer drugs ever used and are descendants ofmustard gas. As stated previously, alkylating agents are non-cell-proliferating depend-ent, and are therefore generally more effective against slow-growing tumors. The alkyl-ating agents are typically divided into six classes: nitrogen mustards, ethylenimines,alkyl alkone sulfonates, nitrosureas, platinum-containing compounds and nonclassicalalkylators.

The major toxicity common to all of these agents is myelosuppression or bone marrowsuppression. Additionally, alkylating agents often cause gastrointestinal upset; how-ever, these effects may be offset by prescribing the appropriate anti-emetic agents. Oneof the more widely used classes of alkylating agents, and the one that is of the greatestinvestment significance, is the platinum-based class of agents. Bristol is clearly thedominant player with Platinol (cisplatin) and its second-generation compoundParaplatin (carboplatin). Together, these compounds generated close to $500 millionin U.S. sales in 1999, according to IMS. Notably, Eli Lilly and Sanofi attempted to gettheir platinum-based agent Eloxatine (oxaliplatin) approved in the U.S. for colorectalcancer; however, the Food and Drug Administration (FDA) advisory committee didnot believe that the Phase III trial data were sufficient to warrant an approval. In mid-October, Eli Lilly returned its oxaliplatin rights to Sanofi and the companies dissolvedtheir joint venture. Sanofi is currently conducting two Phase III trials for the drug inthe second-line treatment of metastatic colorectal cancer. The following table illustratessome of the most common alkylating agents used today.


21

Exhibit 12: Commonly Used Alkylating Agents

Alkylating Agents

Brand Name Generic Name CompanyApprovedIndication Admin

1999 U.S.Revenues

BiscloroethylaminesLeukeran Chlorambucil GlaxoWellcome CLL, Hodgkin's

lymphoma and Non-Hodgkin'slymphoma

Oral $8 million

Cytoxan Cyclophosphamide Bristol-Myers breast, ovarian,CML, ALL,lymphomas

Oral, IV $33 million

Ifex Ifosamide Bristol-Myers testicular IV $80 millionMustargen Mechlorethamine Merck Lung, CLL, CML,

Hodgkin'slymphoma

IV $1 million

Alkeran Melphalan GlaxoWellcome ovarian, multiplemyeloma


AziridinesThioplex Thiotepa Immunex bladder, breast,

Hodgkin'slymphoma, non-

Hodgkin'slymphoma

IV, IM $32 million

Alkyl alkone sulfonatesMyleran Busulfan GlaxoWellcome CML Oral $2 millionBiCNU Carmustine Bristol-Myers Hodgkin's

lymphoma, non-Hodgkin's

lymphoma, multiplemyeloma, primary

brain

IV $5 million

CeeNu Lomustine Bristol-MyersHodgkin's

lymphoma, primaryand metastatic brain

Oral $1 million

Zanosar Streptozocin Pharmacia pancreatic IA, IV $1 millionNonclassic agents

DTIC-Dome Dacarbazine Bayer Hodgkin'slymphoma,metastaticmelanoma

IV $5 million

Generics Dacarbazine Various " " IV $4 millionMatulane Procarbazine Roche Hodgkin's

lymphomaIV $1 million

Temodar Temozolomide Schering-Plough brain Oral Launched 2000Platinum based agents

Paraplatin Carboplatin Bristol-Myers ovarian IV $396 millionPlatinol Cisplatin Bristol-Myers bladder, ovarian,

testicularIV, IA $103 million

Generics Cisplatin Various " " IV,IA $1 millionEloxatine Oxaliplatin Sanofi colorectal IV N/A

Source: UBS Warburg LLC, IMS America.

Antibiotics

The antibiotics are a large, diverse class of drugs that are grouped together solely basedon their origin. They are effective against a variety of tumor types. The major class ofdrugs in this group is the anthracyclines, which include doxorubicin, daunorubicin,epirubicin, idarubicin and mitoxantrone. The anthracyclines are thought to interferewith the replication of DNA. When DNA replicates, the double helix must be pulledapart into two strands. A specific enzyme helps with this process. That enzyme isknown as topoisomerase. Antibiotics interfere with the action of DNA topoisomerase II,resulting in DNA strand breaks. During cell division, the levels of topoisomerase II riserapidly and the cell becomes more vulnerable to some of these agents. In the followingtable, we highlight some of the more common antibiotic agents used today.


22

Exhibit 13: Commonly Used Antibiotic Agents

Antibiotic Agents


1999 U.S.Revenues

Adriamycin Doxorubicin Pharmacia ALL, AML, Wilm's,neuroblastoma, softtissue, bone, breast,

ovarian, bladder,thyroid, stomach,

Hodgkin's

IV $15 million

Generics Doxorubicin Various " " IV $26 millionBlenoxane Bleomycin Bristol-Myers cervix, head&neck,

larynx, penis, skin,testicular, Hodgkin'sand non-Hodgkin's

IM,subQ,IV

$25 million

Cosmegen Dactinomycin Merck testicular, Ewing's,Wilm's,

rhabdomyosarcoma

IV >$1 million

Cerubidine Daunorubicin Bedford Labs ALL, AML, acutemonocytic leukemia

IV $10 million

DaunoXome Daunorubicin(liposomal)

GileadKaposi's sarcoma

IV $2 million

Doxil Doxorubicin Alza Kaposi's sarcoma IV $50 millionIdamycin Idarubicin Pharmacia AML, ALL IV $27 million

Mutamycin Mitomycin C Bristol-Myers stomach, pancreatic IV $12 millionGenerics Mitomycin C Various " " IV $3 millionNovantrone Mitoxantrone Immunex leukemias IV $55 million


Antimetabolites

The antimetabolites are a large group of drugs that interfere with metabolic processesvital to the physiology and proliferation of cancer cells. The mechanism of action variesbetween the types of drugs, but in general, they prevent the synthesis of nucleotides orinhibit enzymes by mimicking nucleotides. These drugs have been used since 1948 inthe treatment of cancer. For instance, some antimetabolites are purine or pyrimidineanalogs (recall the four bases that compose DNA: A and G are purines, T and C arepyrimidines). These analogs are sometimes modified into nucleotides, at which point,they are incorporated into DNA and RNA, where they inhibit enzymes or result infaulty transcription or translation. Due to the suppression of cellular division and pro-liferation that is caused by antimetabolite therapies, many tissues that are actively di-viding (i.e., in the bone marrow or the gastrointestinal tract) will experience toxicity.Consequently, patients taking these types of therapies will experience bone marrowsuppression, dry mouth, diarrhea and hair loss. Importantly, the pattern and severityof treatment toxicities vary greatly depending on the drug administered and the sched-ule of administration, among other factors. Eli Lilly has one of the newest entrants tothe market in this class of agents with Gemzar (gemcitabine), which is indicated for thetreatment of non-small-cell lung cancer and pancreatic cancer. Gemzar had approxi-mately $450 million in worldwide sales during 1999 and is currently the key product inLilly’s oncology franchise. The newest entrant into this market is Roche’s oral agentXeloda (capecitabine). Xeloda received FDA approval for the treatment of metastaticbreast cancer in August 1998. This is an oral pro-drug of 5-FU. It is converted to 5-FUin three enzymatic steps. Interestingly, prior to 1999, oral anti-cancer agents were notcovered by Medicare, but the Health Care Financing Administration (HFCA) has sinceissued guidelines indicating that oral pro-drugs are to be covered by Medicare.


23

Another potential new antimetabolite is Bristol-Myers’s Orzel, which is still awaitingFDA approval. This drug is an oral formulation of UFT capsules and leucovorin. UFT,which Bristol in-licensed from Japan’s Taiho Pharmaceuticals in 1995, combines the5-FU pro-drug tegafur with uracil. Uracil is an enzyme inhibitor that increases thehalf-life of 5-FU. On March 17, Bristol withdrew its new drug application (NDA) forthe drug after receiving a favorable review from an FDA advisory committee. On April20, the company resubmitted its NDA, apparently to allow the FDA time to reviewadditional analyses, particularly on the role of uracil in the combination. In the follow-ing table, we highlight some of the more common antimetabolic agents used today.

Exhibit 14: Commonly Used Antimetabolic Agents

Antimetabolic Agents


1999 U.S.Revenues

Generics 5-Fluorouracil Various breast, colon,rectum, stomach,

pancreas, skin

IV, IA $1 million

Generics Cytarabine VariousALL, AML, CLL

subQ,IV

$6 million

Elspar Asparaginase Merck ALL IM, IV $4 millionFludara Fludarabine Berlex CLL IV $49 millionGemzar Gemcitabine Eli Lilly pancreas, lung IV $230 millionHydrea Hydroxyurea Bristol-Myers

head & neck,ovarian, CML,

malignant melanoma

Oral $9 million

Generics Hydroxyurea Varioushead & neck,ovarian, CML,

malignant melanoma

Oral $15 million

Generics Leucovorin Various antidote for folic acidantagonists,

megaloblasticanemia

Oral,IM, IV

$40 million

Leustatin Cladribine Johnson & Johnson hairy cell leukemia IV $12 millionGenerics Methotrexate Various leukemias, breast,

head, neck, lung,Burkitt's lyphoma,

lymphosarcoma, non-metastatic

osteosarcoma

Oral,IM, IV

$56 million*

Nipent Pentostatin SuperGen refractory hairy cellleukemia

IV $2 million

Purinethol Mercaptopurine GlaxoWellcome AML, ALL Oral $40 millionOrzel UFT and leucovorin Bristol-Myers colorectal Oral FiledTabloid Thiguanine GlaxoWellcome AML Oral $2 million

Xeloda Capecitabine Rochemetastatic refractory

breast Oral $15 million


‘


24

Plant-Derived Agents

For more than 200 years, compounds derived from plants have been used to treat can-cer. The oldest such agent is colchicine, which was capable of stopping cell division.During the 1950s, the vinca alkaloids, vincristine and vinblastine, were discovered andto this day remain relatively widely used. Bristol’s Taxol (paclitaxel) and Aventis’sTaxotere (docetaxel) are two of the newer plant-derived compounds and belong to anew class of agents referred to as taxanes. The epipodophyllotoxins, including Bristol’sVePesid (etoposide) and Vumon (teniposide), are semisynthetic compounds derivedfrom plants. The final group of plant-derived agents are derivatives of camptothecin(CPT) and consist of Pharmacia’s Camptosar (irinotecan) and GlaxoSmithKline’sHycamtin (topotecan).

The taxanes and vinca alkaloids are relatively unique among anticancer agents, in thatthey do not target DNA. The vinca alkaloids disrupt cell division by binding to struc-tural cellular proteins called tubulin. Tubulin is the building block of microtubules,which are critical in orchestrating proper cell division. Microtubules are responsible forpulling the chromosomes to either side of the parent cell, ensuring that each daughtercell receives a full set of genes. The taxanes exert their effects by altering the dynamicsof the microtubules. Importantly, since these compounds disrupt cellular division, theyare cell-cycle dependent and are only effective when cells are dividing.

The majority of drugs that are of investment significance are the more recentlylaunched products, such as Bristol’s Taxol, SB’s Hycamtin, Pharmacia’s Camptosar andAventis’s Taxotere. In the following table, we highlight some of the more commonplant-derived agents used today.

Exhibit 15: Commonly Used Plant-Derived Agents

Plant-Derived Agents


1999 U.S.Revenues

Camptosar Irinotecan Pharmacia colorectal IV $248 millionHycamtin Topotecan SmithKline Beecham ovarian IV $90 millionNavelbine Vinorelbine GlaxoWellcome non-small cell lung IV, oral $62 millionOncovin Vincristine Eli Lilly ALL, Hodgkin's

lymphoma, non-Hodgkin's

lymphoma,neuroblastoma,

Wilm's,rhabdomyosarcoma

IV $1 million

Generic Vincristine Various " " IV $1 millionTaxol Paclitaxel Bristol-Myers ovarian, breast, non-

small cell lung, KSIV $830 million

Taxotere Docetaxel Aventis breast IV $140 millionVelban Vinblastine Eli Lilly breast, testicular,

non-Hodgkin'slymphoma,Hodgkin's

lymphoma, KS

IV >$1 million

Generic Vinblastine Various " " IV $1 millionVePesid Etoposide Bristol-Myers refractory testicular,

small cell lungOral, IV $36 million

Generic Etoposide Various" "


Vumon Teniposide Bristol-Myers ALL IV $1 millionSource: UBS Warburg LLC, IMS America.


25

Biological Agents

Another, more recently developed treatment modality for cancer uses biological agentsto elicit tumor regression. The various therapies used include recombinant cytokines,such as IL-2 and interferon-alpha. Additionally, IL-4 and IL-12 are also being evalu-ated. Furthermore, recently approved monoclonal antibodies, such as Genentech’sHerceptin and IDEC’s Rituxan, have recently gotten recognition as viable and effectivetherapies. In the following table, we highlight a few of the more common biologicalagents used in chemotherapy.

Exhibit 16: Common Biological Agents

Biologic Agents


1999 U.S.Revenues

Herceptin Trastuzumab Genentech HER2overexpressing

breast

IV $123 million

Intron-A Interferon alpha Schering-Plough leukemia, Kaposi'ssarcoma

IV $156 million

Ontak Denileukin diftitox Ligand non-Hodgkin'slymphoma

IV >$1 million

Rituxan Rituximab IDEC Pharmaceuticals low-grade refractorynon-Hodgkin's CD20

positive B-celllymphoma

IV $227 million

Roferon-A Interferon alpha Roche leukemia, Kaposi'ssarcoma

IV $18 million


Hormonal Agents

In many organs and cell types, hormones can stimulate cell division and growth. Con-sequently, some hormonal agents are effective at reducing or eliminating tumor cellgrowth in a specific tissue type. Most hormonal agents work as agonists to inhibit tu-mor growth or as antagonists that compete with endogenous hormones that promotegrowth. TAP’s Leupron (leuprolide) and AstraZeneca’s Zoladex (goserelin) are effec-tive in the treatment of prostate cancer because both therapies inhibit production ofluteinizing hormone (LH) and follicle stimulating hormone (FSH), which promoteprostate cancer cell growth. In the following table, we highlight some of the morecommon hormonal agents used today.


26

Exhibit 17: Commonly Used Hormonal Agents

Hormonal Agents


1999 U.S.Revenues

Arimidex Anastrozole AstraZeneca Advanced breast inpostmenopausal

women with diseaseprogression following

tamoxifen

Oral $44 million

Casodex Bicalutamide AstraZeneca Stage D2 metastaticprostate

Oral $146 million

Cytadren Aminoglutethimide Novartis Adrenal carcinoma,ectopic ACTH

producing tumors

Oral >$1 million

Eulexin Flutamide Schering-Plough Prostate Oral $54 millionFareston Toremifene Roberts Metastatic breast in

postmenopausalwomen with estrogen

receptor pos. orunknown tumors

Oral $5 million

Femara Letrozole Novartis Advanced breast inpostmenopausal

women with diseaseprogression following

antiestrogens

Oral $9 million

Lupron Leuprolide TAP Prostate,endometriosis

SC orIM(depot)

$822 million

Lysodren Mitotane Bristol-Myers Adrenal cortexcarcinoma

Oral $3 million

Megace Megestrol Bristol-Myers Breast, uterine andAIDS associated

cachexia

Oral $117 million

Generics Megestrol Various " " Oral $14 millionNilandron Nilutamide Aventis Stage D2 metastatic

prostateOral $9 million

Nolvadex Tamoxifen AstraZeneca Breast Oral $66 millionGenerics Tamoxifen Various " " Oral $278 millionZoladex Goserelin AstraZeneca Advanced prostate SC $190 million



27

Key Concepts: ImmunotherapyAs scientists have gained an increasing amount of knowledge about the human im-mune system, they are rethinking ways to attack disease. Currently, it is clear thatmolecules can be engineered in such a way that we can “convince” our own body to useits defenses to attack cancer cells.

Human immunity is the result of the production of antibodies that are targeted at spe-cific antigens (substances that are recognized by the immune system and that cause theimmune system to create antibodies). Antibodies bind to antigens on foreign cells andinactivate or kill them. Antibody-mediated immunity is regulated by B cells, whichreside in the bone marrow and spleen. B cells are responsible for producing antibodies.B cells divide and form plasma cells and B memory cells. After an antigen is recognized,the plasma cells make and release between 2,000 and 20,000 antibody molecules persecond for the next few days. B memory cells live for months or years. Antibodies bindto specific antigens in a “lock and key” fashion, forming an antigen-antibody complex(see Exhibit 18). Antibodies are “Y” shaped molecules whose functions include recog-nition and binding to antigens and inactivation of the antigen.

Exhibit 18. Antibody and Antigen Structure

Source: DOE.

It is clear thatmolecules can beengineered in sucha way that we can“convince” ourown body to use itsdefenses to attackcancer cells


28

The concept of immunotherapy is not new; the foundations for this theory originatedin the 1800s, when physicians noticed that tumors sometimes regressed in patients whohad bacterial infections. Twenty years ago, some researchers had postulated that bystimulating the immune system, one can increase the body’s capacity to rid itself ofunwanted cells, including cancer. For instance, superficial bladder cancer (canceroccurring on the inner wall of the bladder) responds well to a vaccine used to combattuberculosis (Bacillus Calmette-Guerin—BCG). Usually, superficial bladder cancerrecurs after surgery to remove the malignancy. However, if a physician injects BCGinto the bladder after surgery, the risk of recurrence is reduced significantly. The exactmechanism of how the vaccine works is not known. In theory, the vaccine causes aprolonged inflammatory response, which increases the duration for which immunecells can fight foreign compounds locally. It is important to note that this vaccine isrelatively nonspecific; it works by causing a generalized immune response.

As stated previously, the lethality of cancer is due to its ability to metastasize.Consequently, for an immunotherapy to be truly successful, it must have the ability totarget cancer cells that may have a common site of origin but that are currently foundin distant regions of the body. Additionally, any therapy must also have the ability todifferentiate between healthy and malignant tissue.

Over the years, researchers have identified antigens that are specific to tumors. Asmentioned previously, antibodies “tag” antigen-presenting foreign compounds to bedestroyed by the rest of the immune system.

During the 1970s, researchers began developing antibodies directed specifically againstcertain antigens. Initially, scientists were injecting mice with certain antigens, allowingthe mice to develop immunity and then harvesting the antibodies that the mice pro-duced. The antibody-forming cells are isolated from the mouse’s spleen. Then they arecombined with tumor cells, which is referred to as a hybridoma. Each hybridoma pro-duces relatively large quantities of identical antibody molecules. By allowing the hy-bridoma to multiply in culture, it is possible to produce a population of cells, each ofwhich produces identical antibody molecules. These antibodies are called “monoclonalantibodies” because they are produced by the identical offspring of a single, cloned,antibody-producing cell. However, these types of monoclonal antibodies are ineffectiveas therapeutic agents because the mouse antibodies were recognized as foreign by ourimmune systems and, consequently, are destroyed rapidly.

By the 1980s, researchers developed ways of manipulating the mouse antibodies byincorporating portions of human antibodies. This process, known as “humanizing,”effectively reduces the degree of immunogenicity that an antibody may have. Addition-ally, genetic engineers have created mice that produce antibodies that are 100% human.In Exhibit 19, we illustrate the four types of antibodies being generated for therapeuticuse. Chimeric antibodies are composed of both mouse and human proteins, but thepercentage of mouse protein is much greater than in the humanized antibody.


29

Exhibit 19: Schematic of Various Types of Antibodies

MOUSE

HUMANIZED

CHIMERIC

HUMANSource: UBS Warburg LLC.

There are two ways in which antibodies can destroy tumors. First, they can invade thetumor and elicit other steps in the immune response and have a person’s own bodyattack the tumor. Second, one can use an antibody to deliver some sort of toxic agentto the tumor. A good example of the first scenario is the monoclonal antibody Rituxan(rituximab) marketed by IDEC Pharmaceuticals for the treatment of B-cell non-Hodgkin’s lymphoma. In this form of lymphoma, greater than 90% of the B-cells ex-press an antigen known as CD20. Rituxan binds to this antigen. It is hypothesized thatthe binding of Rituxan induces cell-mediated toxicity and perhaps apoptosis (pro-grammed cell death). Ultimately, the cells Rituxan binds to die.

An example of the second scenario is Coulter Pharmaceutical’s Bexxar (tositumomabplus radiolabeled iodine) for the treatment of non-Hodgkin’s lymphoma. Like Rituxan,Bexxar is a monoclonal antibody that is targeted against the CD20 antigen that is foundon B-cells. However, unlike Rituxan, Bexxar is combined or conjugated with radioac-tively labeled iodine. Conceivably, Bexxar has two mechanisms of killing cancer cells.The first mechanism would be similar to that of Rituxan, but the radioactive iodineoffers the potential to damage DNA within the cells. Bexxar is considered to be a tar-geted chemotherapeutic agent.

Coulter has co-developed Bexxar with SmithKline Beecham. Coulter submitted a biol-ogics license application (BLA) for Bexxar for the second-line treatment of non-Hodgkin’s lymphoma on June 30, 1999. The company was granted a priority review,but received a “refusal to file” letter from the FDA on August 27, 2000. The FDA re-quested that Coulter reformat selected data and reorganize certain analyses. On Sep-tember 18, SmithKline Beecham and Coulter announced that they had resubmitted theBLA to the FDA. On October 5, the companies announced that the FDA had grantedthe product a priority, or six-month, review. Coulter believes they could possiblylaunch Bexxar sometime next year.


30

Vaccines

Recently, two advances have enabled researchers to design more specific vaccines. First,there have been tremendous improvements in the techniques used in molecularbiology. Second, scientists continue to advance their knowledge of the mechanismsinvolved in the immune system activation, specifically in the case of vaccines, theactivation of T cells. As mentioned earlier, bladder cancer responds to the bacillusCalmette-Guerin (BCG). But this vaccine is relatively nonspecific; it works by causing ageneralized immune response. Several trials evaluating nonspecific vaccines or theirproducts have proved ineffective. However, several bacterial agents are now beingcombined with “tumor-associated” antigens (TAAs) as a means of creating a morespecific immune response target at the tumors themselves. TAAs are structures, such asproteins or carbohydrates, which are present on cancer cells and not normal cells.Several TAAs have been identified, and they represent a wide array of molecules. Forexample, carcinoembryonic antigen (CEA) is produced by colon cancers and otheradenocarcinomas such as breast, lung and pancreatic cancer.

Many tumor cell vaccines have entered definitive Phase III trials. Those trials that havebeen completed indicate a prolonged relapse-free survival without an overall survivaldifference. It remains unclear whether the FDA will accept a superior time to relapsewith no survival difference as grounds for approvability. Peptide and other antigen-specific vaccines are slightly earlier in development and may hold more promise forcancer patients.


31

Key Concept: Drug ResistanceMulti-drug resistance is one of the principal mechanisms by which many cancers be-come resistant to chemotherapy and a primary reason behind treatment failure. Thecells of a tumor are heterogeneous, in that some will be killed by chemotherapy whileothers will survive. Consequently, chemotherapy kills drug-sensitive cells, while drug-resistant cells survive. When the tumor grows again, a greater proportion of cells in thetumor will be drug resistant. Tumors may become resistant to chemotherapy for one oftwo reasons. One, the tumor originated in an organ that may be intrinsically resistant(e.g., liver or kidney cancer). These organs have an ability to export large moleculesthrough organic cation transporters. A second means by which the tumor cells becomeresistant to therapy is due to genetic mutations within a subset of cancer cells wherebythe mutation enables these cells to continue to grow and divide even in the presence ofa previously toxic chemotherapeutic agent. Interestingly, most cancers appear to gainresistance to many agents and sometimes to therapies to which they have had no priorexposure. This type of resistance profile can be recreated in a cell culture and led to thediscovery of the multidrug-resistance (mdr) gene family. These genes appear to encodefor transmembrane pumps (see Exhibit 20) involved in the transport of large organiccompounds. mdr-1, a member of this gene family, has been the most intensively stud-ied. It encodes for a transmembrane protein pump, referred to as P-glycoprotein,which exports numerous organic compounds including the anthracyclines and alka-loids. Another cellular pump involved in drug resistance is a multi-drug resistanceprotein, or MRP. The mechanism by which this occurs remains unknown. Notably,drugs like cyclosporine and verapamil can block the export of chemotherapy drugs bymdr-1.

There are other mechanisms by which tumors may become resistant to therapy, all ofwhich are highlighted in Exhibit 21. One well-studied mechanism is through mutationsin the p53 tumor suppressor gene, which allows the cell to ignore the apoptotic, or celldeath, response that occurs after DNA injury mediated by chemotherapy. Anothermechanism of resistance may be decreased drug uptake, or increased drug export thatis mediated by the aforementioned mdr-1-related proteins. Two other possible mecha-nisms could be a compensatory amplification in the amounts of the cellular drugtarget, or a mutation in the target that renders it resistant to the effects of the particulartherapy.

Several companies are involved with the development of drugs that target these twotypes of pumps that confer tumor resistance. It is important to note that companiescan use these molecular data in two ways. The most readily apparent way is to depletethe cancerous cells of their chemoprotective features that are mediated by the pumps,perhaps designing a compound that doesn’t allow the pumps to be synthesized withinthe cells. Another less readily apparent application would be to confer these chemo-protective traits onto bone marrow cells, to allow them to deal with chemotherapybetter. Myelosuppression (bone marrow suppression) continues to be the dose-limiting toxicity in a large proportion of chemotherapeutic regimens.

Multi-drug resist-ance is one of theprincipal mecha-nisms by whichmany cancersbecome resistantto chemotherapyand is a primaryreason behindtreatment failure


32

Exhibit 20: The Possible Mechanism of Chemotherapy Resistance

MDR1

DRUG

Failure to induceapoptosis

Amplification ofdrug target

Mutation in drugtarget

Increaseddrug export

Reduction indrug uptake

Inactivated p53

1

3

2

4

5

Drug resistance can occur through: 1) failure of the drug to induce apotosis—p53 can regulate the sensitivity to drugs bychanging the expression of proapoptotic and anti-apoptotic molecules, such as Bcl-2, and by regulating the polymerizationstate of microtubules-2) Failure of the drug to reach the target because of increased drug export through pumps like MDR-3) Mutation of the drug target-4) Amplification of the drug target-5) A reduction in drug uptake.

Source: Adapted from Scientific American.

Investigations into the methods of drug resistance have yielded a great deal of knowl-edge that will shape the way we treat cancer in the future. DNA injury caused bychemotherapeutic agents and ionizing radiation triggers activation of the p53 gene,leading to programmed cell death. The realization that exposure to chemotherapeuticagents initiates an active cellular suicide program, rather than simply causing cell deaththrough massive DNA damage, raised the possibility that these cell death pathwaysmay be disrupted in drug-resistant cancer cells. Inactivation of p53 in these cells isassociated with resistance to these therapeutic agents. Loss of p53 is a common featureof human cancers, and a number of studies have suggested a correlation between inac-tivation of p53 and resistance to chemotherapeutic agents, as well as a more aggressiveclinical course.


33

The Next Wave of AgentsOver the past few decades, there has been somewhat of a paradigm shift in the waychemotherapeutic drug targets are identified. In the following paragraphs, we attemptto provide details on some of the key classes of developmental compounds. This is notintended to be a complete list, but rather an introduction into the various routes thepharmaceutical companies are taking to develop new therapies to treat cancer. Asstated previously, advances in cell and molecular biology allow us to identify geneticabnormalities in cancer. A key starting point in unearthing potential drug targets isunderstanding the genes that underlie the abnormalities associated with cancer cells. InExhibit 21, we provide a rough cellular diagram of some of these potential drug targetsand their relationships to one another. These potential targets include gene productssuch as growth factors, growth factor receptors, signal transduction pathways and DNAtranscription factors. Furthermore, telomerase, an enzyme that maintains the ends ofchromosomes, must be active for tumors to continue to divide. Interestingly, elevatedtelomerase activity is observed in virtually all human cancers. Furthermore, the HER-2/neu oncogene, which is a member of a family of epidermal growth factors, is overex-pressed (concentrations are above normal) in 20–30% of invasive breast cancers.Genentech’s Herceptin is a monoclonal antibody targeted against this receptor.

Epidermal Growth Factor Receptor Targets

Several companies are currently developing compounds that inhibit the influences ofepidermal growth factor by interacting with the epidermal growth factor receptor(EGFR). EGFR is a large protein receptor. It has an external binding domain whereligands lock on and an intracellular portion. When a ligand—in this case, it would beepidermal growth factor—binds to the receptor, the receptor undergoes a transforma-tion and a cascade of intracellular reactions begin. One key step in this cascade is theactivation of the tyrosine kinase enzyme (see Exhibit 21).

Exhibit 21: Interactions at the Growth Factor Receptor

M e m b ra n e

E X T R A C E L L U L A R

S ig n a llin gm o le c u le s

S ubs tra te

K K K K KS ubs tra te

K

IN T R A C E L L U L A R

= grow th factor

= ty ro s ine k ina s e

= pho sp ha te gro up

Source: Adapted from AstraZeneca.


34

EGFR is important in tumor cells because of its role in apoptosis (cell death), angio-genesis (creation of a new blood supply) and metastasis. Researchers have shown thatinhibiting EGFR can induce apoptosis. Second, in order for a tumor to continue togrow, it must acquire new blood vessels. The activation of EGFR appears to promotethe release of vascular endothelial growth factor (VEGF), which is a key promoter ofangiogenesis. Consequently, when EGFR is inhibited, it will likely inhibit angiogenesisas well.

Currently, several different approaches are being used to inhibit EGFR. One avenueuses monoclonal antibodies to block EGF from binding to the receptor. Second, com-panies are using small molecule inhibitors of the EGFR tyrosine kinase enzyme andconsequently blocking EGFR signaling. A third pathway uses ligand-toxin or immu-notoxin conjugates. Lastly, some companies are using antisense oligonucleotides.These molecules bind to mRNA and thereby inhibit cellular expression of EGFR. Thesetypes of compounds have essentially the same effect of preventing signals from beingtransmitted from the receptor, but they act in different ways. The farthest along in de-velopment are the monoclonal antibodies and the small molecule inhibitors of tyrosinekinase. The monoclonal antibodies that have been designed to date bind to the portionof the EGFR that is outside of the tumor cell and prevent epidermal growth factor frombinding to its receptor. The smaller molecule tyrosine kinase inhibitors are active onthe inside of the tumor cell and prevent the enzyme cascade from proceeding.

A host of both biotech and pharmaceutical companies have EGFR inhibitor moleculesin various stages of clinical development.

Exhibit 22: New Cancer Drug Targets

HER2 EGFPDGF

GROWTHFACTORS

ras

bcr-abl

raf

MEK

MAPK

telomerase

cyclins

ER

Cdk’sp27/p16

p53 NUCLEUS

GTPPKC

mitochondria

Bcl2

ras/CAAX

Cytoplasmic rasPrecursor

FTase

Key: cdk’s, cyclin dependent kinases; EGF, epidermal growth factor receptor; ER, estrogen receptor; Ftase,farnesyltransferase; MEK, MAPK/Erk kinase; PDGF, platelet-derived epidermal growth factor receptor; PKC, proteinkinase C.

Source: Adapted from SCIENCE (vol 270 pp 1970).


35

Farnesyltransferase Inhibitors

Another avenue of drug development that has garnered attention recently is the farne-syltransferase inhibitors. These targets stem from identification of the molecular path-ways that surround the ras oncogene. The ras oncogene is mutated in approximately30% of human cancers. Ras activation stimulates signal transduction pathways andtranscription factors (see Exhibit 22). Farnesyltransferase is a protein necessary for rasto function properly. Technically speaking, ras needs to be farnesylated to work. How-ever, some versions of ras, such as K-ras, can function without farnesylation and can beactivated by another process.

At the annual American Association of Clinical Oncologists (ASCO) meeting this pastMay, several pharmaceutical companies presented early clinical data on their farnesyltransferase inhibitors, including Johnson & Johnson, Schering-Plough, Merck andBristol-Myers, although Merck has since ceased development of its compound.

Matrix Metalloproteinase Inhibitors

Another promising avenue in drug development is the use of matrix metalloproteinaseinhibitors (MMPIs). These compounds block enzymes, matrix metalloproteinases(MMPs) that are secreted by cancer cells. Cancer cells use these compounds to breakdown the extracellular matrix, which enables the cancer to slip through tissues andspread. However, recent studies have shown that these inhibitors can also act to inhibittumor growth by a variety of measures, including preventing local invasion and inhib-iting tumor neovascularization. It is important to note that MMPs are not solely char-acteristic of cancer cells. These enzymes are also responsible for the normal degrada-tion of the extracellular matrix during connective tissue turnover and cell migration.There are 13 different subtypes of MMPs known (see Exhibit 23).

Exhibit 23: Various Matrix Metalloproteinases

Various Matrix MetalloproteinasesName AcronymCollagenase 1 MMP 1Collagenase 2 MMP 8Collagenase 3 MMP 13Matrilysin MMP 7Stromelysin 1 MMP 3Stromelysin 2 MMP 10Stromelysin 3 MMP 11Gelatinase A MMP 2Gelatinase B MMP 9Metalloelastase MMP 12AggrecanaseMembrane Type MMP MMP-MT1, MT2, MT3, MT4MMP 19



36

Currently, there is no proof that MMPIs will prolong survival in cancer patients. Themajority of clinical data presented to date have been disappointing, either failing tomeet the primary endpoint of the trial or being stopped early due to poor interim re-sults. However, British Biotech/Schering-Plough’s marimastat has shown some goodactivity in clinical trials and may prolong survival in patients with locally advancedmetastatic disease.

Since MMPs are active in normal tissue remodeling, it is conceivable that completeinhibition may lead to some related toxicities. In a majority of the MMPI clinical trialsto date, arthritis has been the dose-limiting toxicity. Researchers originally theorizedthat MMP-1 inhibition was the reason behind the dose-limiting arthritis seen with ma-rimastat and Pfizer’s prinomastat. This would also explain why no dose-limitingarthritis was seen in Bayer’s MMPI, as that compound was a selective inhibitor ofMMP-2, MMP-9 and MMP-3. Bayer has since ceased development of its compound.However, Bristol-Myers has a broad-spectrum MMPI in development that appears tobe devoid of dose-limiting arthritis. The activity of Bristol’s compound leads to thehypothesis that the arthritis seen in the other agents is due to the inhibition of anotherrelated set of compounds known as sheddases. Sheddases are members of the MMPfamily and are involved in the proteolytic release of certain membrane proteins intothe circulation in physiologically active forms. The Bristol compound does not inhibitthe sheddases.


37

How Cancer Is StagedOncologists describe the extent of the disease or the spread of cancer in stages. Stagingof disease is essential in determining the proper choice of therapy and the specificprognosis. A cancer’s stage is constructed based on information regarding the primarytumor’s size, location and whether it has metastasized. There are several differentstaging systems that physicians can use. The TNM staging system assesses tumors inthree ways: extent of the primary tumor (T), absence or presence of regional lymphnode involvement (N), and absence or presence of distant metastases (M). Once the T,N and M are determined, a “stage” of I, II, III or IV is given; these stages correspond toin situ, local, regional and distant. In situ applies to a cancer that remains in the tissuewhere it originally developed. If the cancer cells have spread beyond the original layerof tissue, the cancer is then considered invasive. In addition to gross physiological ex-aminations and X-rays, microscopic examination of the cancer cells is used to evaluatethe cancer cells’ aggressiveness.

Importantly, one way in which drug uses are classified is by first- or second-line use.First-line therapies are therapies given after the initial diagnosis, whereas second-linetherapies are those treatments for any subsequent remission. These terms are some-times confused with neoadjuvant or adjuvant therapy. Adjuvant therapy is defined astreatment given following primary treatment to enhance the efficacy of the primarytreatment. It can be chemotherapy, radiation or hormone therapy. Neoadjuvant ther-apy, as the name indicates, is given before the primary treatment.

Terminology

Exhibit 24: Common Cancer Terminology

TERMINOLOGYAdjuvant Treatment given after the primary treatment to make it work better. Adjuvant therapy may

include chemotherapy, radiation therapy, or hormone therapy.Neoadjuvant Treatment given before the primary treatment.Palliative treatment Treatment given to relieve symptoms caused by advanced cancer. Palliative therapy does

not alter the course of a disease, but improves the quality of life.Progression free survival Period of time where the disease does not increase in severity or scope.Remisssion Disappearance of the signs and symptoms of cancer. When this happens, the disease is

said to be "in remission." A remission may be temporary or permanent.Survival rate Percentage of people alive for a given period of time after diagnosis of disease. This can be

given as the observable survival rate, which considers deaths from all causes, cancer orotherwise. In cancer, this rate is commonly expressed in terms of five-year survival. Relativesurvival rate is calculated by adjusting the observed survival rate to remove the effects of allcauses of death except cancer.

Time to disease progression Similar to "progression free survival".

Source: National Cancer Institute (NCI).


38



39

The Individual Cancer Markets


40

IntroductionIn the following pages, we discuss the various aspects of each of the major cancers.Each section commences with a description of the disease followed by the anatomicallayout of the cancer. We then provide details on the predominant therapeutic regimensfor each cancer. It is extremely important to note that the majority of agents are widelyused off label. More specifically, once a compound is approved for a particular indica-tion, many physicians will attempt to use the drug in other settings. Furthermore,when data regarding the use of a drug in a new indication are presented at a large clini-cal symposium (ASCO or AACR), physicians will often adapt similar treatment regi-mens in their particular clinics. These types of off-label practices bring into questionthe issue of reimbursement. This is an extremely complex issue, which we do notdevelop in this report.

Importantly, as part of the disease summaries, we have included proprietary data forthe oncology market. The data provide an admittedly limited, but meaningful, analysisof what therapies are being used in what settings. We obtained these data from a pri-vately held health care company, iKnowMed, located in Berkeley, California. The en-tire data set comprises approximately 10,000 patients that have undergone approxi-mately 15,000 regimens.

iKnowMed is attempting to build a leading clinical infomediary and repository for real-time, point-of-care health information. The company uses a Web-based program to cap-ture, analyze and display patient treatment information. This system enables patients,physicians and the pharmaceutical industry to interact with one another. Currently,iKnowMed is established in the oncology market. In Exhibit 25, we provide a break-down of the iKnowMed patient database that this report used as of November 1999.

Exhibit 25: Total iKnowMed Patient Pool

iKnowMed Complete Patient Pool3436

2305

1768

1156

579 561450

304 309216 184 171 156 137 114 67 54 49 46 43 40 28 17

0

500

1000

1500

2000

2500

3000

3500

4000

BR

EA

ST

CO

LOR

EC

TA

L

NS

CL

LYM

PH

SC

L

OV

AR

IAN

OT

HE

R

PA

NC

RE

AS

LEU

KE

MIA

HE

AD

&N

EC

K

BLA

DD

ER

ST

OM

AC

H

ES

OP

HA

GU

S

PR

OS

TA

TE

ME

LAN

OM

A

BR

AIN

EN

DO

ME

TR

IAL

SA

RC

OM

A

TE

ST

ICU

LAR

RE

NA

L

CE

RV

IX KS

LIV

ER

Cancer Type

Num

bers

ofP

atie

nts

Source: UBS Warburg LLC, iKnowMed.


41

In the following exhibits, we provide expected incidence and death rates for all cancersin the U.S. this year.

Exhibit 26: Incidence of Various Cancers in the U.S.

U.S. Estimated New Cancer Cases by Gender in 2000Total Male Female

All sites 1,220,100 619,700 600,400Oral Cavity/ Pharynx 30,200 20,200 10,000Digestive System 226,600 117,600 109,000

Esophagus 12,300 9,200 3,100Stomach 21,500 13,400 8,100Colon 93,800 43,400 50,400Rectum 36,400 20,200 16,200Liver 15,300 10,000 5,300Pancreas 28,300 13,700 14,600

Respiratory 179,400 101,500 77,900Bone 2,500 1,500 1,000Skin (excluding basal & squamous) 56,900 34,100 22,800Breast 184,200 1,400 182,800Genital System 265,900 188,400 77,500Urinary System 86,700 58,600 28,100Brain 16,500 9,500 7,000Endocrine System 20,200 5,600 14,600Lymphoma 62,300 35,900 26,400

Hodgkin's Disease 7,400 4,200 3,200Non-Hodgkin's 54,900 31,700 23,200

Multiple Myeloma 13,600 7,300 6,300Leukemia 30,800 16,900 13,900

Acute Lymphocytic 3,200 1,800 1,400Chronin Lymphocytic 8,100 4,600 3,500Acute Myeloid 9,700 4,800 4,900Chronic Myeloid 4,400 2,600 1,800Other 5,400 3,100 2,300

Other 34,000 15,700 18,300Source: CA Journal.


42

Exhibit 27: Incidence of Various Cancer Deaths in the U.S.

U.S. Estimated New Cancer Deaths by Gender in 2000Total Male Female

All sites 552,200 284,100 268,100Oral Cavity/ Pharynx 7,800 5,100 2,700Digestive System 129,800 69,300 60,500

Esophagus 12,100 9,200 2,900Stomach 13,000 7,600 5,400Colon 47,700 23,100 24,600Rectum 8,600 4,700 3,900Liver 13,800 8,500 5,300Pancreas 28,200 13,700 14,500

Respiratory 161,900 93,100 68,800Bone 1,400 800 600Skin (excluding basal & squamous) 5,800 2,200 3,600Breast 41,200 400 40,800Genital System 59,000 32,500 26,500Urinary System 24,600 15,700 8,900Brain 13,000 7,100 5,900Endocrine System 2,100 1,000 1,100Lymphoma 27,500 14,400 13,100

Hodgkin's Disease 1,400 700 700Non-Hodgkin's 26,100 13,700 12,400

Multiple Myeloma 11,200 5,800 5,400Leukemia 21,700 12,100 9,600

Acute Lymphocytic 1,300 700 600Chronin Lymphocytic 4,800 2,800 2,000Acute Myeloid 7,100 3,900 3,200Chronic Myeloid 2,300 1,300 1,000Other 6,200 3,400 2,800

Other 36,600 18,500 18,100Source: CA Journal.


43

Breast CancerBreast cancer remains one of the most common forms of cancer affecting women. TheAmerican Cancer Society estimates that approximately 183,000 new cases of breastcancer will be diagnosed in 2000, with 41,000 deaths resulting from the disease. For thepast ten years, incidence rates have been relatively level, which is a deceleration fromthe 4% annual growth seen during most of the 1980s. The flattening of the incidencecurve is likely due to increased vigilance regarding detection and subsequent earlierdiagnoses. The major risk factors for developing breast cancer are advancing age and afamily history of the disease. Incidence increases with age, with approximately 75% ofbreast cancer cases diagnosed in women over 50.

AnatomyBefore a detailed discussion of breast cancer can begin, it is necessary to understandbreast anatomy. The following figure accurately depicts the relevant structures.

Exhibit 28: Anatomical Structures of the Female Breast

Source: American Cancer Society.

Each breast has 15-20 overlapping regions referred to as lobes. Within each lobe aresmaller lobules. The lobes and lobules are connected by ducts. Additionally, within eachbreast, there exist blood vessels and lymph vessels. The lymph vessels lead to small,bean-shaped reservoirs called lymph nodes. Lymph nodes are found throughout thebody. Most lymphatic vessels of the breast lead to lymph nodes under the arm that arereferred to as axillary nodes.

The AmericanCancer Societyestimates thatapproximately183,000 new casesof breast cancerwill be diagnosedin 2000, with 41,000deaths resultingfrom the disease


44

Types of Breast CancerThere are several forms of breast cancer. Often, if a tumor arises in the breast, it is be-nign. Benign breast tumors are merely abnormal growth; they do not spread outside ofthe breast and are rarely, if ever, life threatening. There are four distinct types of malig-nant breast cancer. Ductal carcinoma in situ (DCIS) is the earliest form of breast can-cer. It is completely confined to the ducts of the breast. If a patient presents with DCIS,there is close to a 100% cure rate. DCIS is easily detected by mammogram. The second,more advanced, form of breast cancer is infiltrating (invasive) ductal carcinoma (IDC).This form of cancer begins in the ducts, but then migrates into the fatty tissue of thebreast. IDC is the most common form of breast cancer, accounting for roughly 80% ofthe cases. The third type of cancer is lobular carcinoma in situ (LCIS). This form ofcancer is not a “true” cancer, but it does increase a woman’s risk of developing cancer.Roughly 30% of women with LCIS develop breast cancer. The final form of breast can-cer is infiltrating (invasive) lobular carcinoma, which starts in the lobules and repre-sents 10–15% of all breast cancers. The aforementioned tumor types are usually con-sidered early breast cancer or stages I and II.

A patient with stage III breast cancer characteristically presents with a primary tumormeasuring greater than 5 cm, spreading to the skin or chest wall or lymph nodes. StageIII breast cancer accounts for roughly 10% of all cases. Approximately one-third ofwomen that present with stage III have metastases at the time of diagnosis.

The most severe and aggressive form of breast cancer is stage IV, or metastatic, breastcancer. The median survival time after diagnosis of metastatic disease is 18-24 months.If the disease has advanced this far, it is seldom curable.

Treatment

Exhibit 29: FDA-Approved Breast Cancer TherapiesFDA Approved Uses for Breast Cancer Therapies

Brand Name Generic Name Mnfr. Indication Admin.5-FU 5-Fluorouracil Various Carcinoma IV, OralAdriamycin, Rubex doxorubicin Various Carcinoma IVArimidex anastrozole AstraZeneca 2nd line hormonal therapy in postmenopausal women OralAromasin exemestane Pharmacia 2nd line carcinoma OralCytoxan, Neosar cyclophosphamide Various Carcinoma IV, OralEllence epirubicin Pharmacia Adjuvant therapy IVFareston toremifene Roberts Metastatic OralFemara letrozole Novartis Advanced disease in postmenopausal women with progression after antiestrogens OralHerceptin trastuzumab Genentech Metastatic disease in women who overexpress HER2 receptor IVMegace megestrol acetate Various Advanced carcinoma (palliative) OralMTX methotrexate Various Carcinoma IV, Inj, OralNolvadex tamoxifen Various Breast cancer, risk reduction in high risk women andisk reduction in women with DCIS

after surgery and radiationOral

Taxol paclitaxel Bristol-Myers 2nd line carcinoma, 2nd line therapy following an anthracycline regimen and node positivecancer in combination with doxorubicin and cyclophosphamide

IV

Taxotere docetaxel Aventis Advanced , 2nd line IVThiotepa thiotepa Immunex Adenocarcinoma IV, InjVelban vinblastine Various 3rd line IVXeloda capecitabine Roche 2nd line metastatic OralZoladex goserelin acetate AstraZeneca Premenopausal carcinoma (palliative) Inj

Source: Food and Drug Administration.


45

Exhibit 30: iKnowMed Breast Cancer Incidence by Stage

Stage IIA31%

Stage I16%

Stage IV13%Stage IIIB

6%

Stage IIIA10%

Stage IIB24%

Source: iknowMed.

Early-Stage Disease

Many patients with breast cancer undergo surgery to remove the tumor from thebreast. In many cases, the axillary (under the arm) lymph nodes are removed and ana-lyzed for the presence of cancer. The types of surgery range from a simple lumpectomy(removal of the lump and some surrounding tissue) to a radical mastectomy, in whichthe breast, lymph nodes and chest muscles are removed.

Approximately 60% of women diagnosed with breast cancer will present with localizeddisease that has not spread to the lymph nodes (node-negative); these women are oftencurable. Additionally, numerous trials have indicated that breast-conserving treat-ments consisting of lumpectomy and radiation therapy result in a survival rate that iscomparable to that of more radical treatments like total mastectomies. At present,more than one-third of women with breast cancer in the U.S. are managed by lum-pectomy and radiation.

There are numerous options for women regarding the types of surgery and the use andduration of radiation therapy, but for the purpose of this report, they will not be dis-cussed. However, there is evidence of substantial benefit to patients with early-stagedisease that receive a combination of radiation therapy and chemotherapy. For themost part, patients receiving combination therapy experience higher survival rates.Data indicate that women experience fewer local and regional recurrences and im-proved overall survival when cytoxan, methotrexate and 5-FU (referred to as CMF) aregiven with radiation therapy. One study showed that survival at ten years was 54%among women who were given CMF and radiation compared to 45% for those pa-tients who received radiation alone. Recently, it was noted that women whose tumorsoverexpress the HER2 proto-oncogene and receive Genentech’s Herceptin may benefitfurther from an enhanced radiation effect.


46

In women diagnosed with breast cancer that has spread to local lymph nodes, but notbeyond, the cancer is also often curable. Data indicate that women experience fewerlocal and regional recurrences and improved overall survival when doxorubicin, cyclo-phosphamide and Taxol (ACT) are given.

Metastatic Breast Cancer

Chemotherapy

For the most part, women who have been disease-free for less than two years, havehormone receptor-positive disease, have had prior hormone therapy or have aggressivedisease are good candidates for chemotherapy. Combination chemotherapy results inhigher response rates when compared to single-agent use, varying from 50–70% andup to nine to 12 months in duration. The rate of complete responses in patients re-ceiving combination chemotherapy is approximately 10–20%.

Currently, the most commonly used regimens are methotrexate combined with 5-FUand leucovorin, cyclophosphamide combined with methotrexate and 5-FU, cyclo-phosphamide combined with doxorubicin and 5-FU, or some sort of taxane-contain-ing regimen. Doxorubicin-containing regimens have shown a 10–20% better responserate, but do not appear to offer a survival advantage over regimens that do not containdoxorubicin. In elderly women, a regimen with a less severe side-effect profile that issometimes considered is Genentech’s Herceptin or methotrexate plus 5-FU with leu-covorin. In women where the disease has recurred after doxorubicin or taxane therapy,Navelbine (vinorelbine) with Alza’s Doxil is sometimes used, even though those twoagents are not currently approved for breast cancer therapy. Additionally, Roche’s oraltherapy, Xeloda, is sometimes preferred and offers a 20% response rate.

Exhibit 31: Cytotoxic Therapy for Advanced Breast Cancer

Acronym DrugsResponseRate (%)

Median Durationof Response

(months)CMF cyclophosphamide 49-59% 5-8

methotrexate5-FU

FAC 5-FU 50-75% 6-10Adriamycin (doxorubicin)cyclophosphamide

AC Adriamycin (doxorubicin) 40-80% 6-12cyclophosphamide

CAF cyclophosphamide 60-80% 10-12Adriamycin (doxorubicin)5-FU

Novantrone mitoxantrone 17-35% 4-5Taxol paclitaxel 30% 6Taxotere docetaxel 41% 6

Source: Adapted from Ravdin: Breast Cancer.


47

Endocrine Therapy

As stated earlier in this report, in many organs and cell types, hormones can stimulatecell division and growth. Consequently, some hormonal agents are effective at reducingor eliminating tumor cell growth in a specific tissue type. Most hormonal agents workas agonists to inhibit tumor growth or as antagonists that compete with endogenoushormones that promote growth. In the breast, the key receptor for hormones is theestrogen receptor (ER). In practice, women whose cancer is ER-positive have demon-strated a consistent survival advantage after recurrence compared to ER-negativewomen. Additionally, the presence of both progesterone receptor (PR) and ER indicatea higher response rate than in women with ER-positive tumors alone. For women withno prior history of hormonal therapy, use of the anti-estrogen tamoxifen is currentlythe standard of care.

Tamoxifen is a nonsteroidal anti-estrogen that binds to the estrogen receptors that arepresent in the body, including those in cancerous tissue. Consequently, it effectivelyblocks estrogen from exerting its effects on cells, more specifically inhibiting tumorgrowth. Recently, compounds have been introduced that bind preferentially to formsof the ER present in breast tissue and modulate the actions of this receptor system.These compounds are referred to as selective estrogen receptor modulators (SERMs).Currently, the only marketed SERM is Lilly’s Evista (raloxifene). Notably, Evistaappears to have a neutral effect on the uterus, whereas tamoxifen has a high affinity foruterine tissue. Consequently, tamoxifen use is associated with an increased risk ofuterine cancer.

Aromatase inhibitors are another type of therapy for women with breast cancer. Inpostmenopausal women, the primary source of estrogen is peripheral conversion ofandrostenedione to estrone by the enzyme aromatase, with further conversion of es-trone to estradiol. As the name indicates, aromatase inhibitors inhibit the peripheralconversion to estrogen by inhibiting the aromatase enzyme. Recently, several newaromatase inhibitors have been developed. These agents, including Pharmacia’sAromasin (exemestane), Novartis’s Femara (letrozole) and AstraZeneca’s Arimidex(anastrozole), are highly selective and are substantially more potent inhibitors of aro-matase than previous therapies. These therapies have become the “gold standard” ther-apy for postmenopausal women whose disease no longer responds to tamoxifen.

While the cytotoxic chemotherapies for breast cancer are not administered as oraltherapies, the adjuvant endocrine therapies are, for the most part, oral therapies. Thefollowing table indicates the market share trends for the oral breast cancer therapies.


48

Exhibit 32: Total Prescription Trends for Oral Breast Cancer Therapies

Total Prescriptions (TRXs) in ThousandsJun-99 Jul-99 Aug-99 Sep-99 Oct-99 Nov-99 Dec-99 Jan-00 Feb-00 Mar-00 Apr-00 May-00 Jun-00

Total Aromatase Inhibitors 135 139 144 141 145 143 146 140 142 154 144 161 160

Total Breast Cancer Mkt 346 348 349 342 354 356 377 340 342 366 346 378 372

Growth (year/year)Total Generic Megace 9% 11% 15% 11% 10% 12% 10% 9% 12% 5% 2% 16% 6%

Megace Oral (BMY) 26% 40% 37% 34% 31% 35% 27% 33% 39% 30% 23% 38% 30%Megace (BMY) -24% -22% -22% -22% -19% -11% -16% -13% -12% -19% -15% -17% -25%

Total Megace 20% 33% 31% 28% 26% 30% 23% 29% 35% 26% 20% 34% 26%Arimidex (AZN) 7% 7% 10% 6% 9% 15% 14% 10% 16% 10% 10% 21% 15%Aromasin (PHA) N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/AFemara (NVS) 84% 84% 82% 75% 65% 70% 58% 49% 49% 30% 36% 46% 40%Fareston (SHPGY) 48% 34% 29% 26% 17% 18% 19% 8% 12% -6% -4% 5% -5%

Total Aromatase Inhibitors 16% 21% 22% 18% 18% 21% 17% 18% 23% 16% 13% 26% 18%

Tamoxifen (BRL) 11% 11% 13% 12% 11% 16% 16% 11% 16% 9% 9% 18% 10%Tamoxifen (N/R) N/A N/A N/A 238% 633% N/A N/A -100% -85% -100% -100% -100% -100%

Total Tamoxifen 11% 11% 13% 12% 11% 16% 16% 11% 16% 9% 9% 18% 10%Nolvadex (AZN) -9% -5% -2% -3% -3% 4% -1% -7% 1% -8% -9% 3% -4%

Total Breast Cancer Mkt 7% 8% 10% 9% 8% 14% 13% 7% 13% 6% 5% 15% 7%

Market ShareTotal Generic Megace 37.9% 37.3% 37.2% 36.8% 36.5% 36.0% 36.2% 35.8% 35.2% 34.6% 34.5% 34.7% 34.1%

Megace Oral (BMY) 37.3% 38.4% 39.1% 39.6% 39.5% 39.6% 38.3% 40.3% 40.7% 41.4% 40.3% 40.8% 41.1%Megace (BMY) 2.9% 2.7% 2.7% 2.6% 2.5% 2.6% 2.6% 2.4% 2.3% 2.2% 2.2% 2.0% 1.8%

Total Megace 40.2% 41.1% 41.8% 42.2% 42.0% 42.2% 40.9% 42.7% 43.0% 43.6% 42.6% 42.8% 42.9%Arimidex (AZN) 15.5% 15.2% 15.0% 14.8% 15.4% 15.6% 16.2% 15.2% 15.1% 14.9% 15.5% 14.9% 15.1%Aromasin (PHA) 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.1% 0.4% 0.7% 1.1% 1.4% 1.6%Femara (NVS) 3.0% 3.0% 2.9% 3.0% 3.1% 3.3% 3.5% 3.4% 3.3% 3.4% 3.5% 3.5% 3.6%Fareston (SHPGY) 3.4% 3.3% 3.0% 3.1% 3.0% 2.9% 3.2% 2.9% 2.9% 2.7% 2.8% 2.8% 2.7%

Total Aromatase Inhibitors 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0%

Tamoxifen (BRL) 81.4% 81.7% 81.7% 81.8% 81.9% 82.0% 82.8% 82.6% 82.3% 83.1% 83.4% 83.3% 83.4%Tamoxifen (N/R) 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

Total Tamoxifen 81.5% 81.7% 81.7% 81.8% 81.9% 82.0% 82.8% 82.6% 82.3% 83.1% 83.4% 83.3% 83.4%Nolvadex (AZN) 18.5% 18.3% 18.3% 18.2% 18.1% 18.0% 17.2% 17.4% 17.7% 16.9% 16.6% 16.7% 16.6%

Total Breast Cancer Mkt 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0%

Source: IMS America.

iKnowMed Data: Breast

The data we obtained from iKnowMed indicate that approximately 42% of the womenbeing treated for breast cancer are receiving their first treatment. Of those women re-ceiving first-line therapy, approximately 34% receive Adriamycin (doxorubicin) incombination with cyclophosphamide; 26% of patients receive cyclophosphamide,methotrexate and 5-FU. With regard to second-line therapies, the market is muchmore fragmented. Twenty-two percent of women receive Aventis’s Taxotere, 15% re-ceive Bristol’s Taxol and 11% receive Glaxo’s Navelbine.


49

Exhibit 33: Number of Patients Being Treated, First Line Versus Second Line

1st LINE58%

2nd LINE42%

Note: First line refers to patients receiving their initial treatment. Second line refers to all subsequent treatments.

Various 1st Line Regimensfor Breast Cancer

DOX1%

CNF1%

HER-TAX0%

HER0%

ACMF2%

DOX-TXT1%

OTHER2%

TXT3%

TAX7%

ATC8%

FAC15%

AC34%

CMF26%


50

Exhibit 33 cont’d: Number of Patients Being Treated, First Line Versus Second Line

Various 2nd line Regimensfor Breast Cancer

CARB-TAX1%

ATC1%

TXT22%

TAX15%

VIN11%

OTHER7%

CMF5%

HER6%

FAC5%

AC5%

5FU4%

GEM2%

DOX2%

HER-TAX2%

DOX-TAX2%

5FU-LEUC2%

DOX-TXT2%

NFL2%

5FU-LEUC-TAX1%

XEL-GEM2%

5FU-CIS1%

DOXIL1%

HER-TXT1%

GEM-NAV1%

Source: iKnowMed.


51

Exhibit 34: Acronyms for Breast Cancer Regimens

Acronym Regimen5FU 5-fluorouracil5FU-CIS 5-fluorouracil + cisplatin5FU-LEUC 5-fluorouracil + leucovorin5FU-LEUC-TAX 5-fluorouracil + leucovorin + TaxolAC adriamycin (doxorubicin) + cyclophosphamideACMF adriamycin (doxorubicin) + cyclophosphamide + methotrexate + 5FUATC adriamycin (doxorubicin) + Taxol + cyclophosphamideCARB-TAX Paraplatin + TaxolCMF cyclophosphamide + methotrexate + 5-fluorouracilCNF cyclophosphamide + Novantrone + 5-fluorouracilDOX doxorubicinDOXIL DoxilDOX-TAX doxorubicin + TaxolDOX-TXT doxorubicin + TaxotereFAC 5-fluorouracil + adriamycin (doxorubicin) + cyclophosphamideGEMZAR GemzarGEMZ-NAV Gemzar + NavelbineHER HerceptinHER-TAX Herceptin + TaxolHER-TXT Herceptin + TaxotereNFL Navelbine + 5FU + leucovorinOTHERTAXOL TaxolTXT TaxotereVIN NavelbineXELO-GEMZ Xeloda + Gemzar



52

Lung CancerLung cancer is responsible for approximately one-third of all cancer deaths in theUnited States. The incidence in men is beginning to decline, but the incidence inwomen continues to increase. In the year 2000, it is expected that approximately164,000 new cases of lung cancer will be diagnosed (80,500 in men). Notably, lungcancer passed breast cancer in 1996 as the number one cause of death from cancer inwomen. Increasing incidence is a major reason for the high mortality rate in lung can-cer, but lung cancer is notorious for its aggressive biology (or likelihood ofspread/metastasis) and its relatively low cure rate.

AnatomyThe lung consists of three primary zones. The first zone consists of the cells that linethe trachea (windpipe) and the first portion of the large airways (bronchi). These cellsare flat, referred to as squamoid. These cells serve as a protective layer against inhaledsubstances. The second zone is more central and is usually referred to as the secretoryzone. This zone is lined with a series of cells that produce mucus. The mucus movesconstantly over the cells due to tiny hairs, known as cilia. The third and last portion ofthe lung consists of millions of tiny air sacs, known as alveoli. This is where breathingtakes place and carbon dioxide is exchanged for oxygen.

Exhibit 35: Anatomical Structures in the Human Lung


Types of Lung CancerThere are four distinct types of lung cancer, none of which are alike (see Exhibit 36).Small cell lung cancer (SCLC), which accounts for approximately 20% of all lung can-cer, is cancer that invades the submucosa and is thought to arise from Kulchitsky cells,neuroendocrine cells that secrete peptide hormones in the lung. The three other typesof lung cancer are grouped under non-small-cell lung cancer (NSCLC), whichaccounts for the other 80% of lung cancer. The first type of NSCLC is squamous-cellcancer, which originates in the larger airways. Adenocarcinomas, which includebronchoalveolar carcinomas, occur in the secretory portion of the lung, and are the

In 2000, it isexpected that

approximately164,000 new casesof lung cancer will

be diagnosed(80,500 in men).

Notably, lungcancer passed

breast cancer in1996 as the

number one causeof death from

cancer in women.


53

second type of NSCLC. The final type of NSCLC is large cell carcinoma. Knowledge ofthe specific type of lung cancer and its site of origin are critical factors in the effectivemanagement of the disease. Unfortunately, by the time an individual presents with anyof the “warning signs” of lung cancer, the disease is most likely at a late stage.

Exhibit 36: Pathologies of the Different Forms of Lung Cancer

Lung Cancer PathologyType Frequency CharacteristicsSmall Cell Lung Cancer 20% Central location, strong relationship

with smoking, metastasizes widely,most sensitive to chemo and radiation

Non-Small Cell Lung CancerSquamous 35% Central location, more common in

males, less metastasesAdenocarcinoma 35% Peripheral in location, equal frequency

in both sexes, metastatic potentialcommon, most common type innonsmokers

Large Cell 10% Peripheral in location, equal frequencyin both sexes, metastatic potentialundifferentiated


Staging of lung cancer is slightly different than for other cancers. For SCLC, a two-stage system is typically used consisting of limited stage and extensive stage. Limitedstage refers to a cancer that is localized to one lung and the lymph nodes on that side ofthe chest. Extensive stage refers to a cancer that has spread to the other lung, lymphnodes on the other side of the chest or to distant organs. SCLC is staged this way be-cause it helps separate tumors that can be treated with radiation therapy from thosethat cannot.

Treatment

Exhibit 37: FDA-Approved Drug Uses for Lung CancerFDA Approved Uses for Lung Cancer Therapies

Brand Name Generic Name Mnfr. Indication Admin.Adriamycin, Rubex doxorubicin Various Bronchogenic carcinoma IVEtopophos, VePesid etoposide Various 1st line small cell lung in combination with other therapies IV, OralGemzar gemcitabine Eli Lilly Non-small cell lung IVHycamtin topotecan GlaxoSmithkline Small cell lung in patients with sensitive disease IVMTX methotrexate Various Small cell lung in patients with sensitive disease and squamous

cell carcinoma IV, Inj, OralMustargen meclorethamine Merck Malignant effusions and bronchogenic carcinoma IVNavelbine vinorelbine GlaxoSmithkline Advanced non-small cell lung IVPhotofrin porfimer sodium Sanofi-Synthelabo Non-small cell lung, palliation of endobronchial obstruction InjTaxol paclitaxel Bristol-Myers 1st line non-small cell lung in combination with cisplatin IVTaxotere docetaxel Aventis 2nd line non-small cell lung IV



54

Small Cell Lung Cancer (SCLC)

Exhibit 38: Small Cell Lung Cancer Split

LIMITED50%

EXTENSIVE50%

Source: iKnowMed.

Small cell lung cancer (SCLC) has a high propensity for early metastatic spread. Due toits aggressive nature, small cell cancer has a greater tendency to be widely disseminatedby the time of diagnosis, but it is much more responsive to chemotherapy and radia-tion. Furthermore, due to the likelihood of metastases, local treatments, such as sur-gery or radiation, rarely have an impact on long-term survival.

At the time of diagnosis, approximately 40% of the patients with SCLC will have atumor confined to one side of the chest. These patients are defined as having “limitedstage” small cell carcinoma, as was stated above. The median survival time for patientswith limited-stage disease is 16-24 months, whereas, in patients with significant diseasespread, or “extensive” small cell lung cancer, median survival is six to 12 months withcurrently available therapies, and long-term disease-free survival is rare.

The majority of patients with SCLC are treated with both radiation and chemotherapy.This dual treatment has been shown to be more effective than either type of therapyalone. The standard of care for the chemotherapy of limited-stage SCLC has not beendefined. Currently, the most widely used regimen consists of a platinum-based agentand VePesid (etoposide), which is interesting considering there is no platinum-basedcompound with an FDA approval for this indication. This type of regimen has largelyreplaced the CAV regimen (cyclophosphamide, doxorubicin and vincristine) that was amainstay of therapy in the 1970s and it has replaced the CAE regimen (cyclophospha-mide, doxorubicin and etoposide) that was used in the 1980s because it is less toxic andmore effective.


55

As stated above, the CAV regimen was one of the most commonly used regimens inboth limited- and extensive-stage disease in the 1970s. It produced response rates of80–90% in patients with a median survival time of eight to 14 months. However, rela-tively high rates of bone marrow suppression, neuropathy and pulmonary toxicity wereseen. Notably, if a patient failed the CAV regimen, the response rate to second-linechemotherapy was less than 10% with a survival time of two to three months.

A combination of Bristol’s Platinol and VePesid began being used in the 1970s andproduced 90% response rates, with complete responses in 50% of the patients. Thisregimen also appeared to be active in patients that had failed the CAV regimen. Therewere associated toxicities with this regimen, such as bone marrow suppression, neph-rotoxicity and ototoxicity. Importantly, though, the degree of bone marrow suppres-sion was much less severe than in the CAV regimen. However, under both therapyregimens, the cancers developed resistance. Efforts to enhance efficacy in either regi-men by increasing the dose or frequency of administration have, for the most part,failed to show any survival advantage.

Currently, the use of Bristol’s second-generation, platinum-based compound Para-platin (carboplatin) appears to be the standard therapy. Paraplatin produces less toxic-ity and is easier to administer when compared to Platinol.

Newer agents are currently being studied in SCLC, including Bristol’s Taxol, Aventis’sTaxotere, Pharmacia’s Camptosar, GlaxoSmithKline’s Hycamtin and Lilly’s Gemzar.

iKnowMed Data: Small Cell Lung Cancer (SCLC)

The majority of patients (58%) with limited-stage small cell lung cancer (SCLC) re-ceive Bristol’s Paraplatin in combination with etoposide. Twenty-two percent receive acombination of cisplatin and etoposide. In patients with extensive SCLC, there iswidespread use of several therapies. Twenty-seven percent of patients receiveSmithKline’s Hycamtin; 14% receive Paraplatin in combination with etoposide; 10%receive a combination of cyclophosphamide, adriamycin and vincristine; and 10% re-ceive Bristol’s Taxol.


56

Exhibit 39: Various Regimens for SCLC

TAX-CARB-HYC2%

TAX-HYC3%

PCE3%

CAV5%

OTHER7%

EP22%

CE58%

Various Regimens for Extensive SCLCTAX-HYC

2%VEP2%

VIN2%

TXT3%

HYC-VCR3%

CARB-TAX4%

PCE5%

GEM5%

EP5%

OTHER8%

TAX10% CAV

10%

HYC27%

CE14%

Source: iKnowMed.


57

Exhibit 40: Acronyms for Small Cell Lung Cancer Regimens

Acronym RegimenCARB-TAX Paraplatin + TaxolCAV cyclophosphamide + adriamycin (doxorubicin) + vincristineCE Paraplatin + etoposideEP cisplatin + etoposideGEM GemzarHYC HycamtinHYC-VCR Hycamtin + vincristineOTHERPCE Taxol + Paraplatin + etoposideTAX TaxolTAX-CARB-HYC Taxol + Paraplatin + HycamtinTAX-HYC Taxol + HycamtinTXT TaxotereVEP etoposideVIN Navelbine


Non-Small-Cell Lung Cancer (NSCLC)

In NSCLC, treatment outcomes are poor, except when the cancer is in its most local-ized stages. At this point, surgery is the major potentially curative treatment. In its ad-vanced stages, chemotherapy can only offer modest survival advantages.

At diagnosis, patients with NSCLC can be divided into three groups that, in essence,reflect the extent of the disease. The first group has tumors that are surgically resectable(stages I and II). This group is typically treated with radiation and surgery. The secondgroup includes patients with either locally (T3—T4, see Exhibit 41) or regionally(N2—N3) advanced lung cancer. Typically, this group is treated with radiation andchemotherapy. Finally, the third group consists of those patients with distant metasta-ses (M1) at the time of diagnosis. These patients are also treated with both radiationand chemotherapy.


58

Exhibit 41: TNM Staging for Non-Small-Cell Lung Cancer (NSCLC)

TNM Stagingfor Non-Small Cell Lung Cancer

Primary Tumor (T)TX Primary tumor cannot be assessed (i.e. malignant cells present but can't be visualized by

bronchoscope)T0 No evidence of primary tumorTis Carcinoma in situT1 A tumor that is 3cm or less in greatest dimensionT2 A tumor that is greater than 3cm in dimension or has invaded the pleura (lining of the lungs)T3 A tumor of any size that invades either the chest wall, diaphragm, pleura or pericardiumT4 A tumor of any size that invades either the mediastinum, heart, great vessels, trachea,

esophagus or vertebral bodyRegional Lymph Nodes (N)NX Regional lymp nodes cannot be assessedNO No regional lymph node metastasisN1 Metastasis to same side lymph nodes other than the suncarnial or mediastinal lymph nodesN2 Metastasis to same side suncarnial or mediastinal lymph nodesN3 Metastasis to opposite side lymph nodesDistant Metastasis (M)MX Metastasis cannot be assessedMO No distant metastasisM1 Distant metastasis


As stated previously, early-stage NSCLC is rarely treated with chemotherapy; conse-quently, we will not go into detail on the various treatment modalities for these typesof NSCLC. In stage II cancer (T1, N1, M0 or T2, N1, M0 or T3, N0, M0), surgery isgenerally the treatment of choice, but many patients subsequently develop regional ordistant metastases. Consequently, there has been some emphasis on the use of adjuvantchemotherapy (i.e., in conjunction with radiation and/or surgery). Two clinical trialsin which surgically resected patients were treated with Bristol’s Platinol, doxorubicinand cyclophosphamide indicated that adjuvant chemotherapy can produce a modestincrease in disease-free survival and trends of improved overall survival, especially inthe first year after surgery.

Approximately 40% of patients with NSCLC present with locally advanced or surgi-cally unresectable tumors. The majority of these patients are stage IIIA and IIIB. Instage III (T1, N2, M0 or T2, N2, M0 or T3, N1, M0 or T3,N2, M0), patients are mostoften treated with a combination of radiation, chemotherapy and surgery. Meta-analysis (a retrospective look at a combination of several previous studies) of severalstudies have shown that Platinol-based chemotherapy combinations in addition toradiation can result in a 10% risk reduction compared to radiation therapy alone.Additional studies have been performed to compare concomitant chemotherapy withradiation to sequential radiation and chemotherapy. In the majority of studies, con-comitant chemotherapy was significantly better than sequential.


59

iKnowMed Data: Non-Small-Cell Lung Cancer (NSCLC)

The vast majority of patients (67%) who are receiving initial therapy for non-small-celllung cancer will likely receive a combination of Bristol’s Paraplatin and Taxol. Theother 33% will receive one of several other various therapies. As for second-line ther-apy, 26% of patients will receive the Paraplatin/Taxol combination. 21% will receiveGlaxo’s Navelbine and 17% will receive Lilly’s Gemzar.

Exhibit 42: Various Second-Line Regimens for NSCLC

Various 2nd Line Regimens for NSCLC CARB-TXT1%

HYC1%

CE2%

GEM-CARB1%

CARB-VIN2%

GEM-CIS2%

CIS-VIN3%

TXT4%

GEM-VIN5%

TAX6%

OTHER9%

GEM17%

VIN21%

CARB-TAX26%

Source: iKnowMed.

Exhibit 43: Acronyms for Non-Small-Cell Lung Cancer Regimens

Acronym Regimen5FU 5-fluorouracilCARB-GEM Paraplatin + GemzarCARB-TAX Paraplatin + TaxolCARB-TAX-GEM Paraplatin + Taxol + GemzarCARB-TXT Paraplatin + TaxotereCARB-VIN Paraplatin + NavelbineCIS-VIN cisplatin + etoposideCE Paraplatin + etoposideEP cisplatin + etoposideGEM GemzarGEM-CIS Gemzar + cisplatinGEM-VIN Gemzar + NavelbineHYC HycamtinOTHERTAX TaxolTXT TaxotereVIN Navelbine



60

Colorectal CancerColorectal cancers (cancers of the colon and rectum) are the most common form ofcancers in the United States. The American Cancer Society estimates that approxi-mately 130,200 new cases of colorectal cancer will be diagnosed in 2000 (colon cancerwill compose 72% of the total). Colorectal cancer will likely cause 56,300 deaths thisyear. However, the death rate for colorectal cancer has been declining for the past 20years. This is likely due to increased early detection and improvements in treatment.Ninety percent of people whose colorectal cancer is found and treated early will survivefor at least five years. However, as is the case with other cancers, once the disease hasmetastasized, the five-year survival rate declines.

AnatomyThe colon, or large intestine, is approximately five feet long and consists of four dis-tinct sections (see below): the ascending colon (which attaches to the small intestine),the transverse colon, the descending colon and the sigmoid colon.

Exhibit 44: Anatomy of the Human Colon


A malignancy can form in any of these sections of the colon, but the cancer will alwaysoriginate in the innermost tissue layer. As the tumor grows, it often expands throughthe distinct layers that line the colon and in some cases breaks through. Before a truemalignancy can develop, there are often subtle changes that occur in the intestine. Onesuch change is the growth of a polyp, which is a precancerous lump of tissue.

The AmericanCancer Societyestimates thatapproximately

130,200 new casesof colorectal

cancer will bediagnosed in 2000(colon cancer willcompose 72% of

the total).


61

TreatmentExhibit 45: FDA-Approved Colorectal Therapies

FDA Approved Uses for Colorectal Cancer Therapies

Brand Nam eGeneric Name Mnfr. Indication Admin.5-Fluorouraci fluorouracil, 5-FU Various Carcinoma, palliative IV, OralCamptosar irinotecan Pharmacia 1st line therapy of metastatic disease in combination with 5-FU and

leucovorin and advanced second line following 5-FU IV, OralErgamisol levamisole Johnson & Johnson Adanced in combination with 5-FU OralWellcovorin, Lleucovorin Various 1st line in combination with 5-FU IV, Inj, Oral


For years, the standard adjuvant therapy for stage III colon cancer was 5-FU andJohnson & Johnson’s Ergamisol (levamisole) until 1998 when studies indicated that byadding leucovorin to 5-FU, one can increase the period of tumor inhibition. Overallsurvival was not increased with the addition of leucovorin; however, the response rateincreased significantly. Currently, the foundation of all colorectal cancer therapies isbased on a combination of 5-FU and leucovorin, although that is changing. Data at thispast American Society of Clinical Oncologists (ASCO) meeting in May indicated thatPharmacia’s Camptosar should be combined with 5-FU and leucovorin as part of the“gold standard” for therapy.

As with many other cancers, there is an emphasis on using adjuvant therapies. Severallarge randomized studies have demonstrated the benefit of systemic adjuvant therapywith 5-FU combined with either leucovorin or levamisole after surgery versus patientsthat underwent surgery alone. A meta-analysis of the adjuvant therapy trials of che-motherapy versus surgery alone has revealed a reduction in mortality of 22–33%.Pharmacia has commenced three international studies looking at Camptosar in com-bination with 5-FU and leucovorin in the adjuvant setting.

In patients with advanced disease, some studies have shown that palliation (a reductionin symptoms with no curative effect) may be achieved in 10–20% of patients with 5-FUalone. When leucovorin is added to the regimen, there appears to be an increase in re-sponse rates and palliation of symptoms but some confounding results in terms of sur-vival. Camptosar has shown to be effective in terms of survival and palliation ofsymptoms in patients with advanced disease.

iKnowMed Data: Colorectal Cancer

When reading the following pie charts, please recall that these data are from November1999 and, consequently, do not truly reflect the shift that may be occurring sincePharmacia’s Camptosar received approval for first-line therapy. As of November 1999,5-FU/Leucovorin remained the “gold standard” for first-line therapy with 63% of pa-tients receiving it.

However, Camptosar was used widely in the second-line indication with 51% ofpatients receiving it. Twenty-three percent of the patients were on the combination of5-FU/Leucovorin. Twelve percent received 5-FU. Notably, only 3% of patients receivedRoche’s Xeloda as a second-line therapy.


62

Exhibit 46: Various First-Line Regimens for Colorectal Cancer

Various 1st Line Regimens forColorectal Cancer CAMPTO

3%

OTHER4%

5FU19%

5FU-LEVAM11%

5FU-LEUC63%

Various 2nd Line Regimens forColorectal Cancer

XELODA3%

MITO-C2%

OTHER9%

5FU12%

5FU-LEUC23%

CAMPTO51%

Source: iKnowMed.

Exhibit 47: Acronyms for Colorectal Regimens

Acronym Regimen5FU 5-fluorouracil5FU-LEUC 5-fluorouracil + leucovorin5FU-LEVAM 5-fluorouracil + ErgamisolCAMPTO CamptosarMITO-C mitomycinOTHERXELODA Xeloda



63

Non-Hodgkin’s LymphomaLymphoma is a general term for cancers that are derived from the lymphatic system.Hodgkin’s disease is one type of lymphoma with all other lymphomas being groupedtogether as non-Hodgkin’s lymphoma. Lymphomas account for about 5% of all casesof cancer in this country. It is expected that approximately 55,000 new cases of non-Hodgkin’s lymphoma will be diagnosed in the U.S. this year (out of an approximate62,000 total lymphoma cases). It is expected that roughly 49% of the patients diag-nosed with non-Hodgkin’s lymphoma will die within five years.

Patients with non-Hodgkin’s lymphoma usually present with advanced stage III or IVdisease. Patients with indolent (low-grade) disease tend to have cancers that grow veryslowly and cause fewer symptoms. Aggressive lymphomas, also referred to as interme-diate and high-grade lymphomas, tend to grow and spread quickly and to cause severesymptoms.

AnatomyThe lymphatic system consists of lymph nodes (or lymph glands), lymphatics (thesmall vessels that link the lymph nodes) and the spleen. This system is responsible forreturning excess fluid to circulation and fighting infections and cancers. The lymphnodes (which generally occur in clusters in the neck, armpits and groin) produce somewhite blood cells and antibodies that help protect against infection. The right lym-phatic duct and the thoracic duct drain lymph fluids into two veins that come togetherto form the superior vena cava, which passes into the heart. The cisterna chyli is a wid-ened portion of the thoracic duct, where fluids from several lymph-collecting vesselsare received. The spleen removes and destroys worn-out red blood cells and helps fightinfection.

Lymphomasaccount for about5% of all cases ofcancer in thiscountry. It isexpected thatapproximately55,000 new casesof non-Hodgkin’slymphoma will bediagnosed in theU.S. this year (outof an approximate62,000 totallymphoma cases).


64

Exhibit 48: The Human Lymph System

Source: American Medical Association.


65

TreatmentExhibit 49: FDA-Approved Non-Hodgkin’s Lymphoma Therapies

FDA Approved Uses for Non-Hodgkin's Therapies

Brand Nam e Generic Name Mnfr. Indication Admin.Adriamycin, Rubex doxorubicin Various Non-Hodgkin's IVBCNU, BiCNU carmustine Bristol-Myers 2nd line IVBlenoxane bleomycin Bristol-Myers Palliative therapy of lymphomas IV, InjCytoxan, Neosar cyclophosphamide Various Advanced lymphomas IV, OralLeukeran chlorambucil GlaxoSmithkline Palliative therapy of lymphomas OralMTX methotrexate Various Advanced non-Hodgkin's lymphoma IV, Inj, OralO ncovin vincristine Eli Lilly Non-Hodgkin's IVRituxan rituximab IDEC Relapsed or refractory non-Hodgkin's IVVelban vinblastine Various Non-Hodgkin's IV


For the most part, regional radiation therapy is successful in treating patients whosedisease remains relatively localized (only about 10% of patients with low-grade dis-ease). Radiation offers long-term control, with rates of freedom from relapse rangingbetween 44% and 47% at ten years and survival rates of 75% in patients younger than60. In more advanced stages, adjuvant chemotherapy may be used. The efficacy ofchemotherapy in low-grade lymphoma has yet to be determined because curativetreatment has yet to be established. Low-grade or indolent lymphomas are not curablewith conventional therapies, although most patients respond well initially. The averagesurvival duration for a patient with indolent lymphoma is seven to ten years.

In the past, physicians typically started patients on the gentler chemotherapy regimenssuch as chloramabucil and prednisone or cyclophosphamide+vincristine+prednisone(CVP), and if the patient failed or if there was a disease recurrence, the physicianwould go to the next more intense therapy. However, as with other cancers, there is noset schedule and most often it is a subjective decision based on the individual patient,their disease state, their symptoms and the type of lymphoma. It is possible that if thepatient is symptomatic and has relatively widespread disease, one would put them oncyclophosphamide+doxorubicin+vincristine+prednisone (CHOP) initially on thechance that it may cause remission sooner. Patients who relapse are usually not curablewith conventional treatments, except for stem-cell transplantation, which has a highincidence of mortality associated with it. In more aggressive stages of lymphoma, use ofa combination of chemotherapy and radiation therapy has been highly successful. Themost common chemotherapeutic regimen appears to CHOP.

Several years ago, there was a movement away from alkylating agents as initial therapyto other drugs like Berlex’s Fludara as an initial therapy. Consequently, when themonoclonal antibodies came along, they rapidly moved into second place for the pa-tients who failed initial therapy, but some physicians are beginning to use the antibod-ies as first-line therapy. Three purine nucleoside analogs have received FDA approvalfor use in low-grade lymphoma: Fludara, SuperGen’s NiPent and Johnson & Johnson’sLeustatin. Fludara therapy can result in complete remission in 15–40% of patients withlow-grade disease; the rate tends to be higher in previously untreated individuals.

Use of chlorambucil, CVP, Fludara or Rituxan are all reasonable front-line therapies.In recent years, newly developed immunotherapies have generated a good deal of en-thusiasm. Recently, there have been some studies that indicate some chemotherapy can


66

make the tumors more sensitive to the monoclonal antibodies. For instance,SmithKline and Coulter’s Bexxar, which combines a monoclonal antibody with radio-activity, is used primarily to treat the tumor mass itself, often called debulking. How-ever, there are some studies that have recently been completed that suggest that ifchemotherapy is given early, it may actually make Bexxar more effective.

Most of the data that are available are in the indolent or low-grade lymphomas. Thereis an increasing body of data suggesting activity for the monoclonal antibodies inaggressive lymphomas, which also, for example, express CD-20, and about a third ofpatients with aggressive lymphoma will experience a response to single-agent Rituxan.There is some data combining CHOP, which is the most commonly used chemother-apy for aggressive lymphoma, with Rituxan showing very impressive response rates—virtually everybody responding when administered as front-line therapy. And as aresult of these results, there is a large trial being conducted by the Cancer & LeukemiaB Group (CALGB) and the Houston Cooperative Oncology Group looking at CHOPwith or without Rituxan in patients with aggressive lymphomas. This trial is in elderlypatients, while IDEC has a trial in all age groups.

Front-line use of the monoclonal antibodies is currently getting a lot of attention.Antibodies like Rituxan, Bexxar and Zevalin all target the same molecule, referred to asCD-20, which is present on most B-cell lymphomas. CD is a term that basically indi-cates a marker. These markers are different on lymphocytes; B-lymphocytes have cer-tain types of markers, such as CD-20, CD-22 and CD-19, while T-lymphocytes wouldhave other markers. Some of the other antibodies like Campath target different mole-cules. It is important to note that all of these antibody-based agents have different lev-els of activity. Importantly, they also have different toxicities. For example, Rituxan isan unconjugated antibody, which means that it is not bound to anything, it’s just aprotein and it works by a number of mechanisms. Bexxar and Zevalin are bound toradioisotopes, Bexxar is bound to iodine, whereas Zevalin is bound to yttrium. Conse-quently, these therapies have the potential to be more toxic because radioactivity cansuppress the bone marrow and the thyroid gland, and the suppression can be ratherlengthy in duration—it may last several months after one shot of the antibody. Bexxarcontains I-131 or radiolabeled iodine, which can suppress the thyroid gland. Thateffect is sometimes blocked by giving the pre-treatment. Bexxar and Zevalin arereferred to as “conjugated” or “radiolabeled.” Conceptually, these agents are a moretargeted form of therapy. Essentially, the antibody drags the radiation to the tumorsites, providing local radiation and hopefully sparing normal organ tissue because notall cells express this specific antigen that these agents target on their surface. Rituxan isan unconjugated antibody; consequently, its side effects are not related to radiation,but rather to the infusion, which includes fever, chills and shakes.

iKnowMed Data: Non-Hodgkin’s Lymphoma

It appears as though the majority of patients (60%) with non-Hodgkin’s lymphomareceive a combination of cyclophosphamide, doxorubicin, vincristine and prednisone(CHOP). As is the case with many cancers, there is an increase in the number of agentsused as second-line therapy. Twenty-five percent of patients receiving second-linetherapy receive IDEC’s Rituxan. Fourteen percent of patients receive CHOP and 9%receive Berlex’s Fludara.


67

Exhibit 50: Various Regimens for Non-Hodgkin’s Lymphoma

Various 1st Line Regimens forNon-Hodgkin's Lymphoma

CHLOR1%

CTX1%

RITUX-CHOP1%

FLUD-CTX1%

PROM3%

CHOP60%

CNOP8%

OTHER8%

CVP6%

RITUX4%

FLUD3%

FAMP4%

Various 2nd Line Regimens forNon-Hodgkin's Lymphoma

CTX-VP1%

DICE1%

RITUX-CHOP1%

PROM1%

IFN1%

EPOCH1%

RITUX25%

CHOP14%

OTHER12%

FLUD9%

ESHAP8%

FAMP8%

MINE6%

CVP5%

CNOP5%

DHAP2%

Source: iKnowMed.


68

Exhibit 51: Acronyms for Non-Hodgkin’s Lymphoma Regimens

Acronym RegimenCHLOR LeukeranCHOP cyclophosphamide + doxorubicin + vincristine + prednisoneCNOP cyclophosphamide + Novantrone + vincristine + prednisoneCTX cyclophosphamideCTX-VP cyclophosphamide + etoposideCVP cyclophosphamide + NovantroneDHAP cisplatin + cytarabineDICE cisplatin + etoposide + IfexEPOCH cyclophosphamide + doxorubicin + vincristine + etoposideESHAP cisplatin + cytarabine + etoposideFAMP Fludara + NovantroneFLUD FludaraFLUD-CTX Fludara + cyclophosphamideIFN interferon alphaMINE Novantrone + Ifex + etoposideOTHERPROM

bleomycin + cyclophosphamide + cytarabine + doxorubicin +etoposide + leucovorin + methotrexate + vincristine

RITUX RituxanRITUX-CHOP Rituxan + cyclophosphamide + doxorubicin + vincristine +

prednisone



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Ovarian CancerThe American Cancer Society predicts that approximately 23,100 women will be diag-nosed with ovarian cancer and 14,000 will die. Ovarian cancer causes more deaths thanany other reproductive organ cancer. More than 50% of the women diagnosed are overthe age of 65. If ovarian cancer is detected when it is in a localized stage, treatment willusually result in 95% survival at five years. However, only 25% of ovarian cancers aredetected at an early stage.

AnatomyThe ovaries are located on either side of the female pelvis. The ovaries are responsiblefor producing eggs and are the main source of the female hormones progesterone andestrogen.

Exhibit 52: The Female Reproductive Organs

Source: The Merck Manual.

There are three main types of ovarian malignancies, each named for their site of origin.The most common type is epithelial cell cancer. This tumor type originates in the cellsthat line the ovary. Epithelial carcinoma is the fourth most frequent cause of cancer-related death in women. A second form of ovarian cancer is germ cell, which originatesin the eggs of the ovary. Germ cell cancers account for approximately 5% of ovariancancers. The final type is referred to as stromal cell. Stromal cells are the cells thatessentially hold the ovary together and are responsible for production of the ovarianhormones. Stromal tumors are rare, accounting for only about 5% of ovarian cancers.

Approximately 5–10% of cancers have a distinct genetic component with three com-mon hereditary patterns: ovarian cancer alone, ovarian and breast cancer, ovarian andcolon cancer. The most important risk factor for ovarian cancer is a first-degree rela-tive with the disease. In most families with breast and ovarian cancer, a genetic linkagehas been identified on the BRCA1 locus on chromosome 17.

The AmericanCancer Societypredicts thatapproximately23,100 women willbe diagnosed withovarian cancer and14,000 will die.Ovarian cancercauses moredeaths than anyother reproductiveorgan cancer.


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It appears as though the ovarian cancer-associated antigen, CA 125, has no prognosticsignificance when measured at the time of diagnosis. However, it does have a high cor-relation with survival when measured one month after the third course of chemother-apy in patients with stage III and IV disease.

Patients with ovarian cancer often go symptom-free if the disease is in its early stages.Consequently, the majority of patients have widespread disease at the time of diagnosisand yearly mortality is approximately 65%. Patients with stage III and IV disease onplatinum-based therapies have a five-year survival rate of less than 10%. Importantly,however, if detected early, ovarian cancer is highly curable.

TreatmentExhibit 53: FDA-Approved Ovarian Cancer Therapies

FDA Approved Uses for Ovarian Cancer Therapies

Brand Name Generic Name Mnfr. Indication Admin.Adriamycin, Rubex doxorubicin Various Carcinoma IVAlkeran melphalan GlaxoSmithkline Non-resectable epithelial Inj, OralCytoxan, Neosar cyclophosphamide Various Carcinoma IV, OralDoxil liposomal doxorubicin Alza Epithelial carcinoma - 3rd line IVHexalen altretamine US Bioscience Palliative OralHycamtin topotecan GlaxoSmithkline Carcinoma - 2nd line IVHydrea hydroxyurea Various Advanced carcinoma IVParaplatin carboplatin Bristol-Myers Carcinoma - 1st line and palliative IVPlatinol, Cisplatin cisplatin Various Carcinoma - metastatic IVTaxol paclitaxel Bristol-Myers Epithelial carcinoma - 1st line in combination with Platinol IVThiotepa thiotepa Immunex Adenocarcinoma IV, Inj


Currently, it is thought that all patients with advanced-stage and most patients withearly-stage ovarian cancer should receive post-operative systemic chemotherapy. Priorto the 1980s, alkylating agents were the primary agents used. These agents producedresponse rates of 40–50% in previously untreated patients. Currently, the majority ofpatients with ovarian cancer receive a platinum-based therapy as their initial coursewith overall response rates of 70–80%. A large meta-analysis examined data from 8,000patients and suggested that platinum-based combination therapy was superior toplatinum-based chemotherapy alone in overall response and progression-free survival,but not in overall survival.

During the 1980s, the taxanes were introduced. These agents demonstrated significantresponses in platinum-refractory recurrent ovarian cancer; consequently, they werequickly adopted as part of first-line therapy. The only approved first-line therapies forovarian cancer are Bristol’s Paraplatin (carboplatin) and Taxol. Taxol’s approved indi-cation is for combination use with cisplatin. However, it appears that a majority of pa-tients with ovarian cancer receive a combination of Taxol and Paraplatin as initialtherapy. This may be due to Paraplatin’s more favorable side-effect profile. Other lesswidely used therapies in the initial treatment of ovarian cancer include cisplatinand cyclophosphamide, cisplatin and Taxol, Paraplatin and cyclophosphamide,SmithKline’s Hycamtin and Alza’s Doxil.


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Despite the advances in treatment, only a small fraction of patients are cured with cur-rent therapies. Typically, first-line therapy consists of a taxane in combination with aplatinum-based compound. Unfortunately, 50% of women will relapse within sixmonths after this treatment regimen, while the other 50% will relapse later. Onceovarian cancer recurs, the chances of a complete response with any therapy are ex-traordinarily small. The treatment options for second-line ovarian cancer are muchgreater. This may be due to the incidence of tumors that become resistant to platinum-based therapies. SmithKline’s Hycamtin is approved for therapy after patients havefailed their initial regimen. Doxorubicin has a similar indication. Notably, Alza’s Doxil,which is a liposomal formulation of doxorubicin, has shown solid efficacy in refractoryovarian cancer.

Patients are classified as having platinum-sensitive disease when recurrence occursmore than six months after the completion of platinum-based chemotherapy. Thecancer is considered platinum-resistant if it progresses during platinum-based therapyor prior to six months after completion of treatment. Currently, it appears as though15% of patients are platinum sensitive after relapse. Of the agents approved for second-line therapy, the ones that have the highest response rates in platinum- and taxane-refractory disease are Hycamtin, Vepesid, Doxil and Gemzar.

iKnowMed Data: Ovarian Cancer

An overwhelming majority (77%) of patients will receive a combination of Bristol’sParaplatin and Taxol as first-line therapy for ovarian cancer. If a patient relapses, thetherapeutic options increase significantly. Thirty-three percent of patients receive SB’sHycamtin as a second-line therapy. Nineteen percent receive the combination ofParaplatin and Taxol and 14% receive Alza’s Doxil.

Exhibit 54: Various Regimens for Ovarian Cancer

Various 1st Line Regimensfor Ovarian Cancer

DOXIL1%

CIS-TAX1%

HYC3%

CC4%

OTHER4%

CP10%

CARB-TAX77%


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Exhibit 54 cont’d: Various Regimens for Ovarian CancerVarious 2nd Line Regimens for

Therapy of Ovarian CancerAC1%

5FU-LEUC0%

5FU1%

VIN1%

ALT2%

GEM2%

CP3%

TAX6%

TXT6%

OTHER12%

DOXIL14%

CARB-TAX19%

HYC33%

Source: iKnowMed.

Exhibit 55: Acronyms for Ovarian Cancer Regimens

Acronym Regimen5FU 5-fluorouracil5FU-LEUC 5-fluorouracil + leucovorinAC adriamycin (doxorubicin) + cyclophosphamideALT HexalenCARB-TAX Paraplatin + TaxolCC cisplatin + cyclophosphamideCIS-TAX cisplatin + TaxolCP Paraplatin + cyclophosphamideDOXIL DoxilGEM GemzarHYC HycamtinOTHERTAX TaxolTXT TaxotereVIN Navelbine



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Bladder CancerEvery year, approximately 53,000 Americans learn that they have bladder cancer. TheAmerican Cancer Society estimates that approximately 12,200 will die of this disease.Bladder cancer appears to be more prevalent in men than in women. It is clear bylooking at the survival curves for bladder cancer that early detection is key. Fortu-nately, bladder cancer is often found early, which results in a five-year survival rate of94%. If the cancer spreads to nearby organs in the pelvis, the five-year survival ratedrops to 49%. If distant metastases are present, the five-year survival rate is only 6%.

AnatomyBladder cancer, as the name indicates, originates in the bladder, the muscular pouchthat stores the body’s urine.

Exhibit 56: The Male and Female Excretory Systems


Urine is emptied through a small tube called the urethra. The wall of the bladder con-sists of several layers. The innermost layer of cells is referred to as the transitional layer.These transitional cells are also present in the kidney and the tubes that connect thekidney to the bladder, the ureters. Consequently, if cancer develops in the bladder, itcould likely affect these structures as well.

There are three main types of tumors that can develop in the bladder. The first is theaforementioned transitional cell carcinoma, which accounts for approximately 90% ofall bladder cancers. Cancer that is confined to the lining of the bladder is referred to assuperficial bladder cancer. In some instances, cancer that begins as transitional cellspreads through the lining of the bladder and invades the muscular wall. This is knownas invasive bladder cancer. The second major type of bladder cancer is squamous-cellcarcinoma, which accounts for approximately 8% of cases. Squamous-cell carcinomas


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have a greater propensity to invade other cell layers of the bladder. The final major typeof bladder cancer is adenocarcinoma, which accounts for approximately 1–2% ofall cases.

Some studies have indicated that the tumor suppressor gene p53 is associated with apoor prognosis in individuals diagnosed with bladder cancer. A retrospective study of243 patients with invasive bladder cancer found that the presence of p53 was an inde-pendent predictor of recurrence.

TreatmentExhibit 57: FDA-Approved Bladder Cancer Therapies

FDA Approved Uses for Bladder Cancer Therapies

Brand Name Generic Name Mnfr. Indication Admin.Adriamycin, Rubex doxorubicin Various Transitional cell carcinoma IVBCG, TheraCys, TICE BCG vaccine Organon Carcinoma in situ IV, InjPlatinol, Cisplatin cisplatin Various Carcinoma - metastatic IVThiotepa thiotepa Immunex Carcinoma - intravesicular IVValstar valrubicin Anthra BCG refractory in patients who cannot tolerate surgery IV


In noninvasive bladder cancer, intravesical treatment with chemotherapeutic agentssuch as thiotepa, mitomycin C, doxorubicin, or with immunotherapeutic agents suchas Bacillus Calmette-Guerin (BCG) have demonstrated effectiveness when adminis-tered to patients with multiple tumors or prophylactically following transurethral re-section (TURP). BCG has shown superior protection from tumor recurrence and pre-vention of disease progression as compared to thiotepa, mitomycin C and doxorubicin.BCG is a live, attenuated culture preparation of the bacillus Calmette-Guerin strain ofmycobacterium bovis. Unlike conventional intravesical chemotherapeutic agents thatattack tumor cells directly, BCG is a biological response modifier that is believed toexert its antitumor effect by stimulating various immune responses within the host.

Invasive bladder cancer is one of the more chemosensitive forms of cancer and patientstend to display objective responses in about 50% of the cases. In clinical trials, chemo-therapy is used as neoadjuvant or adjuvant treatment of invasive bladder cancer.Cisplatin as a single agent and/or in combination regimens is the cornerstone of inva-sive bladder cancer therapy. There are only a handful of therapies that are officiallyapproved for the first-line treatment of bladder cancer. A combination of methotrex-ate, vinblastine, doxorubicin and cisplatin, commonly referred to as MVAC, is the cur-rent gold standard for transitional cell carcinoma. It is the only therapeutic regimenwith a proven survival benefit in locally advanced or metastatic disease with mediansurvival approaching one year.


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New agents in clinical trials are revealing equivalent response rates to MVAC, but withless toxicity. These agents include antifolates (trimetrexate and piritrexim), Lilly’sGemzar, taxanes (Taxol and Taxotere), ifosfamide, 5-FU and gallium. However,MVAC continues to be the standard for neoadjuvant and adjuvant therapy of muscleinvasive and metastatic bladder cancer. Apparently, in both first- and second-linetherapies, the use of Paraplatin and Taxol is relatively widespread, even though neitherdrug is approved for bladder cancer. Recently, data on a combination of Gemzar andcisplatin versus MVAC showed that the Gemzar arm had equivalent efficacy but sig-nificantly better safety and tolerability. The FDA did not recommend approval for thisindication. However, Lilly believes that approximately 50% of the U.S. bladder cancermarket is currently using this product off-label.

iKnowMed Data: Bladder Cancer

As the following pie chart indicates, approximately 35% of patients receive MVAC astheir initial therapy for bladder cancer, followed by 26% who receive Bristol’sParaplatin. For patients who relapse, possible therapies include Paraplatin/Taxol(28%), Taxol (22%), MVAC (17%) and Gemzar (11%).

Exhibit 58: Various Regimens for Bladder Cancer

Various 1st Line Regimens forBladder Cancer

CIS-TAX2%

5FU-CARB2%

5FU-LEUC2%

CIS4%

CMV5%

5FU5%

TAX6%

5FU-CIS6%

OTHER7% CARB-TAX

26%

MVAC35%


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Exhibit 58 cont’d: Various Regimens for Bladder CancerVarious 2nd Line Regimens

for Bladder Cancer

CMV5%

GEM11%

OTHER17%

MVAC17%

TAX22%

CARB-TAX28%

Source: iknowMed.

Exhibit 59: Acronyms for Bladder Cancer Regimens

Acronym Regimen5FU 5-fluorouracil5FU-CARB 5-fluoruracil + Paraplatin5FU-CIS 5-fluorouracil + cisplatin5FU-LEUC 5-fluorouracil + leucovorinCARB-TAX Paraplatin + TaxolCIS cisplatinCIS-TAX cisplatin + TaxolCMV cisplatin + methotrexate + vinblastineGEM GemzarMVAC methotrexate + vinblastine + doxorubicin + cisplatinOTHERTAX Taxol



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Pancreatic CancerThe American Cancer Society expects that approximately 28,000 people will be diag-nosed with pancreatic cancer this year. The incidence is equally distributed betweenboth men and women and is the fourth-leading cause of cancer death in both. In al-most 50% of the patients, the tumor has already metastasized at the time of diagnosis.The one-year survival rate is only 18% and the five-year rate, only 3%.

AnatomyThe pancreas is a glandular organ located deep in the abdomen, behind the stomachbut in front of the spine. It is approximately six inches long and produces hormonesand pancreatic juices that enable digestion. The pancreatic juices are transported alonga series of ducts that ultimately empty in the small intestine. The pancreas is responsi-ble for secreting two antagonistic hormones, insulin and glucagon, that are vital toproper metabolism.

Exhibit 60: The Human Pancreas


Approximately 95% of pancreatic cancers originate in the ducts and are referred to asadenocarcinomas. A very rare type of pancreatic cancer originates in the cells that pro-duce insulin and glucagon; these cells are termed the islets. Patients with these types oftumors have a better prognosis than patients with other types of pancreatic cancer.

Approximately28,000 people willbe diagnosed withpancreatic cancerthis year. The one-year survival rate isonly 18%; the five-year rate, only 3%.


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TreatmentExhibit 61: FDA-Approved Pancreatic Cancer Therapies

FDA Approved Uses for Pancreatic Cancer Therapies

Brand Name Generic Name Mnfr. Indication Admin.Adrucil 5-FU, fluorouracil Various Carcinoma - palliative IV, OralGemzar gemcitabine Eli Lilly Carcinoma - advanced IVMitomycin, Mutamycin mitomycin Various Adenocarcinoma IVZanosar streptozocin Pharmacia Carcinoma - palliative IV


Unfortunately, as stated previously, most patients present with pancreatic cancer thatcannot be removed surgically. Consequently, one of the few options is chemotherapy.However, clinical results have been poor. Most patients are severally debilitated andtoo weakened to undergo extensive chemotherapy. Additionally, individuals with pan-creatic cancer exhibit physiological conditions that make it difficult to differentiate theside effects of therapy from disease progression.

Several agents have been used as single agents where results have been minimally effec-tive: 5FU, mitomycin C, streptozocin, ifosfamide and doxorubicin. Unfortunately, re-sponse rates using combinations of agents (streptozocin + mitomycin C + 5FU) havenot shown any survival advantage over single agents.

One agent that has shown some promise is Lilly’s Gemzar, which shows prolonged sur-vival and a relatively mild side-effect profile.

iKnowMed Data: Pancreatic Cancer

In both first- and second-line cancer therapy, Lilly’s Gemzar is the predominant ther-apy, with 61% of patients and 49% of patients receiving it as first- and second-linetherapy, respectively. Twenty-four percent of patients receive 5-FU in both first- andsecond-line regimens.


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Exhibit 62: Various Regimens for Pancreatic Cancer

Various 1st Line Regimensfor Pancreatic Cancer

GEM-XEL2%

GEM-CDDP1%

OTHER3%

5FU-LEUC9%

5FU24%

GEM61%

Various 2nd Line Regimensfor Pancreatic Cancer

OTHER13%

5FU-LEUC14%

5FU24%

GEM49%

Source: iKnowMed.

Exhibit 63: Acronyms for Pancreatic Cancer Regimens

Acronym Regimen5FU 5-fluorouracil5FU-LEUC 5-fluorouracil + leucovorinGEM GemzarGEM + CDDP Gemzar + cisplatinGEM-XEL Gemzar + XelodaOTHER



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Prostate CancerThis year, the American Cancer Society expects 180,000 men to be diagnosed withprostate cancer and approximately 32,000 to die. There was a remarkable increase inthe incidence of prostate cancer between 1976 and 1994, which was likely due to in-creased awareness and prostate-specific antigen (PSA) screening. The rate of incidencehas since leveled off. Prior to 1990, the death rate from prostate cancer was increasing,but the death rate in the period from 1990 to 1995 dropped from 26.5% to 17.3%. Alarge part of the reduction was caused by early diagnosis, in addition to improvedtreatment modalities.

The five-year survival rate for men with prostate cancer is 89%, and 63% of men willlive at least ten years. If the cancer is found before it metastasizes outside of the pros-tate, the five-year survival rate is 100%. If it has spread to tissues near the prostate, thesurvival rate drops to 94%. Even if distant metastases are present, at least 31% of menwill survive for five years.

AnatomyThe prostate gland is a walnut-sized gland located just below the bladder. The tube thatcarries urine, the urethra, runs through the prostate. The prostate is responsible forsecreting some of the fluid contained in semen. Nerves found next to the prostate areresponsible for causing an erection; consequently, damage to these nerves can result inimpotence. The prostate gland is composed of three major sections: the central zone,the peripheral zone and the transitional zone. The large peripheral zone is the mostcommon site for cancer.

Exhibit 64: The Male Genitourinary Tract



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TreatmentExhibit 65: FDA-Approved Prostate Cancer Therapies

FDA Approved Uses for Prosate Cancer Therapies

Brand Name Generic Name Mnfr. IndicationCasodex bicalutamide AstraZeneca 1st line in combination with LHRH analogEmcyt estramustine Pharmacia Carcinoma - advanced, palliativeEulexin flutamide Schering-Plough 1st line in combination with LHRH analogLupron leuprolide TAP Carcinoma - advanced, palliativeNovantrone mitoxantrone Immunex Reduction of pain in combination with prednisoneStilphostrol diethylstilbestrol Various Carcinoma - advancedTrelstar triptorelin Pharmacia palliative treatment of advanced prostate cancer in

patients whom orchiectomy or estrogenadministration is not indicated or not acceptable

Viadur leuprolide implant Alza Carcinoma - advanced, palliativeZoladex goserelin AstraZeneca Carcinoma - advanced, palliative


Approximately 95% of prostate cancers can be defined as adenocarcinomas. Of theremaining 5%, greater than 90% are transitional cell carcinomas. All prostate cancersarise from what are referred to as glandular epithelial cells. Epithelial cells have a longprogression before they become malignant. Premalignant changes can be present forup to ten years before cancer is diagnosed.

Hormone Therapy

In advanced prostate cancer, it is often necessary to manipulate the patient’s androgenlevels, primarily testosterone. (Male sex hormones are often referred to as androgens.)There are three primary tissues that comprise prostate cancer cells: androgen-dependent, androgen-sensitive and androgen-independent.

Androgen secretion is dependent on the secretion of luteinizing hormone releasinghormone (LHRH), which is secreted from the hypothalamus (a small gland at the baseof the brain). LHRH stimulates the pituitary gland to secrete luteinizing hormone (LH)and follicle-stimulating hormone (FSH). These two hormones then act locally on thetestis to produce most of the androgens. The ultimate goal of hormone therapy is todecrease the level of circulating androgens. By reducing levels of androgen, one caneffectively eliminate those androgen-dependent cells in the tumor and halt the growthof the androgen-sensitive cells, thereby reducing the overall size of the tumor. Hormo-nal therapy is not curative, but can produce a reduction in symptoms.

Clearly, one of the most efficient ways to reduce circulating androgen levels is by surgi-cal removal of the testes (orchiectomy). Testosterone levels are reduced by 90–95%after orchiectomy. Estrogen therapy blocks LHRH, effectively blocking production oftestosterone; however, the cardiovascular side effects associated with estrogen make itsuse slightly more risky than some of the current hormonal agents.

In the early 1990s, a definitive study was performed that showed AstraZeneca’s Zoladex(an LHRH agonist) was as effective in lowering blood levels of testosterone in previ-ously untreated patients with metastatic carcinoma as surgical castration. Additionally,response rates, time to treatment failure and overall survival rates were equivalent in


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the two groups. Currently, the LHRH agonists are considered the standard of care.However, these agents are not without their drawbacks. These compounds will initiallyincrease testosterone levels. It is not until after several days of therapy that testosteronelevels begin to fall to a castration level. The surge of testosterone levels after therapy hascommenced is referred to as a “flare.” During a flare, the patient is likely to experienceincreased pain and bladder obstruction. However, administering an antiandrogen (i.e.,AstraZeneca’s Casodex or Schering’s Eulexin) before the LHRH agonist may reduce theflare. Combining an antiandrogen with an LHRH agonist is referred to as total andro-gen ablation. Notably, a meta-analysis of 22 randomized trials, comprising 5,710patients with advanced prostate cancer, failed to show a statistically significant differ-ence in five-year survival rates between those patients who received total androgenablation versus those who underwent surgical castration, although some believe thattotal androgen ablation may increase the time before tumor progression. Importantly,patients tend to respond well to hormonal therapy, on average, 70–90% of the time,and sometimes responses can last for several years.

A new addition to this market is Alza’s Viadur. On March 6, the FDA approvedViadur, a once-yearly implant for the palliative treatment of advanced prostate cancer.This is the first product to provide continuous, 12-month testosterone suppressionwith a single treatment. Viadur’s active compound is leuprolide, which is the same asTAP’s Lupron, although the TAP products must be given every three or four months.The FDA’s approval was based on two open-label, multicenter studies in 131 patientswith advanced prostate cancer who were treated with Viadur and evaluated for up totwo years. Following the initial surgical insertion of the implant, mean serum testos-terone concentrations decreased to therapeutically desirable levels by week four in 99%of the patients. Once testosterone suppression was obtained, testosterone levels re-mained suppressed for the duration of the 12 months. This product is expected tolaunch in early 2001 and will be marketed by Bayer.

Additionally, on June 15, Pharmacia received approval of Trelstar (triptorelin) for thepalliative treatment of advanced prostate cancer in patients for whom orchiectomy orestrogen administration is not indicated or not acceptable. Trelstar is administered asan injection given once a month. The data for approval indicated that following a sin-gle IM injection of Trelstar to healthy male volunteers, serum testosterone levels firstincreased, peaking on day 4, and declined thereafter to low levels by week 4. Similartestosterone profiles were observed in patients with advanced prostate cancer wheninjected with Trelstar Depot. In healthy volunteers, testosterone serum levels returnedto near baseline by week 8. Trelstar Depot was studied in a randomized, active controltrial of 277 men, ages 47 to 89, with advanced prostate cancer. Patients were giveneither Trelstar or an approved GnRH agonist monthly for nine months. The primaryefficacy results were both achievement of castration by day 29 and maintenance of cas-tration from day 57 through day 253. Castration levels of serum testosterone wereachieved in 91.2% of Trelstar patients at day 29 and in 97.7% of patients at day 57.

One notable compound under development is Amgen/Praecis’s Abarelix. This is apeptide antagonist, which inhibits the action of LHRH on the pituitary. Abarelix-depot-M is currently in phase III trials in patients with hormonally responsive prostatecancer. At ASCO this past year, two trials were presented on Abarelix. In one trial, 270


83

patients with hormone-responsive prostate cancer were randomized to either Abarelix(n=180) or TAP’s Lupron (n=91). All of the patients in the Abarelix arm avoided thetestosterone “flare,” whereas in the Lupron arm, 18% of patients had such a “flare.”Seventy-two percent of patients on Abarelix achieved complete testosterone suppres-sion after one week of therapy, whereas none of the patients in the Lupron arm did atone week. Similar results were reported in a second trial that looked at a total of 255patients who were randomized to Abarelix (n=170) or Lupron plus AstraZeneca’sCasodex (n=85). Again, all patients in the Abarelix arm avoided the testosterone surge,whereas 14% of those in the Lupron-Casodex arm suffered “flares.” Sixty-eight percentof patients on Abarelix achieved complete testosterone suppression after one week,whereas no patient in the Lupron/Casodex arm did. All results were statisticallysignificant.

When a patient fails to respond to hormone therapy, the cancer is referred to as hor-mone-refractory prostate cancer (HRPC). At this point, antineoplastic therapy may bean option. Over the past several years, research has produced several drug regimensthat enhance the quality of life of patients with HRPC. Unfortunately, none of thesedrug combinations has been shown to improve survival. Multidrug resistance is a pos-sible explanation for the failure of patients to respond to chemotherapy. Some drugsthat could be useful in HRPC include oral cyclophosphamide, estramustine in combi-nation with Taxotere, or ketoconazole plus doxorubicin. Phase III trials are needed tocompare the current standard of mitoxantrone plus steroid to these other drug combi-nations to identify the best combination for improving quality of life and perhapsaffecting survival.

Exhibit 66: Total Prescription Trends for Oral Prostate Cancer TherapiesTotal Prescriptions (TRXs) in Thousands

Jun-99 Jul-99 Aug-99 Sep-99 Oct-99 Nov-99 Dec-99 Jan-00 Feb-00 Mar-00 Apr-00 May-00 Jun-00Total Prostate Cancer Market 85 84 84 82 83 82 84 79 77 83 79 86 83

Growth (year/year)Casodex (AZN) 15% 11% 12% 9% 5% 9% 6% 3% 6% -2% -2% 8% 2%Emcyt (PHA) 11% 14% 8% 7% 10% 12% 9% 17% 39% 33% 28% 31% 26%Eulexin (SGP) -19% -16% -16% -13% -16% -13% -13% -18% -14% -17% -16% -8% -13%

Total Generic Leuprolide N/A N/A N/A N/A N/A 74400% 3304% 405% 151% 202% 193% 270% 96%Lupron -17% -28% -33% -19% -35% -32% -35% -30% -26% -30% -22% -7% -30%Lupron Depot -2% -2% -1% -2% -5% -4% -6% -8% -5% -15% -13% -2% -7%Lupron Depot-3 Mo. -4% 13% 12% 5% -7% 1% -7% 8% 0% 1% -9% 4% 6%Lupron Depot-4mo. 173% 112% 113% 64% 67% 69% 41% 42% 35% 20% 33% 44% 14%Lupron Depot-Ped 16% 19% 7% 4% 12% 12% -1% -5% 1% -7% -6% 3% -8%

Total Lupron (TAP) 0% 2% 2% 0% -3% -1% -5% -5% -3% -12% -11% 0% -6%Total Generic Diethylstilbestrol -19% -60% -35% -44% -41% 15% -35% -31% -24% -45% -12% -37% -75%Zoladex (AZN) 10% -9% 12% 3% 5% 21% -9% 3% 7% -15% 0% 1% -15%

Total Prostate Cancer Market 3% 3% 4% 3% 0% 3% 0% -1% 1% -5% -4% 5% -2%

Market ShareCasodex (AZN) 49.3% 49.5% 49.6% 49.4% 49.4% 50.1% 51.1% 50.1% 50.7% 50.1% 50.2% 50.2% 51.2%Emcyt (PHA) 1.8% 1.8% 1.9% 1.8% 1.8% 1.9% 1.9% 2.1% 2.2% 2.3% 2.2% 2.4% 2.4%Eulexin (SGP) 22.0% 22.3% 21.8% 22.0% 21.6% 21.1% 21.4% 20.4% 20.1% 20.5% 19.8% 19.6% 19.6%

Total Generic Leuprolide 1.3% 1.6% 1.7% 2.1% 2.5% 1.8% 2.0% 3.2% 2.7% 3.0% 3.8% 3.7% 2.6%Lupron 7.3% 6.6% 6.0% 6.5% 6.8% 5.7% 5.0% 7.1% 6.4% 5.7% 6.6% 6.4% 5.2%Lupron Depot 18.7% 18.3% 18.4% 18.3% 18.1% 18.2% 17.3% 17.4% 17.4% 17.3% 17.3% 17.4% 17.7%Lupron Depot-3 Mo. 2.2% 2.2% 2.4% 2.1% 2.3% 2.3% 2.1% 2.5% 2.3% 2.5% 2.3% 2.3% 2.3%Lupron Depot-4mo. 0.5% 0.5% 0.5% 0.5% 0.5% 0.5% 0.5% 0.5% 0.5% 0.6% 0.6% 0.6% 0.6%Lupron Depot-Ped 2.2% 2.2% 2.1% 2.0% 2.2% 2.3% 2.1% 2.0% 2.2% 2.1% 2.0% 2.1% 2.0%

Total Lupron (TAP) 23.5% 23.2% 23.4% 22.9% 23.0% 23.3% 22.0% 22.5% 22.4% 22.6% 22.2% 22.5% 22.7%Total Generic Diethylstilbestrol 0.3% 0.2% 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.2% 0.2% 0.3% 0.2% 0.1%Zoladex (AZN) 1.7% 1.4% 1.6% 1.6% 1.5% 1.6% 1.4% 1.6% 1.6% 1.4% 1.5% 1.4% 1.4%

Total Prostate Cancer Market 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0%

Source: IMS America.


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85

Company Cancer Portfolios


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IntroductionIn this section, we provide an overview on each company’s cancer product portfolio.Additionally, for the domestic companies officially covered by UBS Warburg LLC, weprovide an analysis regarding the investment significance of these particular productsto their respective companies.

Exhibit 67: Leaders in the Oncology Market

Top Ten Oncology CompaniesCompany 1999 Worldwide Sales in

MillionsMarket Share

Bristol-Myers Squibb 2,376.0 23.4%AstraZeneca 1,739.0 17.2%TAP Pharmaceuticals 730.0 7.2%Aventis 689.6 6.8%Pharmacia 564.4 5.6%Roche/Genentech 489.3 4.8%Eli Lilly 455.8 4.5%Schering-Plough 455.0 4.5%Takeda 298.0 2.9%GlaxoSmithKline 221.2 2.2%Total Market 10,138.5 100.0%

Source: MedAdNews.

Alza

Drug Data

Doxil (Liposomal Doxorubicin)

Doxil is the anthracycline antibiotic encapsulated in Alza’s patented “stealth” lipo-somes. At this year’s American Society of Clinical Oncology (ASCO) meeting in May, alarge head-to-head trial comparing Doxil to SmithKline’s Hycamtin found minimaldifferences between the two regimens for treating patients with relapsed ovariancancer. However, Doxil did slightly better in patients with platinum-sensitive diseaseand it caused a much lower incidence of hematological toxicity.

Currently, both Doxil and Hycamtin are approved in the U.S. for second-line treat-ment of ovarian cancer. In the trial, 474 patients who had failed first-line, platinum-based therapy were randomly assigned to Doxil once every four weeks as a one-hourinfusion or a 30-minute IV infusion of Hycamtin for five days every three weeks. Therewas no significant difference between the two treatment arms for the median time todisease progression, 18.4 weeks for Doxil and 18.3 weeks for Hycamtin. Additionally,there was no significant difference between objective response or median overall sur-vival. However, there was a significant difference in the subset of patients withplatinum-sensitive disease. Patients in the Doxil arm showed a significantly bettermedian overall survival of 86.1 weeks versus 63.6 weeks in the Hycamtin arm(p=0.012). Regarding adverse events, the Hycamtin arm experienced a high degree ofhematological toxicity, with 81% of patients experiencing some level of neutropenia


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and 72% experiencing some level of anemia. In the Doxil arm, 49% of patients experi-enced hand-foot syndrome, also known as Palmar-Plantar Erythrodysesthesia (PPE), atingly sensation in the palms of the hands and the soles of the feet, and 40% experi-enced stomatitis, soreness of the mouth. Importantly, patients on Doxil do not needany stem cell support, whereas patients on Hycamtin do.

Regarding the interesting results in the platinum-sensitive patients, the trial was notdesigned to show this difference and, consequently, it was unexpected. The exactmechanism behind this result remains unclear. It is possible that Doxil is less likely toinduce multi-drug resistance. Importantly, the point of the study was to show thatthere is no disadvantage to using Doxil before Hycamtin.

Schering-Plough has rights to Doxil outside the U.S., where it is branded as Caelyx.Currently, Schering is conducting a large trial in breast cancer, as is the EasternOncology Cooperative Group (ECOG). Other researchers are looking at Doxil’s role inbreast cancer therapy when combined with Genentech’s Herceptin. Alza is looking atDoxil in patients with multiple myeloma who have failed anthracycline therapy, and apossible new drug application (NDA) could be filed in late 2000 or early 2001.

Ethyol (Amifostine)

Ethyol is the first broad-spectrum cytoprotective agent to gain regulatory approval.Broad spectrum refers to cytoprotection against a broad array of cytotoxic therapies(i.e., multiple drug classes as well as radiation, in multiple organ systems). However, itremains unclear as to the chemoprotective effects of Ethyol in the central nervous sys-tem. Ethyol is currently indicated for the reduction of chemotherapy-related toxicity inhead and neck cancers as well as a reduction in the cumulative renal toxicity associatedwith the use of cisplatin, a commonly used platinum-based chemotherapy agent.

The principal toxicities associated with Ethyol include nausea and vomiting and hypo-tension, typically characterized by a transient reduction in blood pressure. These tox-icities are dose related. On October 4, data from a phase III, open-label, prospectivemulticenter randomized trial, which involved more than 300 patients with head andneck cancer, were presented. This trial demonstrated that approximately one monthfollowing treatment, 78% patients given radiation alone experienced moderate tosevere xerostomia (dry mouth), compared with 51% of patients treated with Ethyolprior to radiation. This was a 35% reduction in the incidence of moderate to severe drymouth. Additionally, one year after the completion of radiotherapy, 72% of thepatients receiving Ethyol could produce a clinically relevant volume of saliva, com-pared with only 49% of patients who did not receive Ethyol.

Viadur (Leuprolide Implant)

On March 6, the FDA approved Viadur, a once-yearly implant for the palliative treat-ment of advanced prostate cancer. This is the first product to provide continuous,12-month testosterone suppression with a single treatment. Viadur’s active compoundis the LHRH agonist, leuprolide. Currently, leuprolide is delivered by injections givenevery one, three or four months. The FDA’s approval was based on two open-label,multicenter studies in 131 patients with advanced prostate cancer who were treated


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with Viadur and evaluated for up to two years. Following the initial surgical insertionof the implant, mean serum testosterone concentrations decreased to therapeuticallydesirable levels by week four in 99% of the patients. Once testosterone suppression wasobtained, testosterone levels remained suppressed for the duration of the 12 months.On April 5, Alza and Bayer announced that the companies had entered into a U.S.commercialization agreement for Viadur. Under the terms of the agreement, Bayer willhave the commercial rights to Viadur in the U.S. through 2015. Alza will manufacturethe product for Bayer. The companies anticipate launching this product in early 2001.

American Home Products

Investment Summary

Minimal Investment Significance; Not Really a Key Player in Oncology Market

Mylotarg represents American Home’s most recent foray into the oncology market,and it appears as though the major development pipeline centers around cell-cyclemodifiers that are derivatives of Rapamune, such as the phase I product CCI-779. Themarket potential for Mylotarg is not that significant. The current indication for acutemyeloid leukemia encompasses a patient population of approximately 10,000. Conse-quently, we do not have specific revenue assumptions for Mylotarg built into our model.

American Home markets a handful of other cancer or cancer-related products such asNeumega, Isovorin/Leucovorin, Nipent, Novantrone and Thioplex. With the exceptionof Neumega, all of these products are marketed by American Home outside of theUnited States. As a point of reference, these products had U.S. sales of approximately$134 million during 1999, according to IMS Health.

Drug Data

Mylotarg (Gemtuzumab Ozogamicin)

Mylotarg is the first in a new class of anticancer therapies known as “antibody-targetedchemotherapy.” The product was jointly developed by American Home and Celltech.It is an injectable humanized monoclonal antibody targeting CD-33 linked to the cy-totoxic agent clicheamicin, which is a highly potent antitumor antibiotic. It is currentlyapproved for the treatment of CD-33 positive relapsed adult acute myeloid leukemia(AML). The CD-33 antigen is a glycoprotein commonly found on leukemic cells. Thisantigen is also found on other bone marrow hematopoietic cells, but not on pluripo-tent progenitor cells; consequently, the overall toxicity to blood cells is limited. In1999, American Home obtained the license to market Mylotarg in the U.S. and Europe.Mylotarg, known generically as gemtuzumab ozogamicin, is currently approved for thetreatment of patients 60 years and older in first relapse with CD33-positive acute myeloidleukemia (AML) who are not considered candidates for cytotoxic chemotherapy.

On March 17, an FDA advisory committee recommended accelerated approval foracute relapsed AML in patients 60 years and older but against approval in the generalpopulation, citing efficacy concerns. The efficacy was not shown to be comparable tothat of conventional salvage regimens; however, there was sufficient evidence to sup-port improved safety in the treatment of CD-33 positive relapsed AML.


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At this year’s ASCO meeting, pooled data from three open-label international mul-ticenter phase II clinical trials showed that the product resulted in prolonged survival.One hundred forty-two patients were given Mylotarg in two infusions at 14-day inter-vals. Remission was achieved in 30% of patients and median overall survival was 5.9months. Importantly, there are no controlled trials demonstrating a clinical benefit,such as improvement in disease-related symptoms or increased survival, compared toany other treatment. Interestingly, Mylotarg can be administered in outpatient settings,which may be desirable to patients. AML is the most common type of acute leukemiain adults. The American Cancer Society estimates that close to 10,000 new patients willbe diagnosed with the disease this year. More than 75% of patients are over the age of60. Additionally, American Home is looking at other indications for Mylotarg, whichinclude relapsed AML, using Mylotarg in combination with other therapies and earlierin the disease process, and using Mylotarg in pediatric patients.

Pipeline

The majority of these compounds are very early in development. Some preliminarydata on CCI-779 were presented this past May at the American Society of ClinicalOncologists (ASCO) meeting. CCI-779 is an ester of Rapamune (rapamycin/sirolimus),American Home’s new transplant therapy. It has shown good activity in vitro againstT-cell leukemias, melanomas and malignancies of the central nervous system, breastand prostate. This product will likely be dosed intermittently to avoid theimmunosuppression that is seen with chronic dosing. At the time the data werepresented, the maximum tolerated dose (MTD) had not been encountered, althoughsome patients developed an acneiform rash.

Amgen

Drug Data

Abarelix (LHRH Antagonist)

One notable compound under development is Amgen/Praecis’s Abarelix. This is apeptide antagonist, which inhibits the action of LHRH on the pituitary. Abarelix-depot-M is currently in phase III trials in patients with hormonally responsive prostatecancer. At ASCO this past year, two trials were presented on Abarelix. In one trial, 270patients with hormone-responsive prostate cancer were randomized to either Abarelix(n=180) or TAP’s Lupron (n=91). All of the patients in the Abarelix arm avoided thetestosterone “flare,” whereas in the Lupron arm, 18% of patients had such a “flare.”Seventy-two percent of patients on Abarelix achieved complete testosterone suppres-sion after one week of therapy, whereas none of the patients in the Lupron arm did atone week. Similar results were reported in a second trial that looked at a total of 255patients who were randomized to Abarelix (n=170) or Lupron plus AstraZeneca’sCasodex (n=85). Again, all patients in the Abarelix arm avoided the testosterone surge,whereas 14% in the Lupron-Casodex arm suffered “flares.” Sixty-eight percent of pa-tients on Abarelix achieved complete testosterone suppression after one week, whereasno patient in the Lupron/Casodex arm did. All results were statistically significant.Amgen/Praecis expect to file Abarelix with the FDA during the fourth quarter.


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AstraZeneca

Drug Data

Arimidex (Anastrazole)

Arimidex was first approved for second-line treatment of advanced breast cancer inpostmenopausal women during 1996. Recently, several European countries haveapproved Arimidex for first-line treatment of advanced breast cancer in postmeno-pausal women. On September 1, the FDA granted approval for this indication as well.At this year’s ASCO, data were presented from a meta-analysis of 1,021 patients. Theresults indicated that Arimidex was at least as effective as tamoxifen in time to tumorprogression and in objective response. However, when a subgroup analysis was per-formed on 611 women with estrogen-receptor positive tumors, Arimidex was signifi-cantly more effective than tamoxifen in improving (reducing) time to progression andin objective response rates. Additionally, a separate study of neo-adjuvant treatmentwith Arimidex (given to women prior to surgery) indicated that Arimidex may shrinkthe tumor such that surgery can be avoided. AstraZeneca is conducting two largerstudies to look at this indication.

Casodex (Bicalutamide)

Casodex is the leading anti-androgen worldwide. As of June this year, Casodex was theleading oral prostate cancer agent with a 51.2% total market share. AstraZeneca is con-ducting a study comparing Casodex with placebo in conjunction with standard treat-ment in more than 8,000 men with early prostate cancer; results are expected in 2002.

Nolvadex (Tamoxifen)

Tamoxifen is a nonsteroidal antiestrogen that binds to the estrogen receptors that arepresent in the body, including those present in cancerous tissue. Consequently, iteffectively blocks estrogen from exerting its effects on cells, thereby inhibiting tumorgrowth. This product was launched in 1978. In 1993, as a result of the settlement of apatent challenge of tamoxifen by Barr Labs, AstraZeneca entered into a nonexclusivesupply and distribution agreement. Under the terms of the agreement, Barr purchasestamoxifen directly from AstraZeneca and sells it as a generic product. Currently, Barr isthe only distributor. Although Barr is a nonexclusive distributor, the agreementprovides that should an additional distributor or distributors be selected byAstraZeneca, Barr will be granted terms no less favorable than those granted to anysubsequent distributor. Additionally, Barr has a tentatively approved abbreviated newdrug application (ANDA) for the manufacture of tamoxifen. Consequently, at the timeof the patent expiration in August 2002, Barr can immediately begin the direct manu-facture of tamoxifen.

This past May at ASCO, data from several head-to-head trials of AstraZeneca’sNolvadex versus some of the more recently launched agents were presented. A Finnishstudy compared Shire’s Fareston to Nolvadex. In this study, the mean time to breastcancer recurrence and overall survival were also similar for both groups of patients.When analyzed according to the endpoints of death from breast cancer, there was atrend for fewer breast cancer deaths with Fareston (5.3%) compared to Nolvadex


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(9.6%), (p=.05). The investigators concluded that Fareston is effective and safe for theadjuvant treatment of node-positive breast cancer in postmenopausal women.

On June 30, the FDA granted AstraZeneca a new indication for Nolvadex in the treat-ment of ductal carcinoma in situ (DCIS). Nolvadex is the first therapy approved forthis indication. DCIS is an invasive cancer involving only the cells lining the milk ductsof the breast. The exact indication is for the reduction of risk of invasive breast cancerin women with DCIS following breast surgery and radiation.

Zoladex (Goserelin)

Zoladex is an LHRH agonist for the treatment of prostate cancer. It was launched in1990 and is administered as an injection given once every three months. As of June2000, the product had 1.4% of the prostate cancer market. At this year’s ASCO,Zoladex received further support for its use with standard radiation to improve therecurrence rate in locally advanced prostate cancer; 1,520 patients received fourmonths of Zoladex and Schering-Plough’s anti-androgen Eulexin for two months be-fore and for two months during radiation treatment. The patients were then random-ized to receive either no therapy or 24 months of additional Zoladex therapy alone.Patients were followed for an average of 4.8 years. During the study period, the groupon long-term Zoladex therapy did significantly better than those receiving short-termhormone treatment in terms of disease-free survival (54% versus 34%, p=0.0001), localdisease progression (6% versus 13%, p=0.0001), distant metastases (11% versus 17%,p=0.001) and biochemical failure (21% versus 46%, p=0.0001). However, five-yearsurvival rates were not that much different between the arms: 78% versus 79%. Butpatients at the highest risk for relapse who were treated with long-term Zoladex hadsignificantly better five-year survival (80% versus 69%) and better disease-specific sur-vival (90% versus 78%) than those who had short-term therapy. Notably, patients inthe Zoladex arm had a significant increase in bowel complications.

Pipeline

Faslodex

Faslodex is a new class of breast cancer therapy (selective estrogen receptor downregulator) in phase III as a long-acting, once-monthly injection for advanced disease.Submission for regulatory approval is expected in 2000.

Iressa (ZD1839)

AstraZeneca has several early-stage compounds in development, such as ZD0473, anew generation platinum agent designed to deliver an extended spectrum of anti-tumor activity and to overcome classical platinum resistance; ZD9331, a thymidilatesynthase inhibitor, is being developed as IV and oral formulations and Iressa(ZD1839), a novel oral cancer therapy. Iressa has garnered the most attention of any ofthe compounds. It is an epidermal growth factor receptor (EGFR) tyrosine kinaseinhibitor. The following exhibit highlights how prevalent this receptor is in varioustumor types. Increased expression of this receptor is usually associated with invasion,metastasis, later-stage disease and poor outcome.


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Exhibit 68: Epidermal Growth Factor Receptor Expression

Incidence of EGFR Expression in Various Tumor Types

Non-small Cell Lung Cancer 40-80%Colorectal 25-77%Gastric (advanced) 33%Pancreatic 30-50%Ovarian 35-70%Breast 15-30%Prostate 40%

Source: Adapted from AstraZeneca.

At ASCO, preliminary phase I trials of the once-daily oral agent, Iressa, as a singleagent in several cancer types were presented. Anti-tumor activity was most profound innon-small-cell lung cancer (NSCLC). Many cancers are known to overexpress epider-mal growth factor (EGF), which promotes cell proliferation. Iressa is designed to blockthe signal that causes EGF to bind to its protein receptors. Two NSCLC patients hadpartial responses to Iressa, two showed improvement in disease control and two othershad disease stabilization. The most common adverse events were mild to moderatediarrhea and an acne-like rash. Serious adverse events were rare and usually related todisease progression. The dose-limiting toxicity (DLT) was diarrhea at 700 mg. Phase IIItrials in first-line NSCLC are commencing. Iressa will also be combined with tradi-tional chemotherapy in a whole range of clinical trials in various cancers as well as be-ing tested as monotherapy. Phases I and II are now complete and AstraZeneca hasstated that the FDA has given it preliminary notice that this product would receive fast-track status. AstraZeneca anticipates filing this product with the FDA during the fourthquarter of 2001.

Aventis

Drug Data

Campto (Irinotecan)

Aventis has the marketing rights to Camptosar in Europe, Pharmacia has rights in theAmericas, Australia and New Zealand. Aventis markets this product under the brandname Campto (please see the Pharmacia section for detailed clinical data). Currently,Campto is in phase III for gastric cancer and phase II for non-small-cell lung andsmall-cell lung cancer. Aventis is also in early-stage clinical development of an oralformulation.

Taxotere (Docetaxel)

Taxotere is classified as a taxane and one of the newer entrants to the cancer market. Itis a semisynthetic derivative of a precursor to Taxol (paclitaxel). It is extracted from theneedles of the European yew, which is abundantly available. It was launched in June1996 and is currently the mainstay of Aventis’s cancer portfolio. In 1999, it generatedapproximately $500 million in worldwide sales. In the U.S., Taxotere is currently indi-cated for the treatment of patients with locally advanced or metastatic breast cancerafter failure of prior chemotherapy and for patients with locally advanced or metastaticnon-small-cell lung cancer after failure of prior platinum-based chemotherapy. Notably,


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our iKnowMed database indicates that the majority of Taxotere’s use is in breastcancer. Additionally, it appears that the majority of its use is as a second-line therapy.

Exhibit 69: Various Uses of Taxotere

Taxotere Use

0

100

200

300

400

500

600

BREAST NSCLC OVARIAN OTHER PROSTATE SCLC

Disease

Num

bers

ofP

atie

nts

ADJ 2nd LINE

Source: iKnowMed.

At this past May’s ASCO, several studies were presented on Taxotere looking at its usein prostate and gynecological cancers in addition to further studies in lung cancer. Onestudy in advanced prostate cancer indicated that weekly treatment with Taxotere re-duces pain and disease markers. The study showed that 44% of patients achieved apalliative response in terms of pain reduction. Additionally, 43% of patients had aprostate serum antigen (PSA) response defined as a PSA decline of 50% or more. An-other notable study in prostate cancer was also presented. A study performed atColumbia Presbyterian showed that combination treatment with Taxotere and estra-mustine (a nitrogen mustard derivative) resulted in improved survival for patients withadvanced prostate cancer. In the study, Taxotere was given weekly along with estra-mustine three times a day. At the time these results were presented, the median time tosurvival had not yet been reached and 77% of men were alive at one year versus 68% ina previous study.

The Southwest Oncology Group (SWOG) presented data in non-small-cell lung can-cer. In a phase II study, patients received cisplatin, radiation and Taxotere. The patientsin the Taxotere arm had progression-free survival of 13 months, with a median sur-vival time of 20 months. These results are superior to an earlier SWOG trial in whichconcurrent cisplatin, radiotherapy and etoposide resulted in median survival of only 15months. Importantly, the two-year survival rates were 47% and 34% for the two stud-ies, respectively.


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Pipeline

Flavopiridol

This compound is currently in phase IIa. Aventis expects to launch this product during2003. Flavopiridol has three mechanisms of action. First, it inhibits cyclin-dependentkinase, which effectively inhibits the cell’s ability to reproduce. Second, it inhibitsblood vessel formation within tumors. Lastly, it induces caspase-3 activation and celldeath. Aventis plans to apply for first-line indications and the company believes thatflavopiridol may have utility in multi-drug resistant tumors. The compound seems tobe effective regardless of the patient’s prior treatment history and does not appear tohave any overlapping toxicity with other chemotherapeutic agents.

Exhibit 70: Flavoperidol Patient Data

Flavopiridol Patient Response by Tumor SiteNumber of Patients Response Tumor Metastatic Sites Duration (months)

1 CR Adenocarcinoma(esophageal)

Primary, Mediastinal 13.6

1 PR Adenocarcinoma(gastro-esophageal

junction)

Lymph nodes 7

3 MR Adenocarcinoma(esophageal)

Lung, nodes 2, 2+, 4.5

1 SD Adenocarcinoma(esophageal)

Liver 2.8+

9 SD Neuroendocrine Lymph nodes 9.24 SD Prostate Bone 1.9, 2.1, 2.6, 7.23 SD Pancreas Liver 2.0, 2.1, 6.33 SD Sarcoma Lung 3.2, 3.9, 6.7

Source: Aventis R&D Day, May 2000.

Aventis has also shown data from a phase II dose escalation trial in patients withchronic lymphocytic leukemia (CLL), which was summarized at the company’s R&Dday. Flavopiridol caused shrinkage in lymph node size without causing any dose-related toxicity. In dose-ranging studies presented at ASCO, the dose-limiting toxicitieswere nausea and vomiting, neutropenia and diarrhea.

p53 Gene Therapy

Introgen, in collaboration with Aventis, is developing cancer gene therapies. Its leadproduct, INGN 201, combines the p53 gene with a gene delivery system the companyhas developed. The gene delivery system uses a modified adenovirus, a common coldvirus, to deliver the p53 gene to cancer cells. The companies have commenced phase IIItrials in head and neck cancers. Phase II trials are ongoing in non-small-cell lung cancer.

Ten of the first 16 patients with inoperable non-small-cell lung cancer (NSCLC) whoreceived Introgen’s adenoviral p53 gene therapy were alive at the end of one year. Intotal, five of 17 patients who were too ill to receive chemotherapy had greater-than-50% regression of their total disease after three months, and had a negative biopsywithout evidence of tumor progression at any site, after receiving intratumorial injec-tions of p53 with radiation therapy in phase II. The most common side effects werecardiac arrhythmia and nausea.


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Bayer AG

Drug Data

Viadur (Leuprolide Implant)

Viadur is a version of leuprolide used in the treatment of prostate cancer. Viadur,which was developed by Alza, uses Alza’s patented DUROS implant technology. Theleuprolide is encased in a miniature titanium implant. This product provides a con-venient alternative to the injectable versions of leuprolide. Viadur is placed under theskin delivering a continuous 12-month suppression of testosterone. (Please see Alzacompany section for a more detailed clinical summary.)

Pipeline

Bayer has four other development programs in its cancer portfolio: a camptothecinglycoconjugate in phase 1, a taxane analogue (preclinical), an IL-2 inhibitor and a RAFkinase inhibitor.

The next-generation taxane (IDN 5109) was in-licensed from Indena. Preclinical datahave shown that it has potential efficacy in taxane-resistant tumors and potential effi-cacy in patients with brain metastases and can be delivered orally.

Bristol-Myers Squibb

Investment Summary

Number one marketer in the world for cancer products, patent expiration hurts nearterm, but one of the deepest oncology pipelines in the industry should benefit thecompany longer term. In 1999, Bristol marketed nearly 25% of the world’s oncologyproducts. The company is recognized by physicians worldwide as a premier force inthis market. However, over the past several months, investors have focused on the U.S.patent expiry of Bristol’s flagship chemotherapeutic agent, Taxol. We have accountedfor this in our U.S. revenue assumptions for Taxol. Importantly, we believe the Taxolmarket will continue to grow, albeit at a slower pace, down from 20% to the doubledigits and then to the mid-single digits in the out years. At the time of the patentexpiry, we lowered our U.S. revenue estimate by taking half of the market share awayfrom Bristol by 2001, which would mean a loss of $350 million (see the followingexhibit).

Exhibit 71: UBS Warburg LLC Assumptions of Generic Taxol Impact

2000 2001 2002Total Taxol Market $1,050 $1,150 $1,250Market Growth 12% 10% 9%RevisedTaxol Revenue $1,009 $784 $638Implied lost revenue $41 $366 $612



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Importantly, we believe that Bristol has an oncology pipeline sound enough to com-pensate for the lost opportunities with Taxol, although the products will not hit untillate 2002 at the earliest. Near-term components of growth in oncology are few, namelyOrzel and Oncology Therapeutic Network (OTN). However, Bristol has several early-stage compounds that hold considerable promise, such as Epothilone (a compoundwith a similar mechanism of action to Taxol), BMS-275291 (a matrix metallopro-teinase inhibitor), and the next-generation taxanes. None of these products are cur-rently in our revenue model, but it is important to note that some of these productsdon’t necessarily have to have a prolonged clinical development cycle and could pro-ceed rapidly to the market. Consequently, if the clinical data play out, there could besignificant upside.

Exhibit 72: Bristol-Myers Cancer Portfolio

Bristol-Myers Cancer Portfolio Worldwide Sales Forecast(dollars in millions)

2000 2001 2002 2003 2004Taxol 1,605 1,475 1,400 1,425 1,450Paraplatin 647 660 680 680 690VepeSid 78 84 86 88 90Platinol 99 155 160 160 160Orzel 20 100 175 275 400OTN 1,055 1,225 1,400 1,575 1,750GMK Vaccine - - - 60 100Other 311 360 370 400 430

Total Oncology 3,865 4,059 4,271 4,663 5,070Growth 5% 5% 9% 9%Total Pharmaceuticals 14,346 14,834 15,656 16,683 17,765Oncology as % of Pharma Sales 27% 27% 27% 28% 29%


Drug Data

Paraplatin (Carboplatin)/Platinol (Cisplatin)

Bristol’s oncology platform is composed of several agents, including two platinum-based agents, the second-generation Paraplatin and its predecessor, Platinol. Bothagents continue to be widely used. However, both Bristol and physicians are switchingover to Paraplatin because of its milder side-effect profile. Nephrotoxicity, ototoxicity,neurotoxicity, and dose-limiting nausea and vomiting are lessened with Paraplatin.Additionally, Platinol has gone generic. Paraplatin and Platinol have similar spectrumsof activity. The following pie charts highlight Paraplatin’s use in both first- and second-line chemotherapy. Paraplatin’s major dose-limiting toxicity is myelosuppression.


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Exhibit 73: Paraplatin Use

1st Line Paraplatin UsePERITONEAL

1%BREAST1%

COLORECTAL1%ENDOMETRIAL

1%

ESOPHAGEAL2%

H&N2%

BLADDER2%

OTHER9%

OVARIAN11%

SCLC15%

NSCLC55%

2nd Line Paraplatin Use COLORECTAL1%

ENDOMETRIAL1%

BREAST4%

ESOPHAGEAL4%

BLADDER5%

H&N5%

OTHER8%

OVARIAN16%

SCLC11%

NSCLC45%

Source: iKnowMed.


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Currently, Paraplatin is only indicated for first- and second-line treatment of ovariancancer. However, several clinical studies have shown that Paraplatin has activity in lungcancers, squamous-cell cancers of the head and neck, gastrointestinal cancer andtesticular cancer.

Taxol

Currently, the company’s flagship chemotherapeutic agent is Taxol (paclitaxel). Taxolis the prototype of the taxanes. It was originally derived from the bark of the Pacific orWestern yew tree, which was rare. However, semisynthetic production of Taxol can bedone using the needles and twigs of the Himalayan yew, a much more abundant andrenewable source. In 1995, the FDA approved the production of semisynthetic Taxol.

Taxol is currently indicated for first-line treatment of ovarian cancer in combinationwith cisplatin, ovarian cancer that has spread beyond the ovaries (metastasized) and isnot responsive to other types of chemotherapy drugs, breast cancer that has spread tothe lymph nodes (node positive) following surgery and doxorubicin-containing che-motherapy, and non-small-cell lung cancer. It is also indicated as a second-line treat-ment of AIDS-related Kaposi’s sarcoma. Taxol is one of the most widely studied andwidely prescribed cancer therapies in the history of the industry.

Exhibit 74: Various Uses of Taxol

Taxol Use

0

200

400

600

800

1000

NS

CL

BR

EA

ST

OV

AR

IAN

OT

HE

R

H&

N

SC

L

BLA

DD

ER GI

EN

DO

ME

TR

IAL

PR

OS

TA

TE

Disease

Num

bers

ofP

atie

nts

ADJ 2nd LINE

Source: iKnowMed.


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Even though Taxol is widely used, there are some impediments to the success of thetherapy in all cancers. First, many cancers become resistant to Taxol, due to multi-drug-resistance-associated proteins, which effectively pump the drug out of the cellbefore it has any effect. Second, because it is not soluble in water, Taxol must be ad-ministered with the lung surfactant Chremophor, which sometimes causes severe hy-persensitivity reactions.

During July, the FDA approved a more convenient dosing regimen for Taxol in ad-vanced ovarian cancer. Patients will now be able to take the drug in an outpatient set-ting, using a higher dose for a shorter, three-hour infusion. This approval was based onresults from a multinational phase III trial in 600 women with stage IIb-IV ovariancancer. In the study, women received Taxol, given in a three-hour infusion every threeweeks in combination with cisplatin. This regimen significantly improved survivalcompared with the standard therapy of cyclophosphamide and cisplatin. Taxol hadbeen previously approved for use in advanced ovarian cancer, but was given in a 24-hour infusion every three weeks.

This past March, Bristol-Myers lost a patent dispute with IVAX, a generic drug maker.On September 15, IVAX received approval of its generic from the FDA. After severalmonths of legal jockeying, it appears as though IVAX will be able to launch its genericversion of paclitaxel sometime in late 2000. IVAX has 180 days of market exclusivityfor its version, after which other generic versions will be able to enter the market.

On September 20, Bristol and Roche announced a European clinical research partner-ship. The alliance is designed to facilitate the development of clinical trials involvingTaxol and Roche/Genentech’s Herceptin. The companies will attempt to elucidate howTaxol and Herceptin work together. The collaboration will cover breast cancer as wellas other solid tumors where scientific evidence of the combination suggests there maybe efficacy.

Pipeline

BMS-275291

This is Bristol’s matrix metalloproteinase inhibitor (MMPI) that was in-licensed fromCelltech (formerly Chiroscience). Matrix metalloproteinases (MMPs) are enzymes thatdegrade proteins of the extracellular matrix, thus facilitating tumor growth, metastasesand neovascularization. BMS-275291 is an oral MMP inhibitor that has been shown toinhibit a broad range of MMPs and to reduce tumor growth rates in preclinical studies.Theoretically, Bristol may have the one MMP that makes it through to the market,after disappointments from Bayer and British Biotech. BMS-275291 is a potent in-hibitor of MMPs, but it does not inhibit the group of related enzymes known as shed-dases. It is the inhibition of the sheddases that apparently leads to the dose-limitingarthralgia that we have seen in the trials of other MMPs. Consequently, one could con-ceivably deliver higher doses of the Bristol drug without encountering the dose-limiting side effects seen in other drugs in this arena. The following two exhibits indi-cate this compound’s selectivity for MMP inhibition while having a minimal impact onsheddase inhibition. (Note: IC

50 refers to the concentration of a drug needed to inhibit

50% of the activity of a target molecule.)


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Exhibit 75: Profiles of Various Matrix Metalloproteinase Inhibitors

MMP Selectivity ProfileIC 50 Values (nanomolar)

Compound MMP1 MMP8 MMP13 MMP7 MMP3 MMP2 MMP9 MMP14BMS-275291 9 10 4 23 157 41 25 40Marimastat 2 4 2 2 36 9 7 14AG3340 N/D 2 0.2 60 30 2 4 8


Exhibit 76: Profiles of Various Matrix Metalloproteinase Inhibitors

Sheddase Selectivity ProfileIC 50 Values (micromolar)

Compound TNF-alpharelease

TNF-alpha RIIsheddin g

L-SelectinSheddin g

IL1-RIIsheddin g

IL-6Rsheddin g

BMS-275291 >100 >100 >100 >100 >100Marimastat 4 6 1 3.4 3.6AG3340 1.6 14 0.8 1.8 12


This compound is currently in phase II/III for advanced or metastatic non-small-celllung cancer (NSCLC). Currently, a non-U.S. trial is enrolling patients with stage IIIb orIV NSCLC. Patients will be randomized to one of two arms. In the active arm, patientswill receive Bristol’s Taxol and Paraplatin in addition to receiving oral BMS-275291 fora 21-day cycle. Patients in the control arm will receive Taxol and Paraplatin plus anoral placebo. A total of 700 patients (60 for phase II and 640 for phase III) will beaccrued over two years.

Epothilone (BMS-247550)

Epothilones were discovered approximately 15 years ago when German scientists werelooking at soil bacteria. The epothilones were extracted from a bacterium found insouthern Africa named Sorangium cellulosum. S. cellulosum produces four differentversions of the epothilone, A-D. All four stabilize microtubules in the same manner asTaxol, but they are also effective against Taxol-resistant tumors and are water-soluble.BMS-247550, an oral semi-synthetic analog of epothilone B, has demonstrated signifi-cant improvement over Taxol in several critical aspects. It is active against human can-cer models that are naturally insensitive to or have developed resistance to Taxol, bothin cell culture systems in vitro and in human tumor xenografts grown in nude mice.This compound has the ability to overcome all major forms of Taxol-resistance mecha-nisms, including the 170 kD P-glycoprotein-mediated multidrug resistance andtubulin mutation. Furthermore, it exhibits a very broad spectrum of antitumor activityagainst Taxol-sensitive ovarian and colorectal cancers, as well as Taxol-resistant ovar-ian and colorectal cancers. Apparently, BMS-247550 can be combined with several an-tineoplastic agents and has demonstrated therapeutically significant interaction in vitro.


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Farnesyltransferase Inhibitor (BMS-214662)

This compound is in early-stage development as both an oral and an IV anticanceragent. Specifically, it blocks growth signals from the ras oncogene and induces pro-grammed cell death. As stated previously, ras oncogenes are found in a high percentageof pancreatic, lung and colon cancers.

GMK Vaccine

This vaccine is designed to stimulate the body’s immune system to control or eliminateresidual cancer cells after the tumor has been resected. GMK incorporates the GM2ganglioside, which is a cancer antigen found in about 95% of melanoma cells. Bristol isin a collaboration with Progenics Pharmaceuticals for the development of this vaccinein addition to an MGV vaccine. On May 26, Progenics announced that the EasternCooperative Oncology Group (ECOG) concluded their participation in the phase IIIclinical trial for the GMK melanoma vaccine. At that time, the trial was roughly half-way enrolled. ECOG stated that the interim analysis indicated that the relapse-free andoverall survival rates for patients receiving the vaccine were lower than for patients re-ceiving high-dose alpha interferon. As expected, GMK had a much better side-effectprofile. Progenics plans to continue the trial under the assumption that the follow-upperiod had been too brief. Currently, 880 patients are enrolled in the trial. The earlyresults versus alpha interferon were anticipated, considering that GMK requires thebody to build up an immune response to the vaccine. Consequently, the vaccine showsits clinical benefit much later than standard therapies. At the next interim analysis,Bristol will ultimately decide whether to keep this product and its follow-on MGV vac-cine or give the two products back to Progenics.

Orzel (UFT)

This is Bristol’s new antimetabolite. This drug is an oral formulation of UFT capsulesand leucovorin. UFT, which Bristol in-licensed from Japan’s Taiho Pharmaceuticals in1995, combines the 5-FU prodrug tegafur with uracil. Uracil is an enzyme inhibitorthat increases the half-life of 5-FU. On March 17, Bristol withdrew its NDA for thedrug after receiving a favorable review from an FDA advisory committee. On April 20,the company resubmitted its NDA, apparently to allow the FDA time to review addi-tional analyses, particularly on the role of uracil in the combination and proof that it isnot inferior to 5-FU. If approved, this product could have significant promise as one oftwo potential oral antimetabolite therapies (Roche’s Xeloda is the other). The productwas recently approved in Spain, which will serve as the reference member state for themutual recognition process in the European Union.

Next-Generation Taxanes

Bristol has two compounds that can be considered next-generation Taxols. These mole-cules appear to work in animal models where Taxol and Aventis’s Taxotere do not,perhaps including gastrointestinal tumors, yet they have a better side-effect profile. Thefirst is BMS 184476, which is currently in phase II and is administered over only twohours. The second compound, BMS 188797, trails BMS 184476 by several months, butis administered by short infusion (more than one hour), and requires no premedi-cation. BMS 188797 is similar to BMS 184476 biologically but different chemically.


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At ASCO in 1999, results from a phase I pharmacokinetic study of BMS-188797 wereshown. In the trial, the drug was administered as a one-hour infusion every 21 days. Atotal of 28 patients were enrolled into seven dosage tiers. The nonhematologic toxici-ties at the lower dosage tiers were minor, with only grade 2 or lower toxicities (e.g.,neutropenia, fever, diarrhea, nausea, myalgia, arthralgia and edema) observed. Nota-bly, several pretreated patients experienced grade 3 or 4 hematologic toxicity; however,none were of sufficient duration to be considered a dose-limiting toxicity (DLT).

The pharmacokinetic profile of BMS-18797 was similar to that of Taxol, and the prod-uct appears to have a 27-hour half-life. But importantly, in this trial, no routine pre-medication was administered and no hypersensitivity reactions were reported. How-ever, this formulation did contain Cremophor to make it more water soluble, but thatonly makes the lack of hypersensitivity reactions all the more interesting.

Eli Lilly

Investment Summary

This is not currently a critical franchise for the company, but it is one area of

consistent high-double-digit growth. Its importance to Lilly will likely increase

over time. In 1999, Lilly ranked seventh in the world as a marketer of cancer therapieswith 7.5% of the market. Currently, the company’s franchise revolves around Gemzar,which we expect to generate $555 million in worldwide revenue during 2000. However,Lilly has a handful of unique compounds in early-stage clinical development, such as amolecule to overcome multi-drug resistance. If the clinical data on compounds such asthis come through, Lilly’s position in the cancer market could change dramatically.

Exhibit 77: Eli Lilly’s Cancer Portfolio

Eli Lilly Cancer Portfolio Worldwide Sales Forecast(dollars in millions)

2000 2001 2002 2003 2004Gemzar 555 650 750 850 950Alimta (MTA) - 25 75 150 200Other 31 30 30 30 30

Total Oncology 586 705 855 1,030 1,18020% 21% 20% 15%

Total Pharmaceuticals 10,267 10,960 11,665 13,240 14,055Oncology as % of Pharma Sales 6% 6% 7% 8% 8%


Drug Data

Gemzar (Gemcitabine)

Gemzar is an antimetabolic agent that is currently approved for the treatment of locallyadvanced or metastatic pancreatic cancer, as well as first-line treatment of inoperable,locally advanced or metastatic non-small-cell lung cancer in combination with cis-platin. Gemzar is currently the key member of Lilly’s oncology franchise. The productlaunched in 1995 with the pancreatic cancer indication and has since become oneof the largest revenue generators of any chemotherapy agent. The data in pancreaticcancer are quite convincing. In a study of Gemzar versus 5-FU in previously untreated


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patients, nearly one in five patients was alive at one year after starting therapy withGemzar, compared to one in 50 given 5-FU. The majority of patients had overall sur-vival of six months, which was approximately six weeks longer than the patients given5-FU. Similar results were seen in patients previously treated with 5-FU, although sur-vival times were slightly lower. Additionally, Gemzar is effective at relieving some ofthe symptoms associated with advanced pancreatic cancer.

Gemzar is one of the more widely studied agents and consequently receives a lot ofattention in off-label use as the following bar chart indicates.

Exhibit 78: Various Uses for Gemzar

Gemzar Use

0

50

100

150

200

250

300

NSCLC PANCREATIC OTHER BREAST BLADDER SCLC OVARIAN

Disease

Num

bers

ofP

atie

nts

ADJ 2nd LINE

Source: iKnowMed.

In 1998, Gemzar received a supplemental indication for the treatment of non-small-cell lung cancer (NSCLC) in combination with cisplatin. In the phase III trials thatsupported this indication, 522 previously untreated patients were randomized to re-ceive Gemzar-cisplatin or cisplatin alone. The patients who received Gemzar-cisplatinshowed a statistically significant one-year survival rate of 39% versus 28% in the con-trol arm. The median survival rate was nine months in the Gemzar arm versus 7.6months in the control arm. The median time to disease progression in the Gemzargroup was 5.2 months, compared to 3.7 in the cisplatin group. There was no differencebetween the two groups in terms of their duration of response to either regimen.

Another study that supported the NSCLC indication looked at Gemzar plus cisplatinversus cisplatin plus etoposide. The Gemzar-cisplatin group showed a statistically sig-nificantly higher tumor response rate compared with the cisplatin-etoposide group, 33%versus 14%, respectively. Median time to disease progression was significantly longerfor Gemzar-cisplatin patients compared with cisplatin-etoposide patients, 5.0 monthsversus 4.1 months. Median survival was 8.7 months for patients treated with Gemzar-cisplatin, compared with 7.0 months for patients treated with cisplatin-etoposide.


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Pipeline

Alimta (Premetrexed Disodium)

Alimta, formerly known as MTA or multi-target antifolate, is currently in phase III formesothelioma and in phase II for non-small-cell lung cancer and metastatic breast can-cer. This compound is the furthest along in development of any in Lilly’s oncologypipeline. It has a similar mechanism of action to 5-FU/leucovorin and methotrexate,but also has the added benefit of being able to inhibit glycinamide ribotideformyltransferase (GARFT), a key enzyme for de novo purine synthesis. Purines arenecessary components of DNA and RNA; consequently, Alimta theoretically has threemechanisms of inhibiting cellular division.

Lilly is currently looking at Alimta’s utility in combination with other chemotherapeu-tic agents. Notably, a combination of Gemzar and Alimta may be effective in cancers ofthe breast, lung and pancreas. Lilly plans on filing Alimta with the FDA for mesotheli-oma by the end of 2001.

Exhibit 79: Phase II Experience of ALIMTA

ALIMTA Phase II Experience in Breast CancerAnthracycline

RefractoryAnthracycline

FailureEvaluable Patients 28 44# of complete responses 1 3# of partial responses 4 7Overall response rate (%) 18 23Median survival 7 16Time to disease progression (months) 2.4 4.6Median duration of response (months) 5.3 6.2

Source: Eli Lilly analyst presentation.

Arzoxifene (LY353381)

Arzoxifene is Lilly’s selective estrogen receptor modulator (SERM) that is in phase IIfor metastatic breast cancer. Lilly is currently enrolling patients with newly diagnosedadvanced breast cancer into a phase II trial. The compound appears to compare fa-vorably to tamoxifen in advanced breast cancer. In the phase II trials that have alreadybeen completed, the adverse side effects appear to be minimal and manageable. Theincidence of breast pain and endometrial hyperplasia was only 2% and there was noincidence of vaginal bleeding.

MDR (LY335979)P-Glycoprotein Multidrug Resistance Inhibitor

As was stated earlier in this report, one of the main reasons chemotherapy fails is dueto the P-glycoprotein pump. P-glycoprotein resides in the cell’s membrane and recog-nizes a broad spectrum of anticancer drugs, many of which are naturally occurringsubstances. P-glycoprotein pumps the drugs to the extracellular space, so that an effec-tive concentration at the intracellular target is never achieved. There are only a fewdrugs that are not affected by P-glycoprotein, such as the alkylating agents, theplatinum-containing agents and the antimetabolites.


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Lilly’s compound is currently in late phase I trials and appears to be a potent, specificantagonist of the P-glycoprotein pump. Lilly is developing both IV and oral formula-tions. Importantly, this compound does not appear to change the pharmacokinetics ofthe chemotherapeutic agent being used. Conceivably, the use of Lilly’s drug couldenable physicians to lower the doses of the chemotherapy drug, because the resistancehurdle would be minimal. Consequently, the overall tolerability of the regimen wouldincrease.

Genentech

Drug Data

Herceptin (Trastuzumab)

Herceptin is the first humanized monoclonal antibody approved for the treatment ofbreast cancer. Herceptin monotherapy is indicated for the treatment of patients withmetastatic breast cancer whose tumors overexpress the HER2 (human epidermalgrowth factor receptor2) protein and who have received one or more chemotherapyregimens for their metastatic disease. Additionally, Herceptin in combination withpaclitaxel is indicated for treatment of patients with metastatic breast cancer. In 25–30% of women with metastatic breast cancer, there is a genetic alteration in the HER2gene, which produces an increased amount of the growth factor receptor protein onthe tumor cell surface. This HER2 protein overexpression is associated with moreaggressive disease. The following table highlights Herceptin’s efficacy in the first-linetreatment of metastatic breast cancer. This trial was performed in 469 patients withmetastatic disease.

Exhibit 80: Herceptin Phase III Results

Phase III Clinical Efficacy in 1st Line TreatmentCombined Results Paclitaxel Subgroup AC Subgroup

Herceptin +Chemo Chemo

Herceptin +Paclitaxel Paclitaxel

Herceptin +AC AC

Number of patients 235 234 92 96 143 138Primary EndpointTime to Progression 7.2 4.5 6.7 2.5 7.6 5.7p-value <0.0001 <0.0001 0.002Secondary EndpointOverall Response Rate 45 29 38 15 50 38p-value <0.001 <0.001 0.1Percent Alive at 1-year 79 68 73 61 83 73p-value <0.01 0.08 0.04

Source: Herceptin package insert.

Notably, on May 3, Genentech issued a “dear health care provider” letter in the U.S.alerting doctors to reports of severe adverse events, including 15 deaths, associatedwith Herceptin, its monoclonal antibody for the treatment of metastatic breast cancer.Postmarketing surveillance has revealed 62 cases of severe side effects characterized byat least one of the following: hypersensitivity and infusion and/or pulmonary reactions.Accordingly, the label has been changed so that the boxed warning and other sectionsinclude details of the reactions, which have included anaphylaxis and adult respiratorydistress syndrome. Genentech estimates that 25,000 patients have received the drugworldwide since its launch in 1998 for use as second- or third-line therapy in advanced


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breast cancer in patients whose tumors overexpress the HER-2 growth factor receptor.The product is available in Canada and Switzerland and is awaiting approval in theEuropean Union for this indication.

To date, the hypersensitivity reaction has been very low and comparable to what is seenwith Rituxan. A year after Rituxan’s launch, severe side effects, including eight fatalcases of cytokine release syndrome, were reported, which led to strengthening thewarning on the label. But since non-Hodgkin’s lymphoma is an incurable disease withfew other treatment options, sales of the product were not adversely affected.

Herceptin’s status will likely depend on how the product fares in ongoing studies in theadjuvant setting. The potential for hypersensitivity reactions could ultimately deterpatients. Importantly, physicians and patients will need to weigh this risk against thefact that patients with tumors that overexpress the HER-2/neu receptor have a rela-tively poor prognosis. Additionally, these hypersensitivity concerns supplement therisks associated with Herceptin and cardiotoxicity. The package insert also contains ablack box warning regarding cardiomyopathy; the risk of heart problems is particularlyhigh in patients who also receive anthracyclines.

On September 20, Bristol-Myers and Roche announced a European clinical researchpartnership. The alliance is designed to facilitate the development of clinical trials in-volving Taxol and Roche/Genentech’s Herceptin. The companies will attempt to eluci-date how Bristol’s Taxol and Herceptin work together. The collaboration will coverbreast cancer as well as other solid tumors where scientific evidence of the combinationsuggests there may be efficacy.

Rituxan (Rituximab)

Genentech markets this product in the U.S. (Roche has rights outside of the U.S.) forIDEC Pharmaceuticals. Please see the IDEC subsection.

Pipeline

Anti-VEGF

Genentech has a phase III anti-vascular endothelial growth factor (anti-VEGF) com-pound. This is an antibody developed to inhibit angiogenesis in tumors. Phase III trialsare ongoing in patients with colorectal cancer. Genentech is currently preparing PhaseIII trials for non-small-cell lung cancer and metastatic breast cancer. Data that showedpromising results were presented at this spring’s American Society of ClinicalOncology (ASCO) meeting. However, there were safety concerns and four deaths asso-ciated with sudden bleeding. When added to standard chemotherapy (Paraplatin andTaxol) in non-small-cell metastatic lung cancer, the high-dose anti-VEGF arm had alonger time to disease progression than the control arm and the gold standard.

In the 35 patients randomized to the high-dose anti-VEGF (15 mg/kg), arm time toprogression was 7.5 months, compared with 4.4 months for 32 patients on the lowerdose (7.5 mg/kg) and 4.3 months for patients on chemotherapy alone. Median survivalin the high-dose arm was 18 months compared to 12 months in the low-dose armversus 14 months in the control arm.


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Additionally, phase II results from a trial in 104 untreated metastatic colorectal cancerpatients were presented. Patients were randomized to one of three arms, 5 mg of anti-VEGF antibody plus 5-FU/leucovorin, 10 mg of the anti-VEGF antibody plus 5-FU/leucovorin or the control arm of 5-FU and leucovorin. The low-dose anti-VEGFarm showed the best response rate of 40%, followed by the high-dose arm (24%) andthe control arm (17%). Time to disease progression was highest in the low-dose arm atnine months compared to 7.2 months and 5.2 months in the high-dose and controlarm, respectively. In this trial, the antibody was generally well tolerated except for a25% incidence of blood clots in the low-dose arm and an 11% incidence in the high-dose arm.

Additionally, Genentech has commenced phase III trials in colorectal cancer lookingat its monoclonal antibody to vascular endothelial growth factor (anti-VEGF) incombination with Camptosar. The trial will have three arms: anti-VEGF plus Camp-tosar and 5-FU/leucovorin, Camptosar plus 5-FU/leucovorin and anti-VEGF plus5-FU/leucovorin.

IDEC Pharmaceuticals

Drug Data

Rituxan (Rituximab)

Rituxan is a monoclonal antibody indicated for the treatment of patients with relapsedor refractory, low-grade or follicular, CD20-positive, B-cell non-Hodgkin’s lymphoma(NHL). At ASCO this past spring, a small, 20-patient study was presented looking atRituxan’s use in first-line treatment of low-grade, follicular, non-Hodgkin’s lym-phoma. The overall response rate was 50%. The results indicated that Rituxan usedprior to chemotherapy is feasible and the side effects and response rates are similar towhen Rituxan is used after chemotherapy. A phase III trial is currently under way toaddress this possible new indication. IDEC and its co-promotion partner, Genentech,have initiated a trial that compares the chemotherapy cocktail of cyclophosphamide,doxorubicin, vincristine and prednisone (CHOP) to Rituxan plus CHOP.

In October 1999, IDEC filed an supplemental Biologic License Application (sBLA) forRituxan in bulky non-Hodgkin’s lymphoma, for treatment and retreatment up to eighttimes. Genentech markets Rituxan in the U.S., while Roche markets Rituxan outsidethe U.S. and in Japan.

Zevalin

Zevalin is the anti-CD-20 mouse parent antibody of Rituxan. This therapy is a new wayof treating people with lymphoma who have already tried chemotherapy. Genericallyknown as ibritumomab tiuxetan, Zevalin is a monoclonal antibody with a chelatingagent that links the antibody to yttrium 90, a beta-emitting radioisotope. The subse-quent radioimmunoconjugate uses the antibody to deliver the radioisotope directly tothe lymphoma. Data from a study performed by the Mayo Clinic indicate that Zevalinin combination with Rituxan produces higher overall response rates than Rituxanalone. In a study of 143 patients with relapsed or refractory low-grade, non-Hodgkin’slymphoma, an interim analysis indicated that the overall response rate in the


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Zevalin/Rituxan arm was 80% compared to 44% in the Rituxan alone arm. Twenty-one percent of the patients in the combination arm had a complete response rateversus 7% in the Rituxan arm. A complete analysis of these data will be available at theAmerican Society of Hematology meeting in December.

Merck & Co.

Investment Summary

Although Merck has a few compounds in early clinical development, oncology doesn’tappear to be one of the areas of emphasis for Merck’s R&D program.

Drug Data

Vioxx (Rofecoxib)

Although Merck has not announced any clinical development for Vioxx in cancer, onecan infer from Pharmacia’s efforts with Celebrex that Merck may be investigating thispossible indication. Theoretically, there appear to be three ways in which the COX-2enzyme has a role in cancer. First, cells with high levels of COX-2 are less susceptible tocell death (or apoptosis). Second, when the COX-2 enzyme synthesizes prostaglandins,it releases free radicals as a by-product. Free radicals, such as oxygen ions, have beenshown to cause mutations in cells. Finally, COX-2 has been shown to promote theproduction of blood vessel formation in tumors. The initiation of blood flow is criticalfor a tumor to grow.

Pipeline

One interesting point is Merck’s discontinuation of its farnesyltransferase inhibitor(L-778,123) this past spring. In a small trial of 15 patients who took the Merck drug incombination with Bristol’s Taxol, significant dose-limiting toxicities were seen at thestarting dose and included neutropenia. It may be the case that this drug was not trulya specific inhibitor of farnesyltransferase.

Novartis

Drug Data

Aredia (Pamidronate)

Aredia is currently the gold standard for the treatment of hypercalcemia due to bonemetastases. This intravenous bisphosphonate was launched in 1991 and generated $491million in worldwide sales during 1999. Novartis plans to convert patients to its neweragent, Zometa, when it gets FDA approval (see below for more details).

Femara (Letrozole)

Femara is an oral, nonsteroidal aromatase inhibitor that was launched in 1997 for thetreatment of advanced breast cancer in postmenopausal women with disease progres-sion following antiestrogen therapy. Femara has been slowly gaining market share inthe oral breast cancer market and as of June had 3.6% of the total market. It competes


109

directly against branded and generic megestrol, which had 42.9% of the market as ofJune. Patients on Femara who were refractory to antiestrogen therapy display objectiveresponse rates of 23.8% versus 14.8% for women on megestrol. Femara significantlyreduces plasma estrogen levels.

On September 11, Novartis announced that Femara had been given a priority reviewby the FDA for use as a first-line treatment of advanced breast cancer.

Pipeline

Amdray (Valspodar)

Amdray is a derivative of cyclosporine that is nonimmunosuppressive and nontoxic tothe kidneys. It binds to P-glycoprotein with very high affinity. As stated previously, theP-glycoprotein pump is one of the main mechanisms of multi-drug resistance in tu-mors. Amdray is five to 30 times more potent than cyclosporine A in decreasing theefflux of chemotherapeutic agents from resistant cells. It will likely be available in IVand oral formulations.

Novartis is currently conducting phase III trials for the treatment of multi-drug-resistant ovarian cancer and acute myelogenous leukemia. The ovarian cancer trials arebeing conducted in combination with Bristol’s Taxol. The endpoint in this trial is timeto disease progression. The results are expected to be available by the third quarter of2001 with a filing in the same timeframe.

STI-571

Novartis has generated a good deal of attention with this product. STI-571 is a signaltransduction inhibitor and a breakthrough treatment of early-stage chronic myeloge-nous leukemia (CML). Approximately 90% of patients with CML have a diagnosticmarker, the Philadelphia chromosome (Ph1). This is characterized by chromosomenumber 22 missing a portion, which has been translocated to chromosome number 9.This results in the activation of a proto-oncogene known as c-abl. When the proto-oncogene c-abl is translocated from chromosome 9 to 22, a new oncogene, bcr-abl, isformed. This gene produces a protein that is associated with triggering growth factorreceptors. It is hypothesized that this gene may induce uncontrolled growth of leuke-mic cells. However, not everyone with the diagnostic marker develops CML. Interest-ingly, 96% of CML patients have been shown to have an abnormality of genetic mate-rial swapping between chromosome 9 and 22. Researchers have found that bcr-abl isalso activated in 20% of patient with acute lymphoblastic leukemia (ALL). STI-571 is avery specific inhibitor of abl-kinase.

At ASCO this past spring, data were presented from 33 acute leukemia patients, in-cluding 21 myeloid blast crisis CML patients and 12 Bcr-Abl positive ALL or lymphoidblast crisis CML patients. These individuals were give daily, oral, forms of the drug. Allbut seven patients had received at least one prior chemotherapy regimen for their acuteleukemia. There were four early deaths, two from disease progression prior to com-pleting one week of therapy and two from infections in heavily pretreated patients. Themedian duration of treatment when the study was presented was 68 days with a range


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of one to 182 days. Nineteen of 29 evaluable patients had responded to therapy, as de-fined by a decrease in the percentage of bone marrow blasts to 15% or less. Responseshad been observed in 55% of myeloid blast crisis patients with complete responses in22% of patients. However, all of the patients with lymphoid leukemias have relapsedon drug between 45 and 81 days. In terms of adverse events, of 19 responding patients,ten have experienced grade 3-4 neutropenia.

These data come on top of data presented at the December 1999 meeting of theAmerican Society of Hematologists (ASH). All 31 patients with early-stage CML whowere treated with the product had complete normalization of white blood cells andplatelet counts for up to eight months. Taken in their entirety, these results suggest thatSTI-571 works better in patients with myeloid leukemia compared to those withlymphoid leukemia. Novartis expects to file this product with the FDA sometimeduring 2001.

Zometa (Zoledronic Acid)

Zometa is an intravenous bisphosphonate for the treatment of hypercalcemia ofmalignancy (HCM), which is the most common life-threatening metabolic complica-tion associated with cancer. On September 22, Novartis announced that it had receivedan “approvable letter” from the FDA. The FDA withheld the full approval until itfinalizes its review of additional data, including serum creatinine data from Novartis’songoing trials for the treatment of bone metastases. Elevated serum creatinine levelsare indicative of changes in kidney function.

The FDA is basing its decision on data derived from two identical pivotal studies com-paring the drug with Novartis’s Aredia (pamidronate), which is the current treatmentstandard. The combined results showed that by day 10 of treatment, a statistically sig-nificantly higher percentage of patients responded to Zometa at 4 mg (88.4%) versuspamidronate at 90 mg (70%) in reducing serum calcium levels to the normal range.The FDA has given Zometa a priority review.

Hypercalcemia of malignancy affects more than 10% of all cancer patients, generallylate in the course of the disease. It is characterized by elevated serum calcium levels,with symptoms of nausea, vomiting and confusion. It occurs most often in cases ofbreast cancer, multiple myeloma and non-small-cell lung cancer. It may also occur inhead and neck cancer, lymphoma, leukemia, kidney cancer and gastrointestinal cancer.

Novartis plans to convert patients on Aredia to Zometa. Additionally, phase III trialsare currently under way evaluating Zometa’s effectiveness in treating bone metastasesand preventing their complications.


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Pfizer

Investment Summary

Pfizer’s drug development platform in oncology is in its infancy. The Agouron pipelineacquired as part of the Warner-Lambert merger helps, but it remains to be seen ifPfizer will be able to achieve a meaningful presence in this potentially lucrative market.

Drug Data

Celebrex (Celecoxib)

A full description of Celebrex’s role in cancer exists in the Pharmacia subsection below.

Pipeline

Prinomastat (AG3340)

Prinomastat is Pfizer’s matrix metalloproteinase inhibitor (MMPI). Prinomastat is anorally active, synthetic molecule designed to potently and selectively inhibit certainmembers of a family of enzymes known as matrix metalloproteinases (MMPs) that arebelieved to be involved in tumor angiogenesis, invasion and metastasis. On August 4,Pfizer announced that preliminary results of phase III trials in advanced hormone re-fractory prostate cancer and advanced non-small-cell lung cancer (NSCLC) had failedto meet their primary endpoints. However, patients with earlier-stage NSCLC who hadbeen recruited into another trial will continue to be studied. Pfizer is planning to lookat prinomastat in other tumor types and in earlier-stage disease. Six phase II trials arecurrently under way. The most common side effects of prinomastat have been ob-served in the joints, and include joint stiffness, joint swelling, and in a few patients,some limits on the mobility of certain joints, most often in the shoulders and hands.All of these effects were reversible and were managed effectively by treatment rests anddose reductions.


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Pharmacia Corp.

Investment Summary

“The New Oncology Challenger”; Camptosar Remains a Key Growth Driver

Pharmacia has recently dubbed itself “The New Oncology Challenger” and the foun-dation of Pharmacia’s oncology portfolio rests on Camptosar (irinotecan). In 1999, thecompany ranked fifth in the world for oncology products with 5.6% of the market. Theacquisition of Sugen in the spring of 1999 has allowed Pharmacia to accelerate its can-cer development platform—specifically, the development of its kinase platform, ofwhich the angiogenesis signaling inhibitor SU-5416 is the lead candidate.

Exhibit 81: Pharmacia Cancer Portfolio

Pharmacia Cancer Portfolio Worldwide Sales Forecast(dollars in millions)

2000 2001 2002 2003 2004Camptosar 436 515 585 670 730Ellence/Pharmorubicin 206 220 230 240 250Leridistim - - 50 100 200Aromasin 5 60 90 120 150SU5416 - 5 15 25 35

Total Oncology 647 800 970 1,155 1,365Growth 24% 21% 19% 18%Total Pharmaceuticals 10,711 11,965 13,070 14,010 15,195Oncology as % of Pharma Sales 6% 7% 7% 8% 9%


Drug Data

Aromasin

Pharmacia’s aromatase inactivator, Aromasin (exemestane), is approved for the treat-ment of advanced breast cancer in postmenopausal women whose disease has pro-gressed following tamoxifen therapy. Pharmacia launched this product in January.Aromasin is the first approved oral aromatase inactivator. This past May, data werepresented at ASCO that compared the activity and safety of Aromasin 25 mg/day withtamoxifen 20 mg/day as first-line hormonal therapy in postmenopausal women withadvanced breast cancer. Of 97 randomized patients, data were available on 63 for re-sponse and 76 for toxicity. In the study, the median time to tumor progression in pa-tients treated with Aromasin was 8.9 months compared with 5.2 months in patientstreated with tamoxifen. Women treated with Aromasin experienced the following sideeffects in comparison to those treated with tamoxifen: grade 2/3 fatigue (5% versus13%), pain (11% versus 18%), hot flashes (3% versus 15%), sweating (0 versus 10%),edema (3% versus 8%), nausea (3% versus 8%) and dyspnea (11% versus 5%). Therewas no difference between patients treated with Aromasin and patients treated withtamoxifen in the incidence of weight gain. We currently have relatively modest esti-mates for Aromasin revenue; however, if head-to-head data on Aromasin versus tam-oxifen continue to roll out in favor of the drug, our estimates could prove conservative.


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Camptosar (Irinotecan)

Exhibit 82: Camptosar Use

Camptosar Adjuvant Versus 2nd Line Use

2nd LINE92%

ADJ8%

Source: iKnowMed.

Exhibit 83: Various Uses of Camptosar

Various Uses of Camptosar

COLORECTAL2nd LINE

86%

COLORECTAL-ADJ8%

OTHER-2nd LINE5% OTHER-ADJ

1%

Source: iKnowMed.

Note: These data are from November 1999; consequently, they may underrepresent the trends in Camptosar use that arecurrently occurring.


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This past May at the annual American Society of Oncologists (ASCO) meeting, it be-came apparent that Camptosar is quickly becoming the “gold standard” for colorectalcancer, one of the more prevalent forms of cancer. The American Cancer Society esti-mates that approximately 130,200 new cases of colorectal cancer will be diagnosed in2000. Up until this past spring, Camptosar’s only approved indication was for second-line therapy of colorectal cancer. However, on April 20, the FDA gave approval forCamptosar’s use as a first-line therapy in combination with 5-FU and leucovorin. TheFDA based its approval on two clinical trials in which patients with metastatic diseasewere infused with Camptosar in addition to the standard treatment of 5-FU and leuco-vorin. These studies indicated that patients in the Camptosar arm had median survivalprolonged by approximately three months. Pharmacia said that it expects a 60% in-crease in patients using Camptosar as a result of this new indication. That level ofgrowth may be accelerated by the enormous interest displayed at the ASCO meeting,where a meta-analysis of data from the FDA registration trial was presented. Whenresearchers looked at subgroup analyses of the entire patient pool, they noticed thatresponse rates and median time to disease progression improved in every subgroup.Consequently, clinicians believe that all patients with metastatic colorectal cancerwould benefit from receiving Camptosar as a first-line therapy.

Pharmacia has also commenced adjuvant studies with Camptosar, 5-FU and leuco-vorin with three major clinical trials. Some clinicians have postulated that this type ofaggressive initial therapy may potentially have a curative effect. Additionally,Camptosar appears to be active in other cancers as well. Data were presented at ASCOfrom a phase II study using a combination of Camptosar and Lilly’s Gemzar in thetreatment of pancreatic cancer. The results showed a 20% response rate, which is dou-ble the response rate seen in Gemzar alone. Importantly, there was no increase in tox-icity; phase III international trials are enrolling now. Interestingly, Genentech hascommenced phase III trials in colorectal cancer looking at its monoclonal antibody tovascular endothelial growth factor (anti-VEGF) in combination with Camptosar. Thetrial will have three arms: anti-VEGF plus Camptosar and 5-FU/leucovorin, Camptosarplus 5-FU/leucovorin and anti-VEGF plus 5-FU/leucovorin.

Additionally, a Japanese phase III study using Camptosar in combination with cisplatinshowed increased survival compared with the current standard treatment for patientswith extensive small-cell lung cancer of etoposide plus cisplatin. A total of 154 patientswere enrolled, with the primary endpoint being survival. In the Camptosar arm, 58.4%of patients lived one year or longer compared with 37.7% of patients receiving standardtreatment. At two years, the survival benefit was 18.9% in the Camptosar arm versus6.5% in the control arm. The study was stopped at a pre-planned interim analysis pointdue to the survival benefit. The overall response rate in the Camptosar arm was 83.1%with 2.7% complete responders and 80.5% partial responders. The overall response ratesin the control arm were 67.5% (58.4% partial responders and 9.1% complete responders).In this trial, the side-effect profile favored the patients taking Camptosar. Pharmaciaplans to file for the non-small-cell lung cancer indication during 2002. Apparently,Pharmacia is investigating an oral formulation. At this past May’s ASCO, a phase I studyin pediatric patients with solid tumors was shown. It was a small trial in 17 patients, soit is difficult to extrapolate the significance. However, the compound was only 10%bioavailable, which is slightly disappointing. We currently have a worldwide revenueforecast for Camptosar of $490 million for 2001, growing to $730 million by 2004.


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Celebrex (Celecoxib)

Theoretically, there appear to be three ways in which the COX-2 enzyme has a rolein cancer. First, cells with high levels of COX-2 are less susceptible to cell death (orapoptosis). Second, when the COX-2 enzyme synthesizes prostaglandins, it releasesfree radicals as a by-product. Free radicals, such as oxygen ions, have been shown tocause mutations in cells. Finally, COX-2 has been shown to promote the production ofblood vessel formation in tumors. The initiation of blood flow is critical for a tumorto grow.

On December 23, 1999, the FDA granted approval for Celebrex for a reduction in thenumber of polyps in patients with familial adenomatous polypsis (FAP), as an adjunctto surgery. Approximately 40,000 patients in the U.S. are affected by FAP; conse-quently, the market opportunity in this specific population is not large. This past year,the National Cancer Institute (NCI), in collaboration with Pharmacia and Pfizer, initi-ated a phase III study looking at Celebrex’s role in preventing the occurrence of newsporadic adenomatous polyps in the colon. This trial is currently known as theAdenoma Prevention with Celecoxib (APC) trial. The trial will recruit more than 1,000patients over the age of 40 at centers across the United States. Patients will be requiredto have had at least one colorectal adenomatous polyp removed within the past threemonths and cannot have any history of FAP or hereditary nonpolyposis colorectal can-cer. Patients will be randomized to receive either Celebrex or a placebo twice a day forthree years and will be evaluated for adenomatous colorectal polyps at one and threeyears. Additionally, Pharmacia researchers have also shown that the COX-2 gene isoveractive in skin cancer and breast cancer as well.

Ellence (Epirubicin)

Ellence is an anthracycline chemotherapeutic agent. On September 15, 1999, the FDAapproved Ellence as a component of adjuvant therapy following resection of earlybreast cancer that has spread to the axillary lymph nodes. Notably, in June, prior to theapproval, an FDA advisory committee unanimously recommended approval of Ellencefor the aforementioned indication. However, the committee voted against a broaderindication in patients with locally advanced or metastatic breast cancer, due to ques-tions regarding overall survival data.

The FDA based its approval of Ellence on two, randomized, open-label multicenterstudies involving 1,281 women. The first trial in 716 women compared the combina-tion of Ellence, cyclophosphamide and 5-FU to cyclophosphamide, methotrexate and5-FU. The Ellence arm showed significantly longer five-year relapse-free survival withan overall reduction in risk of death of 29%. The second study enrolled 565 patients onEllence (low dose), cyclophosphamide and 5-FU to Ellence (high dose), cyclophos-phamide and 5-FU. The high-dose arm had a significantly longer five-year survival rate(65% versus 52%) and overall survival rate (76% versus 65%). The overall reduction inthe risk of relapse was 32% and the relative reduction in the risk of death was 31%.Adverse effects of Ellence therapy include severe local tissue necrosis, myocardial tox-icity, secondary acute myelogenous leukemia and myelosuppression.


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Trelstar (Triptorelin)

Although not a significant driver to the franchise, Trelstar is one of the newer additionsto Pharmacia’s cancer portfolio. On June 15, Pharmacia received FDA approval ofTrelstar for palliative treatment of advanced prostate cancer in patients for whom or-chiectomy or estrogen administration is not indicated or not acceptable. Trelstar isadministered as an injection given once a month. The data for approval indicated thatfollowing a single IM injection of Trelstar to healthy male volunteers, serum testoster-one levels first increased, peaking on day 4, and declined thereafter to low levels byweek 4. Similar testosterone profiles were observed in patients with advanced prostatecancer, when injected with Trelstar Depot. In healthy volunteers, testosterone serumlevels returned to near baseline by week 8. Trelstar Depot was studied in a randomized,active control trial of 277 men, ages 47 to 89, with advanced prostate cancer. Patientswere given either Trelstar or an approved GnRH agonist monthly for nine months. Theprimary efficacy results were both achievement of medical castration by day 29 andmaintenance of castration from day 57 through day 253. Castration levels of serumtestosterone were achieved in 91.2% of Trelstar patients at day 29 and 97.7% of pa-tients at day 57.

Pipeline

Leridistim

Another potential cancer product is leridistim, which is a blood cell growth factor be-ing developed to help stimulate white blood cells in cancer patients receiving chemo-therapy. We expect a filing with the FDA in late 2000 or early 2001. This product willlikely compete with Amgen’s Neupogen. We have yet to see any data on leridistim;consequently, our revenue assumptions remain conservative. Importantly, Pharmaciaannounced on May 1 that leridistim had failed in a pediatric study.

SU-5416

SU-5416 is the lead candidate from Sugen’s platform. It is a synthetic, small-molecule,angiogenesis-signaling inhibitor. At ASCO, several preliminary trials were presentedfor SU-5416 indicating that when the drug is given to patients with untreated, ad-vanced colorectal cancer, the drug may extend the time patients remain free of tumorgrowth and spread. One study evaluated 28 patients with untreated advanced colorec-tal cancer receiving increasing doses of SU-5416 intravenously twice each week, withstandard doses of 5-FU and leucovorin. Twelve patients achieved a complete or partialremission. Patients remained free of tumor growth and spread for an average of ap-proximately nine months, compared with standard chemotherapy, which delays theprogression for about six months. Seven percent of the patients showed no response.The drug appears to be well tolerated when combined with 5-FU and leucovorin.There is currently an ongoing phase II/III study that will enroll 710 patients in NorthAmerica and Europe comparing 5-FU/leucovorin with 5-FU/leucovorin in combina-tion with SU-5416. The study will be large enough to detect changes in survival, re-sponse rates, time to progression and quality of life.


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Pharmacia is also conducting a pilot study of SU-5416 in combination withCamptosar, 5-FU and leucovorin, for the treatment of metastatic colorectal cancer.The pharmaceutical company is also researching oral forms of SU-5416. We have rela-tively conservative estimates for SU-5416 with worldwide revenue of $35 million in2004.

Roche

Drug Data

Herceptin (see Genentech)

Xeloda (Capecitabine)

In August 1998, Roche launched Xeloda for the treatment of metastatic breast cancer.According to IMS Health, the product had U.S. sales of $42 million in 1999. Xeloda isan oral pro-drug of 5-FU. It is ingested in a relatively inactive form and absorbed read-ily in the intestinal tract. It is metabolized in the liver to 5-DFCR. Cytidine deaminase,an enzyme found in most tissues, including tumors, subsequently converts 5-DFCR to5-DFUR. The enzyme, thymidine phosphorylase, then hydrolyzes 5-DFUR to theactive drug 5-FU. Many tissues throughout the body express thymidine phosphorylase.Some human carcinomas express this enzyme in higher concentrations than sur-rounding normal tissues. Although it is only currently approved in breast cancer, manystudies are ongoing in the cancers where 5-FU has shown good activity. Roche sub-mitted an NDA for the first-line treatment of colorectal cancer on September 20, 1999.On September 25, 2000, the company received an “approvable” letter from the FDA.

Exhibit 84: Various Uses of Xeloda

Xeloda Use

0

5

10

15

20

25

30

BREAST COLORECTAL PANCREATIC LIVER RENAL GASTRIC

Disease

Num

bers

ofP

atie

nts

ADJ 2nd LINE

Source: iKnowMed.


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At the 1999 ASCO, phase II trials of Xeloda in taxane-refractory metastatic breast can-cer results were shown. An overall response rate of 25% was seen in Xeloda patients,with a median duration of response of 8.3 months and a median survival time of 12.3months. Roche is conducting phase III trials, which will compare Xeloda and Aventis’sTaxotere in combination versus Taxotere monotherapy in advanced and/or metastaticbreast cancer. The primary endpoint in this trial will be superiority in time to progres-sion. In a phase III colorectal cancer study involving 1,200 patients, Xeloda showed agreater overall response rate (shrinking tumors by at least 50%) in 21% of patients,compared with 11% of patients given 5-FU/leucovorin (the Mayo regimen). Xelodaalso showed similar time to progression and survival when compared to the Mayoregimen. Xeloda’s safety profile differs from that of the Mayo regimen, as it was associ-ated with fewer grade 3/4-related stomatitis and neutropenia, but had a higher inci-dence of grade 3 hand-foot syndrome. In the trial, Xeloda had a lower hospitalizationrate due to drug-related adverse events and fewer concomitant medications were re-quired to manage Xeloda patient side effects.

Schering-Plough

Investment Summary

Successful use of in-licensing has enabled Schering to have a presence in this market,but it has yet to reach critical mass.

Drug Data

Caelyx (Liposomal Doxorubicin)

Schering-Plough has successfully used in-licensing strategies to build its cancer portfo-lio. Currently, Schering has three marketed compounds and four compounds in devel-opment (two that were in-licensed). One marketed compound is Caelyx (brandeddomestically as Doxil), where Schering in-licensed international marketing rights fromSEQUUS Pharmaceuticals (now merged with Alza). Caelyx was recommended forEuropean Union approval in June to treat advanced ovarian cancer.

A large head-to-head trial comparing this liposomal formulation of doxorubicin(Doxil/Caelyx) with SB’s Hycamtin found minimal differences between the regimensfor treating patients with relapsed ovarian cancer. However, Doxil did slightly better inpatients with platinum-sensitive disease and it caused a much lower incidence ofhematological toxicity.

Both Doxil and Hycamtin are approved in the U.S. for second-line treatment of ovar-ian cancer. In the trial, 474 patients who had failed first-line platinum-based therapywere randomly assigned to Doxil once every four weeks as a one-hour infusion or a 30-minute IV infusion of Hycamtin for five days every three weeks. There was no signifi-cant difference between the two treatment arms for the median time to disease pro-gression, 18.4 weeks for Doxil and 18.3 weeks for Hycamtin. Additionally, there was nosignificant difference between objective response or median overall survival. However,there was a significant difference in the subset of patients with platinum-sensitive dis-ease. Patients in the Doxil arm showed a significantly better median overall survival of


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86.1 weeks versus 63.6 weeks in the Hycamtin arm (p=0.012). Regarding adverseevents, those in the Hycamtin arm experienced a high degree of hematological toxicitywith 81% of patients experiencing some level of neutropenia and 72% experiencingsome level of anemia. In the Doxil arm, 49% of patients experienced hand-foot syn-drome, also known as Palmar-plantar erythrodysesthesia (PPE), a tingly sensation inthe palms and soles, and 40% experienced stomatitis, soreness of the mouth. Impor-tantly, patients on Doxil do not need any stem cell support, whereas the patients onHycamtin do.

Regarding the interesting results in this trial subset, the trial was not designed to showthis difference and, consequently, the results were unexpected. The exact mechanismbehind this remains unclear. It is possible that Doxil is less likely to induce multi-drugresistance. Importantly, the point of the study was to show that there is no disadvan-tage to using Doxil before Hycamtin.

Currently, Schering is conducting a large trial in breast cancer, as is the EasternOncology Cooperative Group (ECOG). Other researchers are looking at Doxil’s role inbreast cancer therapy when combined with Genentech’s Herceptin. Alza is looking atDoxil in patients with multiple myeloma who have failed anthracycline therapy, and anNDA could be filed during the fall of 2000.

Intron A (Interferon-Alpha)

Intron A is Schering’s brand of interferon-alpha. This product launched in 1986 andapproximately 50% of its use is in cancer-related disorders. Interferons are naturalsubstances produced by the body in response to infection or disease. They were origi-nally discovered by their ability to prevent viral replication, but they are currentlyviewed as being good anti-cancer agents as well. Alpha-interferons are used to treatseveral diseases such as hepatitis and genital warts. They are also effective in treatinghairy cell leukemia, melanoma, non-Hodgkin’s lymphoma and AIDS-related Kaposi’ssarcoma. Currently, Intron-A’s cancer indications consist of hairy cell leukemia,malignant melanoma, follicular lymphoma, condylomata acuminata and AIDS-relatedKaposi’s sarcoma. Schering’s follow-on compound, Peg-Intron A, uses a new deliverytechnology that allows for less frequent dosing (once a week versus three times a week).The new formulation may allow for a reduction in the adverse events, but maintainequivalent efficacy.

Temodar (Temozolomide)

This product was in-licensed from Cancer Research Campaign Technology Ltd.Temodar is an oral therapy indicated for the treatment of adult patients with anaplasticastrocytoma (a form of brain cancer) at the first relapse with disease progression on anitrosourea- and procarbazine-containing drug regimen. It launched in the U.S. dur-ing August 1999. In a trial of 162 patients with anaplastic astrocytoma, a complete re-sponse was seen in 9% of the patients and a partial response was seen in 13% of thepatients. In this trial, a complete response was noted by tumor loss for two consecutivemonths. Tumor shrinkage was measured by gadolinium-enhanced magnetic resonanceand clinical improvement. A decrease of more than 50% in the tumor area for twoconsecutive months constitutes a partial response. The median duration for all


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responders was 50 weeks, with a range of 16 to 114 weeks, and the median duration forcomplete responders was 64 weeks, with a range of 52 to 114 weeks. Additionally, 45%of patients were progression free at six months. 74% of patients were alive at sixmonths and the overall median survival was 15.9 months. Sixty percent of patients inthis trial had undergone previous chemotherapy. The dose-limiting toxicity (DLT) wasmyelosuppression (reduction in blood counts). This usually occurred within the firstfew cycles of therapy, was not cumulative, and was resolved within 14 days. Notably, inphase III trials, treatment of patients with glioblastoma multiforme (another form ofbrain cancer) with Temodar did not show statistical significance.

Additionally, on March 23, 1999, the FDA advisory panel voted 10-1 not to recom-mend approval of Schering’s NDA for the treatment of melanoma. Temodar did notmeet the primary endpoints of superior overall survival in a 305-patient trial compar-ing Temodar to intravenous dacarbazine. The intent-to-treat analysis showed an in-creased survival of 1.4 months for patients on Temodar (7.7 versus 6.3), but these re-sults failed to be statistically significant. However, Temodar did show an increasedduration of response over the control arm, 5.5 months versus 3.2 months.

Pipeline

Farnesyltransferase Inhibitor (SCH66336)

This is Schering’s phase II farnesyltransferase inhibitor (FTI). At the American Societyof Clinical Oncology (ASCO) meeting this past spring, promising phase I results werepresented. This compound is orally bioavailable and inhibits growth of cells trans-formed by an activated h-ras oncogene and of human tumor cell lines expressing acti-vated k-ras proteins. Schering is currently looking at this compound in monotherapyas well as in combination with other agents, such as Lilly’s Gemzar. In the trials pre-sented at ASCO, 60% of patients exhibited objective responses.

Marimastat

In September 1999, in a reported $60 million dollar deal, Schering licensed worldwiderights (except for certain Far East territories) from British Biotech to several matrixmetalloproteinase inhibitors (MMPIs), including marimastat and BB-3644. Scheringwill assume European and U.S. regulatory filings. To date, marimastat has failed toshow any significant potential. In four phase III studies in patients with advanced can-cers, the drug failed to meet its primary endpoint. In January 2000, results were pre-sented in a pancreatic cancer trial looking at a combination of Lilly’s Gemzar and ma-rimastat. The study was conducted in 293 patients with the primary endpoint beingsurvival. Marimastat combined with Gemzar failed to show any significant statisticaldifferences from the Gemzar-alone group. Additionally, there was no statistical differ-ence in the secondary endpoints, safety or quality of life. The trial was powered so thata positive result would be a 15% improvement in the combination group, which mayhave been too ambitious a goal considering the aggressive nature of pancreatic cancer.Results showed that the survival curves were almost identical. Median survival was 164days in the control arm versus 165.5 days in the active arm. However, subset analysesdid reveal some interesting trends. In patients with earlier-stage disease (stages I andII), the median survival was 451 days in patients receiving the combination versus 250


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days in patients receiving Gemzar alone. But the results are not statistically significant,as only 30 patients were considered early stage.

Marimastat has failed to show statistical benefit in the treatment of glioblastoma andgastric cancer. Recently, the drug failed again. On September 26, British Biotechannounced the results of a trial in advanced ovarian cancer. Patients enrolled in thistrial had failed to respond to at least one prior treatment with Bristol’s Paraplatin. Inthe active arm of this trial, patients received Paraplatin in combination with marimas-tat. This combination showed no statistically significant advantage over Paraplatinalone in either primary or secondary endpoints. British Biotech believes that the drugstill has potential in earlier-stage cancers.

Notably, marimastat is associated with tendonitis, which could restrict its use in early-stage disease. British Biotech is hoping that this side effect may be eliminated with itsfollow-on compound BB-3644, which has not shown this tendency in animal models.The product is currently being tested in humans in a phase Ib trial. Phase II trials areexpected to start in mid-2001.

Melacine

This is a vaccine that Schering has in-licensed from Corixa (formerly RibiImmunoChem Research). Melacine consists of lysed cells from two human melanomacell lines combined with Corixa’s proprietary Detox adjuvant. Detox adjuvant includesMPL adjuvant (monophosphoryl lipid A) and mycobacterial cell wall. During February2000, phase III results of Melacine were reported. The study endpoint was a compari-son of disease-free survival in patients with Stage II melanoma who, following surgicalremoval of the patient’s primary tumor, received adjuvant immunotherapy with Mela-cine, versus no adjuvant therapy. Patients in the active arm received ten treatments ofMelacine over a 27-week cycle. This cycle was to be repeated three times. This trial wasthe largest study of a cancer vaccine completed to date. Patient accrual was completedin November 1999; the intent-to-treat population comprised 689 patients, who wererandomized. An analysis of the eligible patient population found no statistically signifi-cant difference in disease-free survival between the patients who received Melacineversus those who did not. However, the results of the intent-to-treat analysis on thetotal population indicated there was a statistically significant difference in disease-freesurvival between the patients treated with the Melacine vaccine (103/346 patients diedor relapsed) and patients randomized to the control arm (125/343 patients died orrelapsed) (p=0.04).

The product received approval in Canada during October 1999. On September 27,2000, Corixa announced its intention to file a biological license application (BLA). Thefiling will be based predominantly on the aforementioned data. The entire data poolwill comprise patients that began enrollment in April 1992. Corixa will submit data onthese patients through January 2001. The company plans to file the BLA during thesecond quarter of 2001 and a full 12-month review by the FDA.


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p53

Schering is currently in phase II and earlier studies with its p53 tumor suppressor genetherapy for treating various solid tumors. Schering has a number of agreements thatcontinue to advance this therapeutic platform. Currently, Schering has a collaborationwith Gene Logic, Inc. to help identify patients with a missing or defective p53 gene intumors.

SmithKline Beecham

Drug Data

Hycamtin (Topotecan)

Hycamtin is the company’s semisynthetic derivative of camptothecin, a topoisomeraseI inhibitor. It is more water-soluble than camptothecin, and unlike Pharmacia’sCamptosar, it is not a pro-drug; consequently, it is clinically active in the current form.Hycamtin is currently indicated for the second-line treatment of ovarian cancer andsmall cell lung cancer. In a refractory ovarian cancer trial, 454 patients who had failedone or two platinum-based regimens, had complete or partial response rates combinedranged between 13.3% and 20.5%. These response rates were equivalent to what wasseen with Bristol’s Taxol. However, Hycamtin does cause a higher incidence ofmyelosuppression and neutropenia. Furthermore, it appears as though response ratesdecline in patients who are truly refractory to platinum-based therapies.

In small cell lung cancer (SCLC), 211 patients were treated with either Hycamtin orcyclophosphamide, doxorubicin and vincristine (CAV). The overall response rate inthe Hycamtin arm was 24% compared with 18% in the CAV arm. The median time toprogression also favored Hycamtin at 13.3 weeks compared with 12.3 weeks. Mediansurvival was basically equivalent, at 25.0 weeks in the Hycamtin arm versus 24.7 weeksin the CAV arm.

On September 14, results from a phase II trial that combined Hycamtin with Bristol’sParaplatin in the first-line treatment of advanced non-small-cell lung cancer (NSCLC)were presented at the 9th World Congress on Lung Cancer in Tokyo. This was a non-comparative, multi-center study, which evaluated this combination in chemotherapy-naïve patients. Results from the trial indicate that combination treatment withHycamtin produced an overall response rate of 14% in evaluable patients, with 49% ofpatients achieving an arrest in tumor progression. Results were presented on 42 of 47patients. The median duration of response with this combination was 16 weeks, with amedian survival rate of 32.7 weeks. These results are similar to what was presented atASCO this past spring in a study of 1,594 patients comparing four first-line therapieswhere the median survival rate ranged from 31 to 36 weeks.


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SB continues to develop the Hycamtin franchise. The compound is in phase I trials forsecond-line colorectal cancer, phase I for the first-line indication in SCLC, phase II forfirst-line therapy of non-small-cell lung cancer, phase II for first-line therapy of ovar-ian cancer and phase III for myelodysplastic syndrome. Notably, the company is devel-oping an oral formulation, which is currently in phase III trials for second-line therapyof SCLC.

Pipeline

Bexxar

Bexxar is a monoclonal antibody that is conjugated to a radioisotope. It has completedphase III trials for non-Hodgkin’s lymphoma. Trials for Bexxar are ongoing, includinga phase II study for first or second relapsed indolent B-cell lymphomas, phase I for in-termediate and high-risk B-cell chronic lymphocytic leukemia and an open-labelexpanded-access study of Bexxar in chemotherapy-relapsed/refractory low-grade ortransformed low-grade non-Hodgkin’s lymphoma. In a phase II study presented atASCO in May, Bexxar achieved a 97% overall response rate and a 76% complete re-sponse rate when given to patients with advanced-stage, low-grade non-Hodgkin’slymphoma. Seventy-six patients had been enrolled in the study at the time the datawere presented and the median duration of response had not yet been reached. Nota-bly, at the time the data were presented, 68% of patients had survived for three yearswithout progression of their disease, but 62% of the patients developed human anti-mouse antibodies after therapy.

Coulter has co-developed Bexxar with SmithKline Beecham. Coulter submitted a bio-logic license application (BLA) for Bexxar for the second-line treatment of non-Hodgkin’s lymphoma on June 30, 1999. The company was granted a priority review,but received a “refusal to file” letter from the FDA on August 27. The FDA requestedthat Coulter reformat selected data and reorganize certain analyses. On September 18,SmithKline Beecham and Coulter announced that they had resubmitted the BLA to theFDA. On October 5, the companies announced that the FDA had granted the producta priority, or six-month, review. Coulter believes they could possibly launch Bexxarsometime next year.


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Cancer Terms


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Aabdomen: The part of the body thatcontains the pancreas, stomach, intes-tines, liver, gallbladder and other organs.

accelerated phase: Refers to chronicmyelogenous leukemia that is progress-ing. The number of immature, abnormalwhite blood cells in the bone marrowand blood is higher than in the chronicphase, but not as high as in the blastphase.

acetylcysteine: A drug usually used toreduce the thickness of mucus and easeits removal. It is also used to reverse thetoxicity of high doses of acetaminophen.Also called N-acetylcysteine.

acitretin: A drug used in cancer preven-tion that belongs to the family of drugscalled retinoids. It is also used in thetreatment of psoriasis.

acridine carboxamide: DACA. A sub-stance that is being studied as an anti-cancer drug. It belongs to the family ofdrugs called topoisomerase inhibitors.

actinic keratosis: A precancerous con-dition of thick, scaly patches of skin.Also called solar or senile keratosis.

acustimulation: Mild electrical stimula-tion of acupuncture points to controlsymptoms such as nausea and vomiting.

acute: Having the abrupt onset ofsymptoms and a short course; notchronic.

acute leukemia: Cancer of the blood-forming tissue (bone marrow) that pro-gresses rapidly.

acute lymphoblastic leukemia: ALL. Aquickly progressing disease in which toomany immature white blood cells, calledlymphoblasts, are found in the bloodand bone marrow. Also called acutelymphocytic leukemia.

acute lymphocytic leukemia: ALL. Aquickly progressing disease in which toomany immature white blood cells, calledlymphoblasts, are found in the bloodand bone marrow. Also called acutelymphoblastic leukemia.

acute myelogenous leukemia: AML. Aquickly progressing disease in which toomany immature blood-forming cells arefound in the blood and bone marrow.Also called acute myeloid leukemia oracute nonlymphocytic leukemia.

acute myeloid leukemia: AML. Aquickly progressing disease in which toomany immature blood-forming cells arefound in the blood and bone marrow.Also called acute myelogenous leukemiaor acute nonlymphocytic leukemia.

acute nonlymphocytic leukemia: Aquickly progressing disease in which toomany immature blood-forming cells arefound in the blood and bone marrow.Also called acute myeloid leukemia oracute myelogenous leukemia.

adenocarcinoma: Cancer that begins incells that line certain internal organs andthat have glandular (secretory) properties.

adenoid cystic cancer: A rare type ofcancer that usually begins in the salivaryglands.


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adenoma: A noncancerous tumor.

adenovirus: A group of viruses thatcause respiratory tract and eye infec-tions. Adenoviruses used in gene therapyare altered to carry a specific tumor-fighting gene.

adjuvant therapy: Treatment given afterthe primary treatment to make it workbetter. Adjuvant therapy may includechemotherapy, radiation therapy orhormone therapy.

adrenal glands: A pair of small glands,one located on top of each kidney. Theadrenal glands produce the hormonesepinephrine and norepinephrine thathelp control heart rate, blood pressure,the way the body uses food, and othervital functions.

adrenaline: A hormone. Also calledepinephrine.

Adverse effect: An unwanted side effectof treatment.

aflatoxins: Substances made by a fungusthat is often found on poorly storedgrains and nuts. Aflatoxins have beenimplicated as a factor in the etiology ofprimary liver cancer.

AFP: Alpha-fetoprotein. A protein nor-mally produced by a developing fetus.AFP levels are usually undetectable inthe blood of healthy nonpregnant adults.An elevated level of AFP suggests thepresence of either a primary liver canceror germ cell tumor.

aggressive: A quickly growing cancer.

aggressive lymphoma: A quickly grow-ing cancer that arises in the cells of thelymphatic system.

agonists: Drugs that trigger an actionfrom a cell or another drug.

agranulocyte: A type of white blood cell;monocytes and lymphocytes areagranulocytes.

alkylating agents: A family of anticancerdrugs that interfere with the cell’s DNAand inhibit cancer cell growth.

allogeneic: Taken from different indi-viduals of the same species.

allogeneic bone marrow transplanta-tion: A procedure in which a person re-ceives stem cells, the cells from which allblood cells develop, from a compatible,though not genetically identical, donor.

allopurinol: A drug that lowers high uricacid (a by-product of metabolism) levelsin the blood caused by some cancertreatments.

alpha-fetoprotein: AFP. A protein nor-mally produced by a developing fetus.AFP levels are usually undetectable inthe blood of healthy nonpregnant adults.An elevated level of AFP suggests thepresence of either a primary liver canceror germ cell tumor.

altretamine: An anticancer drug thatbelongs to the family of drugs called al-kylating agents.

alum: A type of immune adjuvant (asubstance used to help boost the im-mune response to a vaccine). Also calledaluminum sulfate.

alveoli: Tiny air sacs at the end of thebronchioles in the lungs.

amikacin: An antibiotic drug used totreat infection. It belongs to the family ofdrugs called aminoglycoside antibiotics.


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aminocamptothecin: An anticancerdrug that belongs to the family of drugscalled topoisomerase inhibitors.

aminoglutethimide: An anticancer drugthat belongs to the family of drugs callednonsteroidal aromatase inhibitors.Aminoglutethimide is used to decreaseestrogen production and to suppress thegrowth of tumors that need estrogen togrow.

aminolevulinic acid: A drug used inphotodynamic therapy that is absorbedby tumor cells; when exposed to light, itbecomes active and kills the cancer cells.

aminopterin: An anticancer drug thatbelongs to the family of drugs calledantimetabolites.

amphotericin B: An antifungal drugused to treat infection.

amsacrine: An anticancer drug that be-longs to the family of drugs called to-poisomerase inhibitors.

amylase: An enzyme that helps the bodydigest starches.

amyloidosis: A group of diseases inwhich protein is deposited in specificorgans (localized amyloidosis) orthroughout the body (systemic amyloi-dosis). Amyloidosis may be either pri-mary (with no known cause) or secon-dary (caused by another disease,including some types of cancer). Gener-ally, primary amyloidosis affects thenerves, skin, tongue, joints, heart andliver; secondary amyloidosis often affectsthe spleen, kidneys, liver and adrenalglands.

analgesics: Drugs that reduce pain.These drugs include aspirin, acetamino-phen and ibuprofen.

analog: In chemistry, a substance that issimilar, but not identical, to another.

anaplastic: A term used to describe can-cer cells that divide rapidly and bear littleor no resemblance to normal cells.

anastomosi: A procedure to connecthealthy sections of tubular structures inthe body after the diseased portion hasbeen surgically removed.

androgen suppression: Treatment tosuppress or block the production of malehormones. Androgen suppression isachieved by surgical removal of the testi-cles, by taking female sex hormones orby taking other drugs. Also called andro-gen ablation.

androgens: A family of hormones thatpromote the development and mainte-nance of male sex characteristics.

anemia: A condition in which the num-ber of red blood cells is below normal.

angiogenesis: Blood vessel formation.Tumor angiogenesis is the growth ofblood vessels from surrounding tissueinto a solid tumor. This is caused by therelease of a chemical by the tumor cells.

angiogenesis inhibitor: A substance thatmay prevent the formation of bloodvessels. In anticancer therapy, an angio-genesis inhibitor prevents the growth ofblood vessels from surrounding tissueinto a solid tumor.

angiosarcoma: A type of cancer that be-gins in the lining of blood vessels.

ansamycins: A group of anticancerdrugs that belong to the family of drugscalled antineoplastic antibiotics.


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anterior mediastinotomy: A procedurein which a tube is inserted into the chestto view the tissues and organs in the areabetween the lungs and between thebreastbone and spine. The tube is in-serted through an incision next to thebreastbone. This procedure is usuallyused to get a tissue sample from thelymph nodes on the left side of the chest.Also called the Chamberlain procedure.

anthracenediones: A subgroup of thefamily of anticancer drugs called anti-cancer antibiotics.

anthracycline: A member of a family ofanticancer drugs that are also antibiotics.

anthraquinones: A family of anticancerdrugs.

anti-CEA antibody: An antibody againstcarcinoembryonic antigen (CEA), aprotein present on certain types of can-cer cells.

anti-idiotype vaccine: A vaccine madeof antibodies that see other antibodies asthe antigen and bind to it. Anti-idiotypevaccines can stimulate the body to pro-duce antibodies against tumor cells.

antiandrogen therapy: Treatment withdrugs used to block production or in-terfere with the action of male sexhormones.

antiangiogenesis: Prevention of thegrowth of new blood vessels into a solidtumor.

antibiotic: A drug used to treat infec-tions caused by bacteria and othermicroorganisms.

antibody: A type of protein made bycertain white blood cells in response to aforeign substance (antigen). Eachantibody can bind only to a specific anti-

gen. The purpose of this binding is tohelp destroy the antigen. Antibodies canwork in several ways, depending on thenature of the antigen. Some antibodiesdestroy antigens directly. Others make iteasier for white blood cells to destroy theantigen.

antibody therapy: Treatment with anantibody, a substance that can directlykill specific tumor cells or stimulate theimmune system to kill tumor cells.

anticancer antibiotics: A group of anti-cancer drugs that block cell growth byinterfering with DNA, the genetic mate-rial in cells. Also called antitumor anti-biotics or antineoplastic antibiotics.

anticoagulants: Drugs that help preventblood clots from forming. Also calledblood thinners.

antiemetics: Drugs that prevent or re-duce nausea and vomiting.

antifungals: Drugs that treat infectionscaused by fungi.

antigen-presenting cell: APC. A cell thatshows antigen on its surface to othercells of the immune system. This is animportant part of an immune response.

antigen-presenting cell vaccine: A vac-cine made of antigens and antigen-presenting cells (APCs). Also called APCvaccine.

antigens: Substances that cause the im-mune system to make a specific immuneresponse.

antimetabolite: A chemical that is verysimilar to one required in a normal bio-chemical reaction in cells.Antimetabolites can stop or slow downthe reaction.


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antineoplastic antibiotics: A group ofanticancer drugs that block cell growthby interfering with DNA, the geneticmaterial in cells. Also called anticancerantibiotics or antitumor antibiotics.

APC vaccine: A vaccine made of anti-gens and antigen-presenting cells(APCs). Also called antigen-presentingcell vaccine.

aplastic anemia: A condition in whichthe bone marrow is unable to produceblood cells.

aplidine: An anticancer drug obtainedfrom a marine animal.

apoptosis: A normal series of events in acell that lead to its death.

arterial embolization: The blocking ofan artery by a clot of foreign material.This can be done as treatment to blockthe flow of blood to a tumor.

ascites: Abnormal buildup of fluid in theabdomen.

asparaginase: An anticancer drug that isan enzyme.

aspergillosis: An infectious fungal dis-ease that occurs most often in the skin,ears, nasal sinuses and lungs of personswith a suppressed immune system.

aspirate: Fluid withdrawn from a lump,often a cyst.

astrocytomas: Tumors that begin in thebrain or spinal cord in small, star-shapedcells called astrocytes.

asymptomatic: Having no signs orsymptoms of disease.

ataxic gait: Awkward, uncoordinatedwalking.

atypical hyperplasia: A benign (noncan-cerous) condition in which cells haveabnormal features and are increased innumber.

autologous: Taken from an individual’sown tissues, cells or DNA.

autologous bone marrow transplanta-tion: A procedure in which bone mar-row is removed from a person, storedand then given back to the person fol-lowing intensive treatment.

autologous lymphocytes: A person’swhite blood cells. Lymphocytes have anumber of roles in the immune system,including the production of antibodiesand other substances that fight infectionand disease.

autologous tumor cells: Cancer cellsfrom the person’s tumor.

axilla: The underarm or armpit.

axillary: Pertaining to the armpit.

axillary lymph node dissection: Surgeryto remove lymph nodes found in thearmpit region.

axillary lymph nodes: Lymph nodesfound in the armpit that drain the lymphchannels from the breast.

azacitidine: An anticancer drug that be-longs to the family of drugs calledantimetabolites.


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BB cells: White blood cells that makeantibodies and are an important part ofthe immune system. B cells come frombone marrow. Also called Blymphocytes.

B lymphocytes: White blood cells thatmake antibodies and are an importantpart of the immune system. B lympho-cytes come from bone marrow. Alsocalled B cells.

B3 antigen: A protein found on sometumor cells.

bacterial toxin: A toxic substance, madeby bacteria, that can be modified to killspecific tumor cells without harmingnormal cells.

Barrett’s esophagus: A condition inwhich the cells lining the lower part ofthe esophagus have changed or been re-placed with abnormal cells that couldlead to cancer of the esophagus. Thebacking up of stomach contents (reflux)may irritate the esophagus and over timecause Barrett’s esophagus.

basal cell carcinoma: A type of skin can-cer that arises from the basal cells, smallround cells found in the lower part, orbase, of the epidermis, the outer layer ofthe skin.

basal cells: Small, round cells found inthe lower part, or base, of the epidermis,the outer layer of the skin.

basophil: A type of white blood cell.Basophils are granulocytes.

BCG vaccine: An anticancer drug(Bacille Calmette-Guerin) that activatesthe immune system. Filling the bladder

with a solution of BCG is a form of bio-logical therapy for superficial bladdercancer.

benign: Not cancerous; does not invadenearby tissue or spread to other parts ofthe body.

benign prostatic hyperplasia: A benign(noncancerous) condition in which anovergrowth of prostate tissue pushesagainst the urethra and the bladder,blocking the flow of urine. Also calledbenign prostatic hypertrophy, or BPH.

benign tumor: A noncancerous growththat does not invade nearby tissue orspread to other parts of the body.

beta carotene: A vitamin A precursor.Beta carotene belongs to the family offat-soluble vitamins called carotenoids.

biafine cream: A topical preparation toreduce the risk of and treat skin reac-tions to radiation therapy.

bilateral: Affecting both the right andleft side of body.

bilateral cancer: Cancer that occurs inboth paired organs, such as both breastsor both ovaries.

bile: A fluid made by the liver and storedin the gallbladder. Bile is excreted intothe small intestine, where it helps digestfat.

bile duct: A tube through which bilepasses in and out of the liver.

biological response modifier: BRM. Asubstances that stimulates the body’sresponse to infection and disease.


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biological therapy: Treatment to stimu-late or restore the ability of the immunesystem to fight infection and disease.Also used to lessen side effects that maybe caused by some cancer treatments.Also called immunotherapy or biologicalresponse modifier (BRM) therapy.

biomarkers: Substances sometimesfound in an increased amount in theblood, other body fluids or tissues, andthat may suggest the presence of sometypes of cancer. Biomarkers include CA125 (ovarian cancer), CA 15-3 (breastcancer), CEA (ovarian, lung, breast, pan-creas and GI tract cancers), and PSA(prostate cancer). Also called tumormarkers.

biopsy: A procedure used to removecells or tissues in order to look at themunder a microscope to check for signs ofdisease. When an entire tumor or lesionis removed, the procedure is called anexcisional biopsy. When only a sample oftissue is removed, the procedure is calledan incisional biopsy or core biopsy.When a sample of tissue or fluid is re-moved with a needle, the procedure iscalled a needle biopsy or fine-needleaspiration.

bladder: The organ that stores urine.

blast crisis: The phase of chronic mye-logenous leukemia in which the numberof immature, abnormal white blood cellsin the bone marrow and blood is ex-tremely high. Also called blast phase.

blast phase: The phase of chronic mye-logenous leukemia in which the numberof immature, abnormal white blood cellsin the bone marrow and blood is ex-tremely high. Also called blast crisis.

blasts: Immature blood cells.

bleomycin: An anticancer drug that be-longs to the family of drugs called anti-tumor antibiotics.

blood transfusion: The administrationof blood or blood products into a bloodvessel.

blood-brain barrier: A network of bloodvessels with closely spaced cells thatmakes it difficult for potentially toxicsubstances (such as anticancer drugs) topenetrate the blood vessel walls and en-ter the brain.

bolus: A single dose of drug usually in-jected into a blood vessel over a shortperiod of time.

bolus infusion: A single dose of drugusually injected into a blood vessel over ashort period of time.

bone marrow: The soft, sponge-liketissue in the center of bones that pro-duces white blood cells, red blood cellsand platelets.

bone marrow ablation: The destructionof bone marrow using radiation ordrugs.

bone marrow aspiration: The removalof a small sample of bone marrow (usu-ally from the hip) through a needle forexamination under a microscope.

bone marrow biopsy: The removal of asample of tissue from the bone marrowwith a needle for examination under amicroscope.

bone marrow metastases: Cancer thathas spread from the original (primary)tumor to the bone marrow.


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bone metastases: Cancer that has spreadfrom the original (primary) tumor to thebone.

bone scan: A technique to create imagesof bones on a computer screen or onfilm. A small amount of radioactive ma-terial is injected into a blood vessel andtravels through the bloodstream. It col-lects in the bones and is detected by ascanner.

bowel: The long, tube-shaped organ inthe abdomen that completes the processof digestion. There is both a small and alarge bowel. Also called the intestine.

brachytherapy: Radioactive material,sealed in needles, seeds, wires or cathe-ters, is placed directly into or near thetumor. Also called internal radiationtherapy or implant radiation.

brain metastases: Cancer that hasspread from the original (primary)tumor to the brain stem. The part of thebrain that is connected to the spinalcord.

brain stem glioma: A tumor located inthe part of the brain that connects to thespinal cord (the brain stem). It maygrow rapidly or slowly, depending on thegrade of the tumor.

brain stem tumor: A tumor in the partof the brain that connects to the spinalcord (the brain stem).

BRCA1: A gene located on chromosome17 that normally helps to suppress cellgrowth. Inheriting an altered version ofBRCA1 predisposes an individual tobreast, ovarian or prostate cancer.

breast reconstruction: Surgery to re-build a breast’s shape after a mastectomy.

breast-conserving surgery: An opera-tion to remove the breast cancer but notthe breast itself. Types of breast-conserving surgery include lumpectomy(removal of the lump), quadrantectomy(removal of one quarter of the breast),and segmental mastectomy (removal ofthe cancer as well as some of the breasttissue around the tumor and the liningover the chest muscles below the tumor).

brief pain inventory: A questionnaireused to measure pain.

bronchi: The large air passages that leadfrom the trachea (windpipe) to thelungs.

bronchioles: The tiny branches of airtubes in the lungs.

bronchoscopy: A procedure in which athin, lighted tube is inserted through thenose or mouth. This allows examinationof the inside of the trachea and bronchi,air passages that lead to the lung, as wellas the lung itself. Bronchoscopy may beused to detect cancer or to perform sometreatment procedures.

bronchus: A large air passage that leadsfrom the trachea (windpipe) to the lung.

broxuridine: A drug that makes cancercells more sensitive to radiation and isalso used as a diagnostic agent to deter-mine how fast cancer cells grow.

bryostatin-1: A drug used for its anti-tumor activity.

buccal mucosa: The inner lining of thecheeks and lips.

Burkitt’s lymphoma: A type of non-Hodgkin’s lymphoma that most oftenoccurs in young people between the ages


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of 12 and 30. The disease usually causes arapidly growing tumor in the abdomen.

buserelin: An anticancer drug that be-longs to the family of drugs called gona-dotropin-releasing hormones. In pros-tate cancer therapy, buserelin blocks theproduction of testosterone in thetesticles.

busulfan: An anticancer drug that be-longs to the family of drugs called alkyl-ating agents.

buthionine sulfoximine: A drug thatmay help prevent resistance to someanticancer drugs.

bypass: A surgical procedure in whichthe doctor creates a new pathway for theflow of body fluids.


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Cc-erbB-2: The gene that controls cellgrowth by making the human epidermalgrowth factor receptor 2. Also calledHER2/neu.

CA-125: Substance sometimes found inan increased amount in the blood, otherbody fluids, or tissues and that may sug-gest the presence of some types ofcancer.

calcitonin: A hormone secreted by thethyroid that lowers blood calcium levels.

calcitriol: A vitamin D analogue (a drugmade in the laboratory that is chemicallysimilar to vitamin D).

calcium: A mineral found in teeth,bones and other body tissues.

camptothecin: An anticancer drug thatbelongs to the family of drugs calledtopoisomerase inhibitors.

camptothecin analogue: An anticancerdrug related in structure to camptothe-cin, a topoisomerase inhibitor. One suchdrug is aminocamptothecin.

cancer: A term for diseases in which ab-normal cells divide without control.Cancer cells can invade nearby tissuesand can spread through the bloodstreamand lymphatic system to other parts ofthe body.

cancer of unknown primary origin:Cancer cells are found in the body, butthe place where the cells first startedgrowing (the origin or primary site)cannot be found.

cancer vaccine: A vaccine designed toprevent or treat cancer.

capecitabine: An anticancer drug thatbelongs to the family of drugs calledantimetabolites.

capsaicin: A component of certainplants, including cayenne and red pep-per, used topically for peripheral nervepain. Also being studied for controllingmucositis pain following chemotherapyand radiation therapy.

carbendazim: An anticancer drug thatbelongs to the family of drugs called an-tifungal agents.

carboplatin: An anticancer drug thatbelongs to the family of drugs calledplatinum compounds.

carboxyamidotriazole: An anticancerdrug that belongs to the family of drugscalled angiogenesis inhibitors.

carboxypeptidase-G2: A bacterial en-zyme that belongs to the family of drugscalled chemoprotective agents. It is usedto neutralize the toxic effects ofmethotrexate.

carcinoembryonic antigen peptide-1:CAP-1. A protein that can stimulate animmune response to certain tumors.

carcinogen: Any substance that causescancer.

carcinogenesis: The process by whichnormal cells are transformed into cancercells.

carcinoma: Cancer that begins in theskin or in the tissues that line or coverinternal organs.


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carcinoma in situ: Cancer that involvesonly the cells in which it began and hasnot spread to neighboring tissues.

cardiac: Pertaining to the heart.

cardiopulmonary: Pertaining to theheart and lungs.

Carmustine: An anticancer drug thatbelongs to the family of drugs called al-kylating agents.

carotenoids: Substance found inyellow/orange fruits and vegetables anddark green leafy vegetables that may re-duce the risk of developing cancer.

carzelesin: An anticancer drug that be-longs to the family of drugs called alkyl-ating agents.

Castleman’s disease: A rare disorder inwhich noncancerous growths develop inlymph node tissue.

castration: Removal or destruction ofthe testicles or ovaries using radiation,surgery or drugs. Medical castration re-fers to the use of drugs to suppress thefunction of the ovaries or testicles.

CC-49 monoclonal antibody: A type ofmonoclonal antibody used in cancerdetection or therapy. Monoclonal anti-bodies are laboratory-produced sub-stances that can locate and bind to can-cer cells.

CD34 antigen: A protein found on thesurface of some bone marrow and bloodcells.

CEA: Carcinoembryonic antigen. Asubstance that is sometimes found in anincreased amount in the blood of peoplewith certain cancers.

CEA assay: A laboratory test to measurecarcinoembryonic antigen (CEA), asubstance that is sometimes found in anincreased amount in the blood of peoplewho have certain cancers.

celecoxib: A drug that reduces pain.Celecoxib belongs to the family of drugscalled nonsteroidal anti-inflammatoryagents. It is also being studied for cancerprevention.

cell: The individual unit that makes upall of the tissues of the body. All livingthings are made up of one or more cells.

cell differentiation: The process duringwhich young, immature (unspecialized)cells take on individual characteristicsand reach their mature (specialized)form and function.

cell proliferation: An increase in thenumber of cells as a result of cell growthand cell division.

cellular adhesion: The close adherence(bonding) to adjoining cell surfaces.

central nervous system: CNS. The brainand spinal cord.

central venous access catheter: A tubesurgically placed into a blood vessel forthe purpose of giving intravenous fluidand drugs. It also can be used to obtainblood samples. This device avoids theneed for separate needle insertions foreach infusion.

cerebellum: The portion of the brain inthe back of the head between the cere-brum and the brain stem. The cerebel-lum controls balance for walking andstanding, and other complex motorfunctions.


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cerebrospinal fluid: CSF. The fluidflowing around the brain and spinalcord. Cerebrospinal fluid is produced inthe ventricles in the brain.

cerebrum: The largest part of the brain.It is divided into two hemispheres, orhalves, called the cerebral hemispheres.The cerebrum controls muscle functionsof the body and also controls speech,emotions, reading, writing and learning.

cervical intraepithelial neoplasia: CIN.A general term for the growth of abnor-mal cells on the surface of the cervix.Numbers from 1 to 3 may be used todescribe how much of the cervix con-tains abnormal cells.

cervix: The lower, narrow end of theuterus that forms a canal between theuterus and the vagina.

chemoembolization: A procedure inwhich the blood supply to the tumor isblocked surgically or mechanically, andanticancer drugs are administered di-rectly into the tumor. This permits ahigher concentration of drug to be incontact with the tumor for a longer pe-riod of time.

chemoprevention: The use of drugs,vitamins or other agents to try to reducethe risk of or delay the development orrecurrence of cancer.

chemoprotective: A quality of somedrugs used in cancer treatment. Chemo-protective agents protect healthy tissuefrom the toxic effects of anticancerdrugs.

chemosensitivity assay: A laboratorytest to analyze the responsiveness of atumor to a specific drug.

chemosensitizer: A drug that makes tu-mor cells more sensitive to the effects ofchemotherapy.

chemotherapy: Treatment with antican-cer drugs.

chlorambucil: An anticancer drug thatbelongs to the family of drugs called al-kylating agents.

cholangiosarcoma: A tumor of the con-nective tissues of the bile ducts.

chondrosarcoma: A type of cancer thatforms in cartilage.

chordoma: A type of bone cancer thatusually starts in the lower spinal column.

choriocarcinoma: A rare cancer inwomen of child-bearing age in whichcancer cells grow in the tissues that areformed in the uterus following concep-tion. Also called gestational trophoblas-tic disease, gestational trophoblasticneoplasia, gestational trophoblastic tu-mor or molar pregnancy.

choroid plexus tumor: A rare type ofcancer that occurs in the ventricles of thebrain. It usually occurs in childrenyounger than two years old.

chromosome: Part of a cell that containsgenetic information. Except for spermand eggs, all human cells contain 46chromosomes.

chronic: A disease or condition thatpersists or progresses over a long periodof time.

chronic granulocytic leukemia: A slowlyprogressing disease in which too manywhite blood cells are made in the bonemarrow. Also called chronic myelogenousleukemia or chronic myeloid leukemia.


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chronic leukemia: Cancer of the blood-forming tissues that progresses slowly.

chronic lymphoblastic lymphoma: Aslowly progressing disease in which toomany immature white blood cells calledlymphoblasts are found in the body.

chronic lymphocytic leukemia: A slowlyprogressing disease in which too manywhite blood cells called lymphocytes arefound in the body.

chronic myelogenous leukemia: CML.A slowly progressing disease in whichtoo many white blood cells are made inthe bone marrow. Also called chronicmyeloid leukemia or chronic granulo-cytic leukemia.

chronic myeloid leukemia: CML. Aslowly progressing disease in which toomany white blood cells are made in thebone marrow. Also called chronic mye-logenous leukemia or chronic granulo-cytic leukemia.

chronic phase: Refers to the early stagesof chronic myelogenous leukemia orchronic lymphocytic leukemia. Thenumber of mature and immature, ab-normal white blood cells in the bonemarrow and blood is higher than nor-mal, but lower than in the accelerated orblast phase.

chronic phase chronic myelogenousleukemia: A phase of chronic myeloge-nous leukemia that may last from severalmonths to several years. Although theremay be no symptoms of leukemia, thereare too many white blood cells.

cidofovir: A drug used to treat infectioncaused by viruses.

cirrhosis: A type of chronic, progressiveliver disease.

cisplatin: An anticancer drug that be-longs to the family of drugs called plati-num compounds.

cladribine: An anticancer drug that be-longs to the family of drugs calledantimetabolites.

clinical resistance: The failure of a can-cer to shrink after treatment.

clinical trial: A research study that testshow well new medical treatments orother interventions work in people. Eachstudy is designed to test new methods ofscreening, prevention, diagnosis ortreatment of a disease.

clodronate: A drug used as treatment forhypercalcemia (abnormally high levels ofcalcium in the blood) and for cancer thathas spread to the bone (bone metasta-ses). It may decrease pain, the risk offractures, and the development of newbone metastases.

CMA-676: An anticancer drug used inthe treatment of acute myelogenousleukemia.

CNS: Central nervous system. The brainand spinal cord.

CNS metastases: Cancer that has spreadfrom the original (primary) tumor to thecentral nervous system.

CNS prophylaxis: Chemotherapy orradiation therapy given to the centralnervous system (CNS) as a preventivetreatment. It is given to kill cancer cellsthat may be in the brain and spinal cord,even though no cancer has been detectedthere.

CNS tumors: Tumors of the centralnervous system, including brain stemglioma, craniopharyngioma, medullo-blastoma and meningioma.


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coactivated T cells: T cells that havebeen coated with monoclonal antibodiesto enhance their ability to kill tumorcells.

colectomy: An operation to remove thecolon. An open colectomy is the removalof the colon through a surgical incisionmade in the wall of the abdomen. Lapa-roscopic-assisted colectomy uses a thin,lighted tube attached to a video camera.It allows the surgeon to remove the co-lon without a large incision.

colon: The long, coiled, tubelike organthat removes water from digested food.The remaining material, solid wastecalled stool, moves through the colon tothe rectum and leaves the body throughthe anus.

colonoscope: A thin, lighted tube used toexamine the inside of the colon.

colonoscopy: An examination of theinside of the colon using a thin, lightedtube (called a colonoscope) inserted intothe rectum. If abnormal areas are seen,tissue can be removed and examinedunder a microscope to determine if dis-ease is present.

colony-stimulating factors: Substancesthat stimulate the production of bloodcells. Colony-stimulating factors includegranulocyte colony-stimulating factors(also called G-CSF and filgrastim),granulocyte-macrophage colony-stimulating factors (also called GM-CSFand sargramostim), and promegapoietin.

colorectal: Having to do with the colonor the rectum.

colostomy: An opening into the colonfrom the outside of the body. A colos-tomy provides a new path for waste ma-

terial to leave the body after part of thecolon has been removed.

colposcopy: Examination of the vaginaand cervix using a lighted magnifyinginstrument called a colposcope.

combination chemotherapy: Treatmentusing more than one anticancer drug.

combretastatin A4 phosphate: An anti-cancer drug that reduces the blood sup-ply to tumors; it is a tubulin bindingagent.

common bile duct: Carries bile from theliver and gallbladder into the duodenum(the upper part of the small intestine).

complementary medicine: Practices notgenerally recognized by the medicalcommunity as standard or conventionalmedical approaches and used to enhanceor complement the standard treatments.Complementary medicine includes suchpractices as dietary supplements, mega-dose vitamins, herbal preparations, spe-cial teas, massage therapy, magnet ther-apy, spiritual healing and meditation.

complete remission: The disappearanceof all signs of cancer. Also called com-plete response.

complete response: The disappearanceof all signs of cancer. Also called com-plete remission.

computed tomography: A series of de-tailed pictures of areas inside the body;the pictures are created by a computerlinked to an X-ray machine. Also calledcomputed tomography (CT) scan orcomputed axial tomography (CAT) scan.

condylomata acuminata: Genital wartscaused by certain human papilloma vi-ruses (HPV).


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cone biopsy: Surgery to remove a cone-shaped piece of tissue from the cervixand cervical canal. Cone biopsy may beused to diagnose or treat a cervical con-dition. Also called conization.

congestive heart failure: Weakness ofthe heart muscle that leads to a buildupof fluid in body tissues.

conization: Surgery to remove a cone-shaped piece of tissue from the cervixand cervical canal. Conization may beused to diagnose or treat a cervical con-dition. Also called cone biopsy.

consolidation therapy: Chemotherapytreatments given after induction che-motherapy to further reduce the numberof cancer cells.

continent reservoir: A pouch formedfrom a piece of small intestine to holdurine after the bladder has beenremoved.

continuous hyperthermic peritonealperfusion: CHPP. A procedure thatbathes the abdominal cavity in fluid thatcontains anticancer drugs. This fluid iswarmer than body temperature and ap-pears to kill cancer cells without harmingnormal cells.

continuous infusion: The administra-tion of a fluid into a blood vessel, usuallyover a prolonged period.

conventional treatment: A currentlyaccepted and widely used treatment for acertain type of cancer, based on the re-sults of past research.

cooperative group: A group of physi-cians and/or hospitals formed to treat alarge number of persons in the same wayso that new treatment can be evaluatedquickly. Clinical trials of new cancer

treatments often require many morepeople than can be cared for by a singlephysician or hospital.

cordycepin: An anticancer drug thatbelongs to a family of drugs called anti-tumor antibiotics.

core biopsy: The removal of a tissuesample with a needle for examinationunder a microscope.

corpus: The body of the uterus.

corticosteroids: Hormones that haveantitumor activity in lymphomas andlymphoid leukemias; in addition, corti-costeroids (steroids) may be used forhormone replacement and for the man-agement of some of the complications ofcancer and its treatment.

craniopharyngioma: A benign braintumor that may be considered malignantbecause it can damage the hypothala-mus, the area of the brain that controlsbody temperature, hunger and thirst.

craniotomy: An operation in which anopening is made in the skull.

crisnatol mesylate: An anticancer drugthat interferes with the DNA in cancercells.

cryosurgery: Treatment performed withan instrument that freezes and destroysabnormal tissues. This procedure is aform of cryotherapy.

cryotherapy: Any method that uses coldtemperature to treat disease.

cryptorchidism: A condition in whichone or both testicles fail to move fromthe abdomen, where they develop beforebirth, into the scrotum. Cryptorchidismmay increase the risk for development of


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testicular cancer. Also called unde-scended testicles.

CSF: Cerebrospinal fluid. The fluidflowing around the brain and spinalcord. CSF is produced in the ventriclesof the brain.

CT scan: Computed tomography scan. Aseries of detailed pictures of areas insidethe body; the pictures are created by acomputer linked to an X-ray machine.Also called computed axial tomography(CAT) scan.

curettage: Removal of tissue with a cu-rette, a spoon-shaped instrument with asharp edge.

cutaneous: Related to the skin.

cutaneous T-cell lymphoma: A diseasein which certain cells of the lymph sys-tem (called T lymphocytes) become can-cerous (malignant) and affect the skin.

cyclophosphamide: An anticancer drugthat belongs to the family of drugs calledalkylating agents.

cyclosporine: A drug used to help re-duce the risk of rejection of organ andbone marrow transplants by the body. Itis also used in clinical trials to make can-cer cells more sensitive to anticancerdrugs.

cyproterone acetate: A drug used toblock the production of or interfere withthe action of male sex hormones.

cyst: A sac or capsule filled with fluid.

cystectomy: Surgery to remove thebladder.

cystoscope: A thin, lighted instrumentused to look inside the bladder and re-move tissue samples or small tumors.

cystoscopy: Examination of the bladderusing a thin, lighted instrument (called acystoscope) inserted into the urethra.Tissue samples can be removed and ex-amined under a microscope to deter-mine if disease is present.

cytarabine: An anticancer drug that be-longs to the family of drugs calledantimetabolites.

cytokines: A class of substances that areproduced by cells of the immune systemand that can affect the immune re-sponse. Cytokines can also be producedin the laboratory by recombinant DNAtechnology and given to people to affectimmune responses.

cytomegalovirus: A virus that may becarried in an inactive state for life byhealthy individuals. It is a cause of severepneumonia in people with a suppressedimmune system, such as those under-going bone marrow transplantation orpeople with leukemia or lymphoma.

cytopenia: A reduction in the number ofblood cells.

cytotoxic chemotherapy: Anticancerdrugs that kill cells, especially cancercells.

cytotoxic T cells: A type of white bloodcell that can directly destroy specificcells. T cells can be separated from otherblood cells, grown in the laboratory andthen given to a patient to destroy tumorcells. Certain cytokines can also be givento a patient to help form cytotoxic T cellsin the patient’s body.


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DDACA: Acridine carboxamide. A sub-stance that is being studied as an anti-cancer drug. It belongs to the family ofdrugs called topoisomerase inhibitors.

dacarbazine: An anticancer drug thatbelongs to the family of drugs called al-kylating agents.

daclizumab: A monoclonal antibodythat is being studied for treatment ofadult T-cell leukemia. Also called da-cliximab. Monoclonal antibodies arelaboratory-produced substances that canlocate and bind to cancer cells.

dactinomycin: An anticancer drug thatbelongs to the family of drugs called an-titumor antibiotics.

dalteparin: A drug that helps prevent theformation of blood clots; it belongs tothe family of drugs called anticoagulants.

danazol: A synthetic hormone that be-longs to the family of drugs called an-drogens and is used to treat endome-triosis. It is being evaluated in thetreatment of endometrial cancer.

daunorubicin: An anticancer drug thatbelongs to the family of drugs called an-titumor antibiotics.

decapeptyl: Belongs to the family ofdrugs called luteinizing hormone-releasing hormone agonists. Used toblock hormone production in ovarianablation.

decitabine: An anticancer drug that be-longs to the family of drugs calledantimetabolites.

deferoxamine: An iron chelating agentthat removes iron from tumors by in-hibiting DNA synthesis and causing can-cer cell death. It is used in conjunctionwith other anticancer agents in pediatricneuroblastoma therapy.

defibrotide: A drug under study for theprevention of veno-occlusive disease, arare complication of high-dose chemo-therapy and stem cell transplantation inwhich small veins in the liver becomeblocked.

dendritic cell: A special type of antigen-presenting cell (APC) that activates Tlymphocytes.

dendritic cell vaccine: A vaccine madeof antigens and dendritic antigen-presenting cells (APCs).

denileukin diftitox: A substance used inthe treatment of cutaneous T-cell lym-phoma that has not responded to previ-ous therapy.

deoxycytidine: A drug that protectshealthy tissues from the toxic effects ofanticancer drugs.

depsipeptide: Anticancer drugs obtainedfrom microorganisms.

dermatitis: Inflammation of the skin.

DES: Diethylstilbestrol. A synthetichormone that was prescribed from theearly 1940s until 1971 to help womenwith complications of pregnancy. DEShas been linked to an increased risk ofclear cell carcinoma of the vagina indaughters of women who had used DES.DES may also increase the risk of breastcancer in women who used DES.


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desmoid tumor: A tumor of the tissuethat surrounds muscles, usually in theabdomen. Desmoid tumors rarelymetastasize.

dexamethasone: A synthetic steroidsimilar to steroid hormones producednaturally in the adrenal gland. Dexa-methasone is used to treat leukemia andlymphoma and may be used to treatsome of the problems caused by othercancers and their treatment.

dexrazoxane: A drug used to protect theheart from the toxic effects of anthracy-cline drugs such as doxorubicin. It be-longs to the family of drugs calledchemoprotective agents.

di-dgA-RFB4 monoclonal antibody: Ananticancer drug that is a combination ofa monoclonal antibody (RFB4) and animmunotoxin (dgA).

diaphragm: The thin muscle below thelungs and heart that separates the chestfrom the abdomen.

diathermy: The use of heat to destroyabnormal cells. Also called cauterizationor electrodiathermy.

diaziquone: AZQ. An anticancer drugthat is able to cross the blood-brain bar-rier and kill cancer cells in the centralnervous system.

diethylstilbestrol (DES): A synthetichormone that was prescribed from theearly 1940s until 1971 to help womenwith complications of pregnancy. DEShas been linked to an increased risk ofclear cell carcinoma of the vagina indaughters of women who had used DES.DES may also increase the risk of breastcancer in women who used DES.

differentiation: In cancer, refers to howmature (developed) the cancer cells arein a tumor. Differentiated tumor cellsresemble normal cells and grow at aslower rate than undifferentiated tumorcells, which lack the structure and func-tion of normal cells and growuncontrollably.

diffusion magnetic resonance imaging:A noninvasive imaging technique that iscapable of detecting changes in bodytissues that are not clearly distinguishedby conventional magnetic resonance im-aging (MRI).

difluoromethylornithine: DFMO. Ananticancer drug that has been shown toreduce the risk of cancer in animals.

dihematoporphyrin ether: A drug usedin photodynamic therapy that is ab-sorbed by tumor cells; when exposed tolight, it becomes active and kills the can-cer cells.

dilation and curettage: D&C. A minoroperation in which the cervix is ex-panded enough (dilation) to permit thecervical canal and uterine lining to bescraped with a spoon-shaped instrumentcalled a curette (curettage).

dimesna: A drug that belongs to thefamily of drugs called chemoprotectiveagents.

dimethylxanthenone acetic acid: Ananticancer drug that belongs to the fam-ily of drugs called angiogenesisinhibitors.

dipyridamole: A drug that preventsblood cell clumping and enhances theeffectiveness of fluorouracil and otherchemotherapeutic agents.


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disease progression: Cancer that contin-ues to grow or spread.

distant cancer: Refers to cancer that hasspread from the original (primary) tu-mor to distant organs or distant lymphnodes.

disulfiram: A drug that slows the me-tabolism of retinoids, allowing them toact over a longer period of time.

diuretic: A drug that increases the pro-duction of urine.

DNA: Deoxyribonucleic acid. The mole-cules inside cells that carry genetic in-formation and pass it from one genera-tion to the next.

docetaxel: An anticancer drug that be-longs to the family of drugs called mi-totic inhibitors.

dose-rate: The strength of a treatmentgiven over a period of time.

double-blinded: A doubled-blinded trialis a clinical trial in which neither themedical staff nor the person knowswhich of several possible therapies theperson is receiving.

doxorubicin: An anticancer drug thatbelongs to the family of drugs called an-titumor antibiotics. It is an anthracycline.

doxycycline: An antibiotic drug used totreat infection.

DPPE: Belongs to a group of antihor-mone drugs.

dronabinol: A synthetic pill form ofdelta-9-tetrahydrocannabinol (THC), anactive ingredient in marijuana that isused to treat nausea and vomiting asso-ciated with cancer chemotherapy.

duct: A tube through which body fluidspass.

ductal carcinoma in situ: DCIS. Abnor-mal cells that involve only the lining of aduct. The cells have not spread outsidethe duct to other tissues in the breast.Also called intraductal carcinoma.

dumping syndrome: A group of symp-toms that occur when food or liquid en-ters the small intestine too rapidly. Thesesymptoms include cramps, nausea, diar-rhea and dizziness. Dumping syndromesometimes occurs in people who havehad a portion of their stomach removed.

duodenum: The first part of the smallintestine.

dysplasia: Cells that look abnormal un-der a microscope, but are not cancer.

dysplastic nevi: Atypical moles; moleswhose appearance is different from thatof common moles. Dysplastic nevi aregenerally larger than ordinary moles andhave irregular and indistinct borders.Often their color is not uniform, andranges from pink to dark brown; theyusually are flat, but parts may be raisedabove the skin surface.

dyspnea: Difficult, painful breathing, orshortness of breath.


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Eechocardiography: A procedure thatuses ultrasonic waves directed over thechest wall to obtain a graphic record ofthe heart’s position, and the motion ofthe walls, or internal parts such as thevalves.

edatrexate: An anticancer drug that be-longs to a family of drugs calledantimetabolites.

edema: Swelling caused by excess fluidin body tissues.

electroporation therapy: EPT. Treat-ment that generates electrical pulsesthrough an electrode placed in a tumorto enhance the ability of anticancerdrugs to enter tumor cells.

embolization: The blocking of an arteryby a clot or foreign material. Emboliza-tion can be done as treatment to blockthe flow of blood to a tumor.

encapsulated: Confined to a specific,localized area and surrounded by a thinlayer of tissue.

endocrine cancer: Cancer that occurs inendocrine tissue, the tissue in the bodythat secretes hormones.

endometrial disorder: Abnormal cellgrowth in the endometrium (the liningof the uterus).

endometriosis: A benign condition inwhich tissue that looks like endometrialtissue grows in abnormal places in theabdomen.

endometrium: The layer of tissue thatlines the uterus.

endoscopy: The use of a thin, lightedtube (called an endoscope) to examinethe inside of the body.

endostatin: A drug that is being studiedfor its ability to prevent the growth ofnew blood vessels into a solid tumor.Endostatin belongs to the family ofdrugs called angiogenesis inhibitors.

eniluracil: An anticancer drug that in-creases the effectiveness of fluorouracil.Also called ethynyluracil.

enoxaparin: A drug used to preventblood clots. It belongs to the family ofdrugs called anticoagulants.

enzyme: A protein that speeds upchemical reactions in the body.

ependymal tumors: A type of brain tu-mor that usually begins in the centralcanal of the spinal cord. Ependymomasmay also develop in the cells lining theventricles of the brain, which produceand store the special fluid (cerebrospinalfluid) that protects the brain and spinalcord. Also called ependymomas.

ependymomas: A type of brain tumorthat usually begins in the central canal ofthe spinal cord. Ependymomas may alsodevelop in the cells lining the ventriclesof the brain, which produce and storethe special fluid (cerebrospinal fluid)that protects the brain and spinal cord.Also called ependymal tumors.

epidermal growth factor receptor: Aprotein found on the surface of somebreast cancer cells that allows epidermalgrowth factor to stimulate cell growth.Also called HER2/neu or c-erb B-2.


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epidermoid carcinoma: A type of cancerin which the cells are flat and look likefish scales. Also called squamous cellcarcinoma.

epidural: The space between the wall ofthe spinal canal and the covering of thespinal cord. An epidural injection isgiven into this space.

epidural block: An injection of an anes-thetic drug given into the space betweenthe wall of the spinal canal and the cov-ering of the spinal cord.

epinephrine: A hormone and neuro-transmitter. Also called adrenaline.

epirubicin: An anticancer drug that be-longs to the family of drugs called anti-tumor antibiotics.

epithelial: Refers to the cells that line theinternal and external surfaces of thebody.

epithelial carcinoma: Cancer that beginsin the cells that line an organ.

epithelial ovarian cancer: Cancer thatoccurs in the cells lining the ovaries.

epithelium: A thin layer of tissue thatcovers organs, glands and other struc-tures within the body.

epoetin alfa: A colony-stimulating factorthat is made in the laboratory. It in-creases the production of red blood cells.

Epstein-Barr virus: EBV. A commonvirus that remains dormant in mostpeople. It has been associated with cer-tain cancers, including Burkitt’s lym-phoma, immunoblastic lymphoma andnasopharyngeal carcinoma.

erythrocytes: Cells that carry oxygen toall parts of the body. Also called redblood cells (RBCs).

erythroleukemia: Cancer of the blood-forming tissues in which large numbersof immature, abnormal red blood cellsare found in the blood and bonemarrow.

erythroplakia: A reddened patch with avelvety surface found in the mouth.

erythropoietin: A colony-stimulatingfactor, produced in the adult kidney,that stimulates the production of redblood cells.

esophageal: Related to the esophagus,the muscular tube through which foodpasses from the throat to the stomach.

estramustine: A combination of thehormone estradiol (an estrogen) andnitrogen mustard (an anticancer drug).Used in the palliative therapy of prostatecancer.

estrogen receptor: ER. Protein found onsome cancer cells to which estrogen willattach.

estrogen receptor negative: ER-. Breastcancer cells that do not have a protein(receptor molecule) to which estrogenwill attach. Breast cancer cells that areER- do not need the hormone estrogento grow and usually do not respond tohormone (antiestrogen) therapy thatblocks these receptor sites.

estrogen receptor positive: ER+. Breastcancer cells that have a protein (receptormolecule) to which estrogen will attach.Breast cancer cells that are ER+ need thehormone estrogen to grow and will usu-ally respond to hormone (antiestrogen)therapy that blocks these receptor sites.


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estrogen replacement therapy: ERT.Hormones (estrogen and/or progester-one) given to postmenopausal women,or women who have had their ovariessurgically removed. Hormones are givento replace the estrogen no longer pro-duced by the ovaries.

estrogens: A family of hormones thatpromote the development and mainte-nance of female sex characteristics.

ethynyluracil: An anticancer drug thatincreases the effectiveness of fluoroura-cil. Also called eniluracil.

etidronate: A drug that belongs to thefamily of drugs called bisphosphonates.Bisphosphonates are used as treatmentfor hypercalcemia (abnormally high lev-els of calcium in the blood) and for can-cer that has spread to the bone (bonemetastases).

etiology: The cause or origin of disease.

etoposide: An anticancer drug that is apodophyllotoxin derivative and belongsto the family of drugs called mitoticinhibitors.

evaluable disease: Disease that cannotbe measured directly by the size of thetumor but can be evaluated by other

methods specific to a particular clinicaltrial.

Ewing’s sarcoma: A type of bone cancerthat usually forms in the middle (shaft)of large bones. Also called Ewing’s sar-coma/primitive neuroectodermal tumor(PNET).

excisional biopsy: A surgical procedurein which an entire lump or suspiciousarea is removed for diagnosis. The tissueis then examined under a microscope.

exemestane: An anticancer drug used todecrease estrogen production and tosuppress the growth of estrogen-dependent tumors.

extensive-stage small cell lung cancer:Cancer that has spread outside the lungto other tissues in the chest or to otherparts of the body.

external radiation: Radiation therapythat uses a machine to aim high-energyrays at the cancer. Also called external-beam radiation.

external-beam radiation: Radiationtherapy that uses a machine to aim high-energy rays at the cancer. Also called ex-ternal radiation.


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Ffallopian tubes: Part of the female re-productive tract. The long slender tubesthrough which eggs pass from the ova-ries to the uterus.

familial dysplastic nevi: A conditionthat runs in certain families in which atleast two members have dysplastic nevi(atypical moles) and have a tendency todevelop melanoma.

familial polyposis: An inherited condi-tion in which numerous polyps (tissuemasses) develop on the inside walls ofthe colon and rectum. It increases therisk for colon cancer.

Fanconi anemia: A rare and often fatalinherited disease in which the bone mar-row fails to produce red blood cells,white blood cells, platelets or a combi-nation of these cells. The disease maytransform into myelodysplastic syn-drome or leukemia.

fatty acids: A major component of fatsthat are used by the body for energy andtissue development.

fazarabine: An anticancer drug that be-longs to the family of drugs called anti-metabolites.

fentanyl: A narcotic opioid drug that isused in the treatment of pain.

fibroid: A benign smooth muscle tumor,usually in the uterus or gastrointestinaltract. Also called leiomyoma.

fibrosarcoma: A type of soft tissue sar-coma that begins in fibrous tissue, whichholds bones, muscles and other organsin place.

fibrosis: The growth of fibrous tissue.

filgrastim: A colony-stimulating factorthat stimulates the production of neu-trophils (a type of white blood cell). It isa cytokine that belongs to the family ofdrugs called hematopoietic (bloodforming) agents. Also called granulocytecolony-stimulating factor (G-CSF).

filgrastim-SD/01: A substance that isbeing studied for its ability to increasenumbers of white blood cells in peoplewho are receiving chemotherapy. It be-longs to the family of drugs called col-ony-stimulating factors.

finasteride: A drug used to reduce theamount of male hormone (testosterone)produced by the body.

fine-needle aspiration: The removal oftissue or fluid with a needle for exami-nation under a microscope. Also calledneedle biopsy.

flavopiridol: Belongs to the family ofanticancer drugs called flavinols.

floxuridine: An anticancer drug thatbelongs to the family of drugs calledantimetabolites.

fluconazole: A drug that treats infectionscaused by fungi.

flucytosine: A drug that treats infectionscaused by fungi.

fludarabine: An anticancer drug thatbelongs to the family of drugs calledantimetabolites.

fludeoxyglucose F 18: The radioactiveform of glucose used in positron emis-


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sion tomography (PET), a diagnosticimaging procedure.

fludrocortisone: A synthetic corticoster-oid. It is used to replace steroid hor-mones normally produced by the adre-nal gland.

fluoroscope: An X-ray machine thatmakes it possible to see internal organsin motion.

fluorouracil: An anticancer drug thatbelongs to the family of drugs calledantimetabolites.

flutamide: An anticancer drug that be-longs to the family of drugs calledantiandrogens.

folate: A B-complex vitamin that isbeing studied as a cancer preventionagent. Also called folic acid.

fractionation: Dividing the total dose ofradiation therapy into several smaller,equal doses delivered over a period ofseveral days.

functional magnetic resonance imaging:A noninvasive tool used to observefunctioning in the brain or other organsby detecting changes in chemical com-position and/or blood flow.

fundus: The larger part of a hollow or-gan that is farthest away from the or-gan’s opening. The bladder, gallbladder,stomach, uterus, eye and the cavity ofthe middle ear all have a fundus.


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GG-CSF: Granulocyte colony-stimulatingfactor. A substance that stimulates theproduction of neutrophils, a type ofwhite blood cell. Also called filgrastim.

gadolinium texaphyrin: A substancethat makes tumor cells more sensitive toradiation; it can also enhance tumor im-ages using magnetic resonance imaging(MRI). Gadolinium texaphyrin belongsto the family of drugs calledmetalloporphyrin complexes.

gallbladder: The pear-shaped organ thatsits below the liver. Bile is concentratedand stored in the gallbladder.

gallium nitrate: A drug that lowersblood calcium. Used as treatment forhypercalcemia (too much calcium in theblood) and for cancer that has spread tothe bone (bone metastases).

gamma knife: Radiation therapy inwhich high-energy rays are aimed at atumor from many angles in a singletreatment session.

gastric: Having to do with the stomach.

gastric atrophy: A condition in whichthe stomach muscles shrink and becomeweak. The digestive (peptic) glands mayalso shrink, resulting in a lack of diges-tive juices.

gastrointestinal tract: The stomach andintestines. Gastroscope (GAS-tro-skope):A thin, lighted tube used to view the in-side of the stomach.

geldanamycin analogue: An antineo-plastic antibiotic drug that belongs to thefamily of drugs called ansamycins.

gemcitabine: An anticancer drug thatbelongs to the family of drugs called an-timetabolites.

gene: The functional and physical unit ofheredity passed from parent to offspring.Genes are pieces of DNA, and mostgenes contain the information for mak-ing a specific protein.

gene deletion: The total loss or absenceof a gene.

gene therapy: Treatment that alters agene. In studies of gene therapy for can-cer, researchers are trying to improve thebody’s natural ability to fight the diseaseor to make the cancer cells more sensi-tive to other kinds of therapy.

gene-modified: Cells that have been al-tered to contain different genetic mate-rial than they did originally.

genetic: Inherited; having to do with in-formation that is passed from parents tochildren through genes in sperm and eggcells.

genetic markers: Alterations in DNAthat may indicate an increased risk ofdeveloping a specific disease or disorder.

Genito-urinary system: The parts of thebody that play a role in reproduction, ingetting rid of waste products in the formof urine, or both.

germ cell tumors: Tumors that begin inthe cells that give rise to sperm or eggs.They can occur virtually anywhere in thebody and can be either benign ormalignant.


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germ cells: The reproductive cells of thebody, specifically either egg or spermcells.

germinoma: The most frequent type ofgerm cell tumor in the brain.

germline mutation: A gene change inthe body’s reproductive cells (egg orsperm) that becomes incorporated intothe DNA of every cell in the body ofoffspring; germline mutations are passedon from parents to offspring. Also calledhereditary mutation.

Gleason score: A system of gradingprostate cancer cells to determine thebest treatment and to predict how well aperson is likely to do. A low Gleasonscore means the cancer cells are verysimilar to normal prostate cells; a highGleason score means the cancer cells arevery different from normal.

glial tumors: A general term for manytypes of tumors of the central nervoussystem, including astrocytomas, epen-dymal tumors, glioblastoma multiformeand primitive neuroectodermal tumors.

glioblastoma: A general term that refersto malignant astrocytoma, a type ofbrain tumor.

glioblastoma multiforme: A type ofbrain tumor that forms from the glial(supportive) tissue of the brain. It growsvery quickly and has cells that look verydifferent from normal cells. Also calledgrade IV astrocytoma.

glioma: A cancer of the brain that comesfrom glial, or supportive, cells.

gliosarcoma: A type of glioma.

glucocorticoid: A compound that be-longs to the family of compounds called

corticosteroids (steroids). Glucocorti-coids affect metabolism, and have anti-inflammatory and immunosuppressiveeffects. They may be naturally produced(hormones) or synthetic (drugs).

glufosfamide: An anticancer drug thatbelongs to the family of drugs called al-kylating agents.

glutamine: An amino acid used in nutri-tion therapy. It is also being studied forthe treatment of diarrhea caused by ra-diation therapy to the pelvis.

GM-CSF: Granulocyte-macrophage col-ony-stimulating factor. A substance thatstimulates the production of white bloodcells, especially granulocytes and macro-phages, and cells (in the bone marrow)that are precursors of platelets. Alsocalled sargramostim.

gonads: The part of the reproductivesystem that produces and releases eggs(ovaries) or sperm (testicles/testes).

goserelin: A drug that belongs to thefamily of drugs called gonadotropin-releasing hormone analogues. Goserelinis used to block hormone production inthe ovaries or testicles.

gp 100: Glycoprotein 100 (gp 100) is atumor-specific antigen used in the de-velopment of cancer vaccines.

grade: The grade of a tumor is deter-mined by how abnormal the cancer cellsappear when examined under a micro-scope, the probable growth rate of thetumor, and its tendency to spread. Thesystems used to grade tumors vary witheach type of cancer.

grading: A system for classifying cancercells in terms of how abnormal theyappear when examined under a micro-scope. The objective of a grading system


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is to provide information about theprobable growth rate of the tumor andits tendency to spread. The systems usedto grade tumors vary with each type ofcancer. Grading plays a role in treatmentdecisions.

graft: Healthy skin, bone or other tissuetaken from one part of the body andused to replace diseased or injured tissueremoved from another part of the body.

graft-versus-host disease: GVHD. A re-action of donated bone marrow or pe-ripheral stem cells against a person’stissue.

graft-versus-tumor: An immune re-sponse to a person’s tumor cells by im-mune cells present in a donor’s trans-planted tissue, such as bone marrow orperipheral blood.

granisetron: A drug that prevents or re-duces nausea and vomiting.

granulocyte: A type of white blood cellthat fights bacterial infection. Neutro-phils, eosinophils and basophils aregranulocytes.

granulocyte colony-stimulating factor:G-CSF. A substance that stimulates theproduction of blood cells, especiallyplatelets, during chemotherapy. It is acytokine that belongs to the family ofdrugs called hematopoietic (bloodforming) agents. Also called filgrastim.

granulocytopenia: A deficiency in thenumber of granulocytes, a type of whiteblood cell.

growth factors: Substances made by thebody that function to regulate cell divi-sion and cell survival. Some growth fac-tors are also produced in the laboratoryand used in biological therapy.

gynecologic cancer: Cancer of thefemale reproductive tract, including thecervix, endometrium, fallopian tubes,ovaries, uterus and vagina.


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Hhairy cell leukemia: A type of chronicleukemia in which the abnormal whiteblood cells appear to be covered withtiny hairs when viewed under amicroscope.

hemangiopericytoma: A type of cancerinvolving blood vessels and soft tissue.

hematogenous: Originating in the bloodor spread through the bloodstream.

hematologic malignancies: Cancers ofthe blood or bone marrow, includingleukemia and lymphoma. Also calledhematologic cancers.

hematoporphyrin derivative: A drugused in photodynamic therapy that isabsorbed by tumor cells. When exposedto light, it becomes active and kills thecancer cells.

hepatic: Refers to the liver.

hepatoblastoma: A type of liver tumorthat occurs in infants and children.

hepatocellular carcinoma: This is a typeof adenocarcinoma, the most commontype of liver tumor.

hepatocyte: A liver cell.

HER2/neu: Human epidermal growthfactor receptor 2. The HER2-neu proteinis involved in growth of some cancercells. Also called c-erbB-2.

HER2/neu gene: The gene that makesthe human epidermal growth factor re-ceptor 2. The protein produced isHER2/neu antigen, which is involved ingrowth of some cancer cells. Also calledc-erbB-2.

hereditary mutation: A gene change inthe body’s reproductive cells (egg orsperm) that becomes incorporated intothe DNA of every cell in the body ofoffspring; hereditary mutations arepassed on from parents to offspring.Also called germline mutation.

hereditary nonpolyposis colon cancer:An inherited disorder in which affectedindividuals have a higher-than-normalchance of developing colon cancer andcertain other types of cancer, usuallybefore the age of 60. Also called Lynchsyndrome.

histamine dihydrochloride: A drug be-ing studied for its ability to enhance theeffectiveness of IL-2 in treating acutemyeloid leukemia.

Hodgkin’s disease: A malignant diseaseof the lymphatic system that is charac-terized by painless enlargement of thelymph nodes, the spleen or other lym-phatic tissue. It is sometimes accompa-nied by symptoms such as fever, weightloss, fatigue and night sweats.

homoharringtonine: An anticancerdrug that belongs to the plant alkaloidfamily of drugs.

hormonal therapy: Treatment of cancerby removing, blocking or adding hor-mones. Also called endocrine therapy.

hormone receptor test: A test tomeasure the amount of certain proteins,called hormone receptors, in cancertissue. Hormones can attach to theseproteins. A high level of hormonereceptors may mean that hormones helpthe cancer grow.


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hormone replacement therapy: HRT.Hormones (estrogen and/or progester-one) given to postmenopausal women orwomen who have had their ovaries sur-gically removed, in order to replace theestrogen no longer produced by theovaries.

hormone therapy: Treatment of cancerby removing, blocking or adding hor-mones. Also called endocrine therapy.

hormones: Chemicals produced byglands in the body and circulated in thebloodstream. Hormones control the ac-tions of certain cells or organs.

human papilloma virus: HPV. A virusthat causes abnormal tissue growth(warts) and that is often associated withsome types of cancer.

hydrocephalus: The abnormal buildupof cerebrospinal fluid in the ventricles ofthe brain.

hydrocortisone: A drug used to relievethe symptoms of certain hormone short-ages, and to suppress an immuneresponse.

hydroxyurea: An anticancer drug thatbelongs to the family of drugs calledantimetabolites.

hypercalcemia: High levels of calcium inthe blood.

hyperfractionation: A way of giving ra-diation therapy in smaller-than-usualdoses two or three times a day instead ofonce a day.

hyperplasia: An abnormal increase inthe number of cells in an organ or tissue.

hypersensitivity: An exaggerated re-sponse by the immune system to a drugor other substance.

hyperthermia: A type of treatment inwhich body tissue is exposed to hightemperatures to damage and kill cancercells, or to make cancer cells more sensi-tive to the effects of radiation and certainanticancer drugs.

hyperthermic perfusion: A procedure inwhich a warmed solution containinganticancer drugs is used to bathe, or ispassed through the blood vessels of, thetissue or organ containing the tumor.

hyperthyroidism: A condition in whichthe thyroid gland produces too muchthyroid hormone.

hyperuricemia: A buildup of uric acid (aby-product of metabolism) in the blood;a side effect of some anticancer drugs.

hypervascular: Having a large numberof blood vessels.

hypopharynx: The bottom part of thethroat. Cancer of the hypopharynx isalso called hypopharyngeal cancer.

hypothalamus: The area of the brainthat controls body temperature, hungerand thirst.

hysterectomy: An operation in whichthe uterus is removed.


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Iidarubicin: An anticancer drug that be-longs to the family of drugs called anti-tumor antibiotics. Also called 4-deme-thoxydaunorubicin.

IDEC-Y2B8 monoclonal antibody: Ananticancer drug that is a combination ofa monoclonal antibody and a radioiso-tope (yttrium Y 90). Also called ibritu-momab tiuxetan. Monoclonal antibodiesare laboratory-produced substances thatcan locate and bind to cancer cells.

idoxifene: A drug that blocks the effectsof estrogen.

idoxuridine: A drug that reduces the riskof cancer cell growth by interfering withthe cells’ DNA.

ifosfamide: An anticancer drug that be-longs to the family of drugs called alkyl-ating agents.

ileostomy: An opening into the ileum,part of the small intestine, from the out-side of the body. An ileostomy providesa new path for waste material to leavethe body after part of the intestine hasbeen removed.

immune adjuvant: A drug that stimu-lates the immune system to respond todisease.

immune function: Production and actionof cells that fight disease or infection.

immune response: The activity of theimmune system against foreign sub-stances (antigens).

immune system: The complex group oforgans and cells that defend the bodyagainst infection or disease.

immunocompromised: Having a weak-ened immune system caused by certaindiseases or treatments.

immunodeficiency: The decreased abil-ity of the body to fight infection anddisease.

immunodeficiency syndrome: The in-ability of the body to produce an im-mune response.

immunoglobulin: A protein that acts asan antibody.

immunological adjuvant: A substanceused to help boost the immune responseto a vaccine so that less vaccine is needed.

immunosuppression: Suppression ofthe body’s immune system and its abilityto fight infections or disease. Immuno-suppression may be deliberately inducedwith drugs, such as in preparation forbone marrow or other organ transplan-tation in order to prevent rejection ofthe donor tissue. It may also result fromcertain diseases, such as AIDS or lym-phoma, or from anticancer drugs.

immunosuppressive therapy: Therapyused to decrease the body’s immune re-sponse, such as drugs given to preventtransplant rejection.

immunotherapy: Treatment to stimu-late or restore the ability of the person’simmune system to fight infection anddisease. Also used to lessen side effectsthat may be caused by some cancer treat-ments. Also called biological therapy orbiological response modifier (BRM)therapy.


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immunotoxin: An antibody linked to atoxic substance. Some immunotoxins canbind to cancer cells and kill them.

implant radiation: Radiation therapythat is given internally. This is done byplacing radioactive material that is sealedin needles, seeds, wires or catheters di-rectly into or near the tumor. Also calledinternal radiation or brachytherapy.

implantable pump: A small device in-stalled under the skin to administer asteady dose of drugs.

in situ cancer: Early cancer that has notspread to neighboring tissue.

in vitro: In the laboratory (outside thebody). The opposite of in vivo (in thebody).

in vivo: In the body. The opposite of invitro (outside the body).

incidence: The number of new cases of adisease diagnosed each year.

incomplete Freund’s adjuvant: A drugused in vaccine therapy to stimulate theimmune system.

indolent: A type of cancer that growsslowly.

indolent lymphoma: Lymphoma thatgrows slowly and has few symptoms.

induction therapy: Treatment designedto be used as a first step toward shrink-ing the cancer and in evaluating re-sponse to drugs and other agents. In-duction therapy is followed by additionaltherapy to eliminate whatever cancerremains.

infiltrating cancer: Cancer that hasspread beyond the layer of tissue in

which it developed and is growing intosurrounding, healthy tissues. Also calledinvasive cancer.

inflammatory breast cancer: A type ofbreast cancer in which the breast looksred and swollen, and feels warm. Theskin of the breast may also show the pit-ted appearance called peau d’orange(like the skin of an orange). The rednessand warmth occur because the cancercells block the lymph vessels in the skin.

infusion: A method of putting fluids,including drugs, into the bloodstream.Also called intravenous infusion.

inguinal orchiectomy: An operation inwhich the testicle is removed through anincision in the groin.

interferon: A biological response modi-fier (a substance that stimulates thebody’s response to infection and dis-ease). Interferons affect the division ofcancer cells and slow tumor growth.There are several types of interferons,including interferon-alpha, interferon-beta and interferon-gamma. These sub-stances are normally produced by thebody. They are also made in the labora-tory for use in treating cancer and otherdiseases.

interleukin-11: IL-11. A type of biologi-cal response modifier (a substance thatcan improve the body’s natural responseto disease) that stimulates immune re-sponse and may reduce toxicity to thegastrointestinal system resulting fromcancer therapy. These substances arenormally produced by the body. Theyare also made in the laboratory for use intreating cancer and other diseases. Alsocalled oprelvekin.

interleukin-12: IL-12. A type of biologi-cal response modifier (a substance that


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can improve the body’s natural responseto disease) that enhances the ability ofthe immune system to kill tumor cells,and that may interfere with blood flowto the tumor. These substances are nor-mally produced by the body. They arealso made in the laboratory for use intreating cancer and other diseases.

interleukin-2: IL-2. A type of biologicalresponse modifier (a substance that canimprove the body’s natural response todisease) that stimulates the growth ofcertain disease-fighting blood cells in theimmune system. These substances arenormally produced by the body. Theyare also made in the laboratory for use intreating cancer and other diseases. Alsocalled aldesleukin.

interleukin-3: IL-3. A type of biologicalresponse modifier (a substance that canimprove the body’s natural response todisease) that enhances the immune sys-tem’s ability to fight tumor cells. Thesesubstances are normally produced by thebody. They are also made in the labora-tory for use in treating cancer and otherdiseases.

interleukin-4: IL-4. A type of biologicalresponse modifier (a substance that canimprove the body’s natural response todisease) that enhances the immune sys-tem’s ability to fight tumor cells. Thesesubstances are normally produced by thebody. They are also made in the labora-tory for use in treating cancer and otherdiseases.

interleukins: Biological response modi-fiers (substances that can improve thebody’s natural response to disease)that help the immune system fightinfection and cancer. These substancesare normally produced by the body.They are also made in the laboratory foruse in treating cancer and other diseases.

intermediate-grade lymphomas: In-cludes diffuse small, cleaved cell lym-phoma and diffuse large, noncleaved celllymphoma. These are more aggressivethan low-grade lymphomas, but theyhave a better response to anticancerdrugs.

internal radiation: Radiation therapythat is given internally. This is done byplacing radioactive material that is sealedin needles, seeds, wires or catheters di-rectly into or near the tumor. Also calledimplant radiation or brachytherapy.

intracarotid infusion: The introductionof fluids and drugs directly into thecarotid artery, the main artery in theneck; it carries blood from the heart tothe brain.

intracranial tumors: Tumors that occurin the brain.

intraductal carcinoma: Abnormal cellsthat involve only the lining of a duct.The cells have not spread outside theduct to other tissues in the breast. Alsocalled ductal carcinoma in situ.

intraepithelial: Within the layer of cellsthat form the surface or lining of anorgan.

intrahepatic: Within the liver.

intrahepatic bile ducts: The bile ductsthat pass through and drain bile fromthe liver.

intrahepatic infusion: The delivery ofanticancer drugs directly to the bloodvessels of the liver.

intraoperative radiation therapy: IORT.Radiation treatment aimed directly at atumor during surgery.


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intraperitoneal: IP. Within the perito-neal cavity (the area that contains theabdominal organs).

intrathecal: The thin space between thelining of the spinal cord and the brain.

intrathecal chemotherapy: Anticancerdrugs infused into the thin space be-tween the lining of the spinal cord andthe brain to treat or reduce the risk ofcancers in the brain and spinal cord.

intravenous: IV. Injected into a vein.

intravenous pyelogram: IVP. A series ofX-rays of the kidneys, ureters andbladder. The X-rays are taken after a dyeis injected into a blood vessel. The dye,which is concentrated in the urine, out-lines the kidneys, ureters and bladder onthe X-rays.

intraventricular infusion: The deliveryof a drug into a space within an organ.

intravesical: Within the bladder.

invasive cancer: Cancer that has spreadbeyond the layer of tissue in which itdeveloped and is growing into sur-rounding, healthy tissues. Also calledinfiltrating cancer.

invasive cervical cancer: Cancer that hasspread from the surface of the cervix totissue deeper in the cervix or to otherparts of the body.

ionomycin: An antibiotic drug used totreat infection.

IORT: Intraoperative radiation therapy.Radiation treatment aimed directly at atumor during surgery.

irinotecan: An anticancer drug that be-longs to a family of anticancer drugscalled topoisomerase inhibitors. It is acamptothecin analogue. Also calledCPT 11.

irreversible toxicity: Side effects that arecaused by toxic substances or somethingharmful to the body, and that do not goaway.

islet cell cancer: Cancer arising fromcells in the islets of Langerhans, whichare found in the pancreas.

islets of Langerhans: Cells in the pan-creas that produce hormones (includinginsulin).

isoflavones: Compounds found in soybeans that may help prevent cancer.

isolated hepatic perfusion: A procedurein which a catheter is placed into theartery that provides blood to the liver;and another catheter is placed into thevein that takes blood away from theliver. This temporarily separates theliver’s blood supply from blood circu-lating throughout the rest of the bodyand allows high doses of anticancerdrugs to be directed to the liver only.

isolated limb perfusion: A techniquethat may be used to deliver anticancerdrugs directly to an arm or leg. The flowof blood to and from the limb is tempo-rarily stopped with a tourniquet, andanticancer drugs are put directly into theblood of the limb. This allows the personto receive a high dose of drugs in thearea where the cancer occurred.


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isolated lung perfusion: A surgical pro-cedure during which the circulation ofblood to the lungs is separated from thecirculation of blood through the rest ofthe body, and a drug is delivered directlyinto the lung circulation. This allows ahigher concentration of chemotherapyto reach tumors in the lungs.

isotretinoin: A drug that belongs to thefamily of drugs called retinoids. It is usedin the treatment of acne and psoriasisand is being studied in cancer preven-tion. Also called 13-cis retinoic acid.


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J Kjaundice: A condition in which the skinand the whites of the eyes becomeyellow, urine darkens and stool becomesclay colored. Jaundice occurs when theliver is not working properly or when abile duct is blocked.

Kaposi’s sarcoma: A type of cancercharacterized by the abnormal growth ofblood vessels that develop into skinlesions or occur internally.

keloid: A thick, irregular scar caused byexcessive tissue growth at the site of anincision or wound.

keratinocyte growth factor: A substancethat stimulates the growth of epithelialcells that line the surface of the mouthand intestinal tract.

killer cells: White blood cells that attacktumor cells and body cells that have beeninvaded by foreign substances.

Krukenberg tumor: A tumor in theovary caused by the spread of stomachcancer.


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Llaparoscopy: The insertion of a thin,lighted tube (called a laparoscope)through the abdominal wall to inspectthe inside of the abdomen and removetissue samples.

laparotomy: A surgical incision made inthe wall of the abdomen.

large cell carcinomas: A group of lungcancers in which the cells are large andlook abnormal when viewed under amicroscope.

laryngeal: Refers to the larynx.

leflunomide: An anticancer drug thatworks by inhibiting a cancer cell growthfactor. Also called SU101.

leiomyoma: A benign smooth muscletumor, usually in the uterus or gastro-intestinal tract. Also called a fibroid.

leiomyosarcoma: A tumor of the mus-cles in the uterus or abdomen/pelvis.

leptomeningeal cancer: A tumor thatinvolves the tissues that cover the brainand spinal cord.

leptomeningeal metastases: Cancer thathas spread from the original (primary)tumor to the tissues that cover the brainand the spinal cord.

leridistim: A substance that is beingstudied for its ability to increase thenumber of white blood cells in peoplewho are receiving chemotherapy. Itbelongs to the family of drugs calledcolony-stimulating factors.

lerisetron: A drug that prevents or re-duces nausea and vomiting.

lesion: An area of abnormal tissuechange.

letrozole: An anticancer drug that be-longs to the family of drugs called non-steroidal aromatase inhibitors. Letrozoleis used to decrease estrogen productionand suppress the growth of estrogen de-pendent tumors.

leucovorin: A drug used to protect nor-mal cells from high doses of the antican-cer drug methotrexate. It is also used toincrease the antitumor effects of fluo-rouracil and tegafur-uracil, an oraltreatment alternative to intravenousfluorouracil.

leukapheresis: Removal of the blood tocollect specific blood cells; the remainingblood is returned to the body.

leukemia: Cancer of blood-formingtissue.

leukocytes: Cells that help the body fightinfections and other diseases. Also calledwhite blood cells (WBCs).

leukoplakia: A white patch that may de-velop on mucous membranes, such asthe cheek, gums or tongue, and may be-come cancerous.

leuprolide: A drug that belongs to afamily of drugs called gonadotropin-releasing hormone analogues. Used toblock hormone production in the ova-ries or testicles.

leuvectin: An agent that delivers thegene for interleukin-2 (IL-2) into cells toincrease production of IL-2 by the cells.


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levamisole: An antiparasitic drug that isalso being studied in cancer therapy withfluorouracil.

LH-RH: Abbreviation for luteinizinghormone-releasing hormone, a hormonethat controls the production of sex hor-mones in men and women.

Li-Fraumeni syndrome: A rare, inher-ited predisposition to multiple cancerscaused by an alteration in the p53 tumorsuppressor gene.

ligation: The process of tying off bloodvessels so that blood cannot flow to apart of the body or to a tumor.

limb perfusion: A technique that may beused to deliver anticancer drugs directlyto an arm or leg. The flow of blood toand from the limb is temporarilystopped with a tourniquet, and antican-cer drugs are put directly into the bloodof the limb. This allows the person toreceive a high dose of drugs in the areawhere the cancer occurred.

limited-stage small cell lung cancer:Cancer is found in one lung and innearby lymph nodes.

liposarcoma: A rare cancer of the fatcells.

liposomal: A drug preparation thatcontains the active drug in very tiny fatparticles. This fat-encapsulated drug isabsorbed better and its distribution tothe tumor site is improved.

liver metastases: Cancer that has spreadfrom the original (primary) tumor to theliver.

lobaplatin: An anticancer drug that be-longs to the family of drugs called plati-num compounds.

lobular carcinoma in situ: LCIS. Ab-normal cells found in the lobules of thebreast. This condition seldom becomesinvasive cancer. However, having lobularcarcinoma in situ increases one’s risk ofdeveloping cancer in either breast.

lobule: A small lobe or subdivision of alobe.

local cancer: An invasive malignant can-cer confined entirely to the organ wherethe cancer began.

local therapy: Treatment that affectscells in the tumor and the area close to it.

localized: Restricted to the site of originwithout evidence of spread.

localized gallbladder cancer: Cancer isfound only in the tissues that make upthe wall of the gallbladder; it can be re-moved completely in an operation.

locally advanced cancer: Cancer that hasspread only to nearby tissues or lymphnodes.

lomustine: An anticancer drug that be-longs to the family of drugs called alkyl-ating agents.

low-grade lymphomas: Lymphomas thattend to grow and spread slowly, includingchronic lymphocytic lymphoma andfollicular small cleaved cell lymphoma.Also called indolent lymphomas.

lumbar puncture: The insertion of aneedle into the lower part of the spinalcolumn to collect cerebrospinal fluid orto give anticancer drugs intrathecally.Also called a spinal tap.

lumpectomy: Surgery to remove the tu-mor and a small amount of normal tis-sue around it.


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lung metastases: Cancer that has spreadfrom the original (primary) tumor to thelung.

luteinizing hormone-releasing hormoneagonist: LH-RH agonist. A substancethat closely resembles luteinizinghormone-releasing hormone (LH-RH),which controls the secretion of sex hor-mones. However, LH-RH agonists affectthe body differently than does LH-RH.LH-RH agonists eventually cause a de-crease in the secretion of sex hormones.

lutetium texaphyrin: A substance that isbeing studied in photodynamic therapy.It belongs to the family of drugs calledmetallotexaphyrins.

lymph: The almost colorless fluid thattravels through the lymphatic systemand carries cells that help fight infectionand disease.

lymph node: A rounded mass of lym-phatic tissue that is surrounded by acapsule of connective tissue. Also knownas a lymph gland. Lymph nodes arespread out along lymphatic vessels andthey contain many lymphocytes, whichfilter the lymphatic fluid (lymph).

lymphadenectomy: A surgical pro-cedure in which the lymph nodes areremoved and examined to see if theycontain cancer. Also called lymph nodedissection.

lymphangiography: An X-ray study ofthe lymphatic system. A dye is injectedinto a lymphatic vessel and travelsthroughout the lymphatic system. Thedye outlines the lymphatic vessels andorgans on the X-ray.

lymphatic system: The tissues and or-gans that produce, store and carry whiteblood cells that fight infection and other

diseases. This system includes the bonemarrow, spleen, thymus and lymphnodes and a network of thin tubes thatcarry lymph and white blood cells. Thesetubes branch, like blood vessels, into allthe tissues of the body.

lymphedema: A condition in which ex-cess lymph collects in tissue and causesswelling. It may occur in the arm or legafter lymph vessels or lymph nodes inthe underarm or groin are removed.

lymphocyte: A type of white blood cellthat has a number of roles in the im-mune system. Some lymphocytes act astumor-killing cells. Other lymphocytesproduce antibodies or other substancesthat fight cancer, infection and otherdiseases. The main types of lymphocytesare T cells, B cells and natural killer(NK) cells.

lymphokine-activated killer cells: Whiteblood cells that are stimulated in a labo-ratory to kill tumor cells. Also calledLAK cells.

lymphoma: Cancer that arises in cells ofthe lymphatic system.

lymphomatoid granulomatosis: De-structive growth of lymph cells, usuallyinvolving the lungs, skin, kidneys andcentral nervous system. Grades I and IIare not considered cancerous, but gradeIII is considered a lymphoma.

lymphoproliferative disorders: Diseasesin which cells of the lymphatic systemgrow excessively. These disorders areoften treated similarly to cancer.

Lynch syndrome: An inherited disorderin which affected individuals developcolon cancer, usually before the age of60. Also called hereditary nonpolyposiscolon cancer.


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MM proteins: Antibodies or parts ofantibodies found in unusually largeamounts in the blood or urine of peoplewith multiple myeloma.

MAGE-3: A gene found in some types oftumors.

magnetic resonance imaging: MRI. Aprocedure in which a magnet linked to acomputer is used to create detailedpictures of areas inside the body.

maintenance therapy: Treatment that isgiven to help a primary (original)treatment keep working. Maintenancetherapy is often given to help keepcancer in remission.

malabsorption syndrome: A group ofsymptoms such as gas, bloating,abdominal pain and diarrhea resultingfrom the body’s inability to absorbnutrients properly.

malignancy: A cancerous tumor that caninvade and destroy nearby tissue andspread to other parts of the body.

malignant: Cancerous; a growth with atendency to invade and destroy nearbytissue and spread to other parts of thebody.

malignant ascites: A condition in whichfluid containing cancer cells collects inthe abdomen.

malignant fibrous histiocytoma: Asarcoma that usually begins in softtissue. It usually appears as an enlarging,painful mass that can cause fracture dueto destruction of the bone by a spreadingtumor.

malignant meningioma: A rare, rapidlygrowing tumor that occurs in themembranes that cover and protect thebrain and the spinal cord (meninges).

malignant mesothelioma: A rare type ofcancer in which malignant cells arefound in the sac lining the chest orabdomen. Exposure to airborne asbestosparticles increases one’s risk ofdeveloping malignant mesothelioma.

MALT lymphoma: Mucosa-associatedlymphoid tissue lymphoma. A type ofcancer that arises in cells in mucosaltissue that are involved in antibodyproduction.

mammogram: An X-ray of the breast.

mantle field: The area of the neck, chestand lymph nodes in the armpit that isexposed to radiation.

marimastat: An anticancer drug thatbelongs to the family of drugs calledangiogenesis inhibitors. Marimastat is amatrix metalloproteinase inhibitor.

marker: A diagnostic indication thatdisease may develop.

mastectomy: Surgery to remove thebreast (or as much of the breast tissue aspossible).

measurable disease: A tumor that can beaccurately measured in size. Thisinformation can be used to judge re-sponse to treatment.

medial supraclavicular lymph nodes:Lymph nodes located above the collarbone and between the center of the body


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and a line drawn through the nipple tothe shoulder.

median: A statistics term. The middlevalue in a set of measurements.

mediastinum: The area between thelungs. The organs in this area include theheart and its large blood vessels, thetrachea, the esophagus, the bronchi andlymph nodes.

medical castration: Refers to the use ofdrugs to suppress the function of theovaries or testicles.

medroxyprogesterone: A hormonalanticancer drug that is also used incancer prevention. It belongs to thefamily of drugs called progestins.

medulloblastoma: A malignant braintumor that begins in the lower part ofthe brain and that can spread to thespine or to other parts of the body.Medulloblastomas are sometimes calledprimitive neuroectodermal tumors(PNET).

megestrol: A drug that belongs to thegroup of hormones called progestins,used as hormone therapy to blockestrogen and to suppress the effects ofcancer.

melanin: The substance that gives theskin its color.

melanocytes: Cells in the skin thatproduce and contain the pigment calledmelanin.

melanoma: A form of skin cancer thatarises in melanocytes, the cells thatproduce pigment. Melanoma usuallybegins in a mole.

melanoma vaccine: A cancer vaccineprepared from human melanoma cancer

cells. It is used either alone or with othertherapy in treating melanoma.

melphalan: An anticancer drug thatbelongs to the family of drugs calledalkylating agents.

membrane: A very thin layer of tissuethat covers a surface.

meningeal: Refers to the meninges, thetissue covering the brain and spinal cord.

meningeal metastases: Cancer that hasspread from the original (primary)tumor to the tissue covering the brainand/or spinal cord.

meningioma: A type of tumor thatoccurs in the meninges, the membranesthat cover and protect the brain and thespinal cord. Meningiomas usually growslowly.

menopause: The time of life when awoman’s menstrual periods stop for atleast a year. Also called “change of life.”

menstrual cycle: The monthly cycle ofhormonal changes from the beginning ofone menstrual period to the beginning ofthe next.

menstruation: Periodic discharge ofblood and tissue from the uterus. Untilmenopause, menstruation occurs approx-imately every 28 days when a woman isnot pregnant.mercaptopurine: An anticancer drugthat belongs to the family of drugs calledantimetabolites.

Merkel cell cancer: A rare type of cancerthat develops on or just beneath the skin.

mesenchymal: Refers to cells thatdevelop into connective tissue, bloodvessels and lymphatic tissue.


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mesna: A drug that helps protect thekidneys and bladder from the toxiceffects of anticancer drugs, such asifosfamide and cyclophosphamide.

metabolism: The total of all chemicalchanges that take place in a cell or anorganism. These changes produce energyand basic materials that are needed forimportant life processes.

metaplasia: A change of cells to a formthat does not normally occur in thetissue in which it is found.

metastasis: The spread of cancer fromone part of the body to another. Whencancer cells metastasize and formsecondary tumors, the cells in themetastatic tumor are like those in theoriginal (primary) tumor. The plural ismetastases.

metastatic cancer: Cancer that hasspread from the place in which it startedto other parts of the body.

methotrexate: An anticancer drug thatbelongs to the family of drugs calledantimetabolites.

methylprednisolone: A corticosteroidhormone replacement.

metoclopramide: A drug that preventsor reduces nausea and vomiting.

microcalcifications: Tiny deposits ofcalcium in the breast that cannot be feltbut that can be detected on amammogram. A cluster of these verysmall specks of calcium may indicatethat cancer is present.

mifepristone: An anticancer drug thatblocks the action of progesterone, ahormone that affects the growth of somecancers.

misoprostol: A radioprotective agentthat belongs to the family of drugs calledprostaglandins.

mitolactol: An anticancer drug thatbelongs to the family of drugs calledalkylating agents.

mitomycin: An anticancer drug thatbelongs to the family of drugs calledantitumor antibiotics.

mitotic inhibitors: Drugs that kill cancercells by interfering with cell division(mitosis).

mitoxantrone: An anticancer drug thatbelongs to the family of drugs calledantitumor antibiotics.

mivobulin isethionate: An anticancerdrug that belongs to the family of drugscalled mitotic inhibitors. Also called CI-980.

mixed gliomas: Brain tumors that occurin more than one type of brain cell,including astrocytes, ependymal cells,and/or oligodendrocytes.

modified radical mastectomy: Surgicalprocedure in which the breast, some ofthe lymph nodes in the armpit, and thelining over the chest muscles areremoved.

mole: A benign growth on the skin(usually tan, brown or flesh-colored)that contains a cluster of melanocytesand surrounding supportive tissue.

monoclonal antibodies: Laboratory-produced substances that can locate andbind to cancer cells wherever they are inthe body. Many monoclonal antibodiesare used in cancer detection or therapy;each one recognizes a different proteinon certain cancer cells. Monoclonal


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antibodies can be used alone, or they canbe used to deliver drugs, toxins orradioactive material directly to the tumor.

monocyte: A type of white blood cell.

MRI: Magnetic resonance imaging. Aprocedure in which a magnet linked to acomputer is used to create detailedpictures of areas inside the body.

mucin/peptide: A protein/sugar com-pound made by some cancer cells.

mucositis: A complication of somecancer therapies in which the lining ofthe digestive system becomes inflamed.Often seen as sores in the mouth.

mucus: A thick, slippery fluid producedby the membranes that line certainorgans of the body, including the nose,mouth, throat and vagina.

multidrug resistance: Adaptation oftumor cells to anticancer drugs in waysthat make the drugs less effective.

multidrug resistance inhibition: Treat-ment used to make cancer cells lessresistant to anticancer drugs.

multimodality treatment: Therapy thatcombines more than one method oftreatment.

multiple myeloma: Cancer that arises inplasma cells (white blood cells thatproduce antibodies).

muromonab-CD3 monoclonal antibody:A type of monoclonal antibody used incancer detection or therapy. Monoclonalantibodies are laboratory-produced sub-stances that can locate and bind tocancer cells.

mutations: Changes in the structure ofgenes. A mutation may be inherited or

caused by an environmental exposure.Certain changes may lead to cancer orother diseases. Also called a genealteration.

mycosis fungoides: A type of non-Hodgkin’s lymphoma that first appearson the skin and can spread to the lymphnodes or other organs such as the spleen,liver or lungs.

myelin: The fatty substance that coversand protects nerves.

myelodysplasia: Abnormal bone marrowcells that may lead to myelogenousleukemia.

myelodysplastic syndrome: Disease inwhich the bone marrow does notfunction normally. Also called pre-leukemia or smoldering leukemia.

myelofibrosis: A disorder in which thebone marrow is replaced by fibroustissue.

myelogenous: Produced by or origi-nating in the bone marrow.

myeloid: Pertaining to, derived from ormanifesting certain features of the bonemarrow. In some cases also pertainsto certain types of non-lymphocytewhite blood cells found in the bonemarrow, including granulocyte, mon-ocyte and platelet lineages. Also calledmyelogenous.

myeloma: Cancer that arises in plasmacells, a type of white blood cell.

myeloproliferative disorders: Diseasesin which too many blood cells are madein the bone marrow.

myelosuppressive therapy: Treatmentthat inhibits blood cell production.


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NN-acetyl cysteine: An antioxidant drugthat may keep cancer cells fromdeveloping or reduce the risk of growthof existing cancer.

neoadjuvant therapy: Treatment givenbefore the primary treatment. Neo-adjuvant therapy can be chemotherapy,radiation therapy or hormone therapy.

neoplasm: A new growth of benign ormalignant tissue.

neoplastic meningitis: Tumor cells thathave spread from the original (primary)tumor to the tissue that covers the brainand/or spinal cord.

nephrectomy: Surgery to remove thekidney. Radical nephrectomy removesthe kidney, the adrenal gland, nearbylymph nodes and other surroundingtissue. Simple nephrectomy removesonly the kidney. Partial nephrectomyremoves the tumor, but not the entirekidney.

neuroblastoma: Cancer that arises inimmature nerve cells and that affectsmostly infants and children.

neuroectodermal tumor: A tumor of thecentral or peripheral nervous systems.

neuroendocrine: Describes the pro-duction of hormone-like substances byneurons or neuron-like cells and the waythe nervous system and the endocrinesystem work together.

neuropathy: A problem in any part ofthe nervous system except the brain andthe spinal cord. Neuropathies can becaused by infection, toxic substances ordisease.

neurotoxicity: The tendency of sometreatments to cause damage to thenervous system.

neutropenia: An abnormal decrease inthe number of neutrophils, a type ofwhite blood cell.

neutrophil: A type of white blood cell.

nevus: A benign growth on the skin,such as a mole. A mole is a cluster ofmelanocytes and surrounding supportivetissue that usually appears as a tan,brown or flesh-colored spot on the skin.

NG-monomethyl-L-arginine: An aminoacid derivative used to counteract highblood pressure caused by interleukin-2.

niacinamide: A vitamin. It is beingstudied to increase the effect of radiationtherapy on tumor cells. Also callednicotinamide.

nitrocamptothecin: An alkaloid drugbelonging to a class of anticancer agentscalled topoisomerase inhibitors.

nitrosoureas: A group of anticancerdrugs that can cross the blood-brainbarrier. Carmustine and lomustine arenitrosoureas.

node-negative: Cancer that has notspread to the lymph nodes.

node-positive: Cancer that has spread tothe lymph nodes.

non-Hodgkin’s lymphoma: A group ofcancers of the lymphoid system, includ-ing acute lymphoblastic leukemia, B celllymphoma, Burkitt’s lymphoma, diffusecell lymphoma, follicular lymphoma,


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immunoblastic large cell lymphoma,lymphoblastic lymphoma, mantle celllymphoma, mycosis fungoides, post-transplantation lymphoproliferative dis-order, small non-cleaved cell lymphomaand T-cell lymphoma.

nonmalignant hematologic disorders:Noncancerous disorders of the blood.They do not destroy or invade nearbytissue and do not spread to other organs.

nonmelanoma skin cancer: Skin cancerthat arises in basal cells or squamouscells but not in melanocytes (pigment-producing cells of the skin).

nonmetastatic: Cancer that has notspread from the primary (original) siteto other sites in the body.

nonseminoma: A group of testicularcancers that begin in the germ cells (cellsthat give rise to sperm). Nonseminomasare identified by the type of cell theybegin in and include embryonalcarcinoma, teratoma, choriocarcinomaand yolk sac carcinoma.

Non-small-cell lung cancer: A group oflung cancers that includes squamous cellcarcinoma, adenocarcinoma and largecell carcinoma.

nonspecific immune cells: Cells such asphagocytes and macrophages that re-spond to many antigens, not just one.

novobiocin: An antibiotic drug used totreat infection.


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Ooat cell cancer: A type of lung cancer inwhich the cells look like oats whenviewed under a microscope. Also calledsmall cell lung cancer.

octreotide: A drug similar to the natu-rally occurring growth hormone inhibi-tor somatostatin. Octreotide is used totreat diarrhea and flushing associatedwith certain types of tumors.

oligodendroglial tumors: Rare, slow-growing tumors that begin in brain cellscalled oligodendrocytes, which providesupport and nourishment for cells thattransmit nerve impulses. Also called oli-godendroglioma.

oligodendroglioma: A rare, slow-grow-ing tumor that begins in brain cellscalled oligodendrocytes, which providesupport and nourishment for cells thattransmit nerve impulses. Also called oli-godendroglial tumor.

Ommaya reservoir: A device surgicallyplaced under the scalp and used to de-liver anticancer drugs to the fluid sur-rounding the brain and the spinal cord.

oncogene: A gene that normally directscell growth. If altered, it can promote orallow the uncontrolled growth of cancer.Alterations can be inherited or caused byenvironmental exposure to carcinogens.

oncology: The study of cancer.

ondansetron: A drug that prevents orreduces nausea and vomiting.

oophorectomy: Surgery to remove oneor both ovaries.

orchiectomy: Surgery to remove one orboth testicles.

oropharynx: The middle part of thethroat that includes the soft palate, thebase of the tongue and the tonsils.

osteolytic: Causing the breakdown ofbone.

osteoporosis: A condition that is char-acterized by a decrease in bone mass anddensity, causing bones to become fragile.

osteosarcoma: A cancer of the bone thatprimarily affects children and adoles-cents. Also called osteogenic sarcoma.

ovarian ablation: Surgery, radiationtherapy or drug treatment to stop thefunctioning of the ovaries. Also calledovarian suppression.

ovarian epithelial cancer: Cancer thatoccurs in the cells lining the ovaries.

ovaries: The pair of female reproductiveglands in which the ova, or eggs, areformed. The ovaries are located in thepelvis, one on each side of the uterus.

overexpress: An excess of a particularprotein on the surface of a cell.

oxaliplatin: An anticancer drug that be-longs to the family of drugs called plati-num compounds.


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PP-32: A radioactive form of phosphorusused in the treatment of cancer.

p-value: A statistics term. A measure ofprobability that a difference betweengroups during an experiment happenedby chance. For example, a p-value of .01(p = .01) means there is a 1/100 chancethe result occurred by chance. The lowerthe p-value, the more likely it is that thedifference between groups was caused bytreatment.

p53 gene: A tumor suppressor gene thatnormally inhibits the growth of tumors.This gene is altered in many types ofcancer.

paclitaxel: An anticancer drug thatbelongs to the family of drugs calledmitotic inhibitors.

palliative therapy: Treatment given torelieve symptoms caused by advancedcancer. Palliative therapy does not alterthe course of a disease, but improves thequality of life.

pamidronate: A drug that belongs to thefamily of drugs called bisphosphonates.Pamidronate is used as treatment forabnormally high levels of calcium in theblood.

Pancoast tumor: Non-small-cell lungcancer that originates in the upperportion of the lung and extends to othernearby tissues such as the ribs andvertebrae. Also called a pulmonarysulcus tumor.

pancreas: A glandular organ in theabdomen. It makes pancreatic juiceswith enzymes that help digestion and itproduces several hormones, including

insulin. The pancreas is surrounded bythe stomach, intestines and other organs.

pancreatectomy: Surgery to remove thepancreas. In a total pancreatectomy, aportion of the stomach, the duodenum,common bile duct, gallbladder, spleenand nearby lymph nodes also areremoved.

pancreatic enzymes: A group of proteinssecreted by the pancreas that aid indigestion of food.

pancreatic juices: Fluids made by thepancreas. Pancreatic juices containproteins called enzymes that aid indigestion.

papillary tumor: A tumor shaped like asmall mushroom with its stem attachedto the epithelial layer (inner lining) of anorgan.

paracentesis: Insertion of a thin needleor tube into the abdomen to removefluid from the peritoneal cavity.

paraneoplastic syndrome: A group ofsymptoms that may develop whensubstances released by some cancer cellsdisrupt the normal function ofsurrounding cells and tissue.

partial remission: The shrinking, butnot complete disappearance, of a tumorin response to therapy. Also calledpartial response.

passive antibody therapy: Treatmentwith injections of antibodies made inanother animal or in the laboratory.

peau d’orange: A dimpled condition ofthe skin of the breast, resembling the


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skin of an orange, sometimes found ininflammatory breast cancer.

PEG-interferon alfa-2B: An anticancerdrug that belongs to the family of drugscalled biological response modifiers.PEG-interferon alfa-2B is a cytokine.

PEG-MGDF: A synthetic form of aprotein that is normally made in thebody to regulate the production ofplatelets.

pegaspargase: A modified form ofasparaginase, an anticancer drug thatbelongs to the family of drugs derivedfrom enzymes.

pelvis: The lower part of the abdomen,located between the hip bones.

penclomedine: Penclomedine is ananticancer drug that belongs to thefamily of drugs called alkylating agents.

pentetic acid calcium: A drug thatprotects healthy tissues from the toxiceffects of anticancer drugs.

pentosan polysulfate: A drug used torelieve pain or discomfort associatedwith chronic inflammation of thebladder. It is also being evaluated for itsprotective effects on the gastrointestinaltract in people receiving radiationtherapy.

pentostatin: An anticancer drug thatbelongs to the family of drugs calledantimetabolites.

peptide: Any compound consisting oftwo or more amino acids, the buildingblocks of proteins. Peptides are com-bined to make proteins.

peptide 946: A protein that causes whiteblood cells to recognize and destroymelanoma cells.

perfusion: Bathing an organ or tissuewith a fluid. In regional perfusion, aspecific area of the body (usually an armor a leg) receives high doses ofanticancer drugs through a blood vessel.Such a procedure is performed to treatcancer that has not spread.

pericardial effusion: An abnormalcollection of fluid inside the sac thatcovers the heart.

perifosine: An anticancer drug thatbelongs to the family of drugs calledalkylphospholipids.

perillyl alcohol: A drug used in cancerprevention that belongs to the family ofplant drugs called monoterpenes.

perimenopausal: The time of a woman’slife when menstrual periods becomeirregular. Refers to the time nearmenopause.

perineal prostatectomy: Surgery toremove the prostate through an incisionmade between the scrotum and the anus.

peripheral blood: Blood circulatingthroughout the body.

peripheral blood lymphocyte therapy:A treatment for Epstein-Barr virusinfection or overgrowth of white bloodcells (lymphocytes) following trans-plantation of organs or bone marrow.Specific lymphocytes from a siblingdonor are infused into the patient in anattempt to cause remission.

peripheral stem cell support: A methodof replacing blood-forming cells de-stroyed by cancer treatment. Immature


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blood cells (stem cells) in the circulatingblood that are similar to those in thebone marrow are removed from theperson’s blood before treatment. Thecells are given back to the person aftertreatment. Also called peripheral stemcell transplantation.

peripheral stem cells: Immature cellsfound circulating in the bloodstream.New blood cells develop from peripheralstem cells.

peristalsis: The rippling motion of mus-cles in the intestine or other tubular or-gans characterized by the alternate con-traction and relaxation of the musclesthat propel the contents onward.

peritoneal cavity: The space within theabdomen that contains the intestines,the stomach and the liver. It is bound bythin membranes.

peritoneal perfusion: A method of de-livering fluids and drugs directly to tu-mors in the peritoneal cavity.

pernicious anemia: A type of anemia(low red blood cell count) caused by thebody’s inability to absorb vitamin B12.

PET scan: Positron emission tomogra-phy scan. A computerized image of themetabolic activity of the body tissuesused to determine the presence ofdisease.

phagocyte: An immune system cell thatcan surround and kill microorganismsand remove dead cells. Phagocytes in-clude macrophages.

pharynx: The hollow tube about fiveinches long that starts behind the noseand ends at the top of the trachea(windpipe) and esophagus (the tube thatgoes to the stomach).

phase I trial: Phase I trials are the firststep in testing a new treatment in hu-mans. These studies test the best way togive a new treatment (for example, bymouth, intravenous infusion or injec-tion) and the best dose. The dose is usu-ally increased a little at a time in order tofind the highest dose that does not causeharmful side effects. Because little isknown about the possible risks andbenefits of treatments being tested, phaseI trials usually include only a smallnumber of patients, who have not beenhelped by other treatments.

phase I/II trial: A trial to study thesafety, dosage levels and response to anew treatment.

phase II trial: Phase II cancer trials testwhether a new treatment has an antican-cer effect (for example, whether itshrinks a tumor or improves blood testresults), and whether it works against acertain type of cancer.

phase II/III trial: A trial to studyresponse to a new treatment and theeffectiveness of the treatment comparedto the standard treatment regimen.

phase III trial: Phase III trials comparethe results of people taking a newtreatment with results of people takingstandard treatment (for example, whichgroup has better survival rates or fewerside effects). In most cases, studies moveinto phase III trials only after atreatment seems to work in phases I andII. Phase III trials may include hundredsof people.

phase IV trial: Once a treatment hasbeen approved and is being marketed, itis studied in a phase IV trial to evaluateside effects of the new treatment thatwere not apparent in the phase III trial.


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Thousands of people are involved in aphase IV trial.

phenylacetate: A drug being studied inthe treatment of cancer.

phenylbutyrate: An anticancer drug thatbelongs to the family of drugs calleddifferentiating agents.

photodynamic therapy: Treatment withdrugs that become active when exposedto light and kill cancer cells.

photofrin: A drug used in photo-dynamic therapy that is absorbed bytumor cells; when absorbed by cancercells and exposed to light, it becomesactive and kills the cancer cells.

photosensitizer: A drug used in photo-dynamic therapy. When absorbed bycancer cells and exposed to light, thedrug becomes active and kills the cancercells.

phyllodes tumor: Rare, benign ormalignant tumors of the breast.

pilocarpine: A drug used to increasesalivation in people who have drymouth. Dry mouth can be caused byopioids or radiation therapy. It belongsto the family of drugs called alkaloids.

pilot study: The initial study examininga new method or treatment.

pineal gland: A small gland located inthe cerebrum that produces melatonin.Also called pineal body or pineal organ.

pineal region tumors: Types of braintumors that occur in or around thepineal gland, a tiny organ near the centerof the brain.

pineoblastoma: A fast-growing type ofbrain tumor that occurs in or around thepineal gland, a tiny organ near the centerof the brain.

pineocytoma: A slow growing type ofbrain tumor that occurs in or around thepineal gland, a tiny organ near the centerof the brain.

piperacillin-tazobactam: A combinationof drugs used to fight infections inpeople who have cancer. Piperacillin is asynthetic penicillin; tazobactam enhan-ces the effectiveness of piperacillin.

piritrexim: An anticancer drug.

pituitary gland: The main endocrinegland; it produces hormones that controlother glands and many body functions,especially growth.

placebo: An inactive substance thatlooks the same as, and is administered inthe same way as, a drug in a clinical trial.

plasma: The clear, yellowish, fluid partof the blood that carries the blood cells.The proteins that form blood clots are inplasma.

plasma cells: A type of white blood cellthat produces antibodies.

plasmacytoma: A tumor that is made upof cancerous plasma cells.

plasmapheresis: The process of sepa-rating certain cells from the plasma inthe blood by a machine. Only the cellsare returned to the person. Plasma-pheresis can be used to remove excessantibodies from the blood.

platelets: A type of blood cell that helpsprevent bleeding by causing blood clotsto form. Also called thrombocytes.


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platinum: A metal that is an importantcomponent of some anticancer drugs,such as cisplatin and carboplatin.

pleura: A thin layer of tissue coveringthe lungs and the wall of the chest cavityto protect and cushion the lungs. A smallamount of fluid that acts as a lubricantallows the lungs to move smoothly in thechest cavity during breathing.

pleural cavity: A space enclosed by thepleura (thin tissue covering the lungsand lining the interior wall of the chestcavity). It is bound by thin membranes.

pleural effusion: An abnormal collec-tion of fluid between the thin layers oftissue (pleura) lining the lung and thewall of the chest cavity.

pneumatic larynx: A device that uses airto produce sound to help a laryngec-tomee talk.

polyp: A growth that protrudes from amucous membrane.

polyposis: The development of numer-ous polyps (growths that protrudes froma mucous membrane).

porfimer sodium: An anticancer drugthat is also used in cancer prevention. Itbelongs to the family of drugs calledphotosensitizing agents.

positive axillary lymph nodes: Lymphnodes in the area of the armpit (axilla) towhich cancer has spread. This is deter-mined by surgically removing some ofthe lymph nodes and examining themunder a microscope to see whether can-cer cells are present.

positron emission tomography scan:PET scan. A computerized image of the

metabolic activity of body tissues used todetermine the presence of disease.

postmenopausal: Refers to the time inlife after menopause. Menopause is thetime in a woman’s life when menstrualperiods stop for at least a year; also called“change of life.”

postremission therapy: Anticancerdrugs to kill cancer cells that surviveafter remission induction therapy.

precancerous: A term used to describe acondition that may or is likely to becomecancer. Also called premalignant.

prednisone: Belongs to the family ofdrugs called steroids. It is used to treatseveral types of cancer and other disor-ders. Prednisone also inhibits the body’simmune response.

preleukemia: Disease in which the bonemarrow does not function normally.Also called myelodysplastic syndrome orsmoldering leukemia.

premalignant: A term used to describe acondition that may or is likely to becomecancer. Also called precancerous.

primary tumor: The original tumor.

prinomastat: An anticancer drug thatbelongs to the family of drugs called an-giogenesis inhibitors. Prinomastat is amatrix metalloproteinase inhibitor. Alsocalled AG3340.

procarbazine: An anticancer drug thatbelongs to the family of drugs called al-kylating agents.

progesterone: A female hormone.

progesterone receptor negative (PR-):Breast cancer cells that do not have aprotein (receptor molecule) to which


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progesterone will attach. Breast cancercells that are PR- do not need the hor-mone progesterone to grow and usuallydo not respond to hormonal therapy.

progressive disease: Cancer that is in-creasing in scope or severity.

promegapoietin: A colony-stimulatingfactor that stimulates the production ofblood cells, especially platelets. It is givenduring chemotherapy to increase bloodcell regeneration. It is a cytokine thatbelongs to the family of drugs calledhematopoietic (blood-forming) agents.

promyelocytic leukemia: A type of acutemyeloid leukemia, a rapidly progressingdisease in which too many immatureblood-forming cells are found in theblood and bone marrow.

prophylactic cranial irradiation: Radia-tion therapy to the head to reduce therisk that cancer will spread to the brain.

prophylactic oophorectomy: Surgeryintended to reduce the risk of ovariancancer by removing the ovaries beforedisease develops.

prophylaxis: An attempt to preventdisease.

prostate gland: A gland in the male re-productive system just below the blad-der. It surrounds part of the urethra, thecanal that empties the bladder. It pro-duces a fluid that forms part of semen.

prostate-specific antigen: PSA. A sub-stance that may be found in an increasedamount in the blood of men who haveprostate cancer or benign prostatichyperplasia.

prostatectomy: An operation to removepart or all of the prostate. Radical (ortotal) prostatectomy is the removal ofthe entire prostate and some of the tissuearound it.

prostatic acid phosphatase: PAP. Anenzyme produced by the prostate. It maybe found in increased amount in menwho have prostate cancer.

prosthesis: An artificial replacement of apart of the body.

proteins: Molecules made up of aminoacids that are needed for the body tofunction properly. Proteins are the basisof body structures such as skin and hair,and of substances such as enzymes, cyto-kines and antibodies.


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Rradiation fibrosis: The formation of scartissue as a result of radiation therapy.

radiation surgery: A radiation therapytechnique that delivers radiation directlyto the tumor while sparing the healthytissue. Also called radiosurgery andstereotactic external beam irradiation.

radiation therapy: The use of high-en-ergy radiation from X-rays, neutronsand other sources to kill cancer cells andto shrink tumors. Radiation may comefrom a machine outside the body (exter-nal-beam radiation therapy) or frommaterial called radioisotopes. Radioiso-topes produce radiation and are placedin or near a tumor or near cancer cells.This type of radiation treatment is calledinternal radiation therapy, implant ra-diation or brachytherapy. Systemic ra-diation therapy uses a radioactive sub-stance, such as a radiolabeledmonoclonal antibody, that circulatesthroughout the body. Also calledradiotherapy.

radical cystectomy: Surgery to removethe bladder as well as nearby tissues andorgans.

radical mastectomy: Surgery to removethe breast, chest muscles, and all of thelymph nodes in the armpit. Also calledthe Halsted radical mastectomy.

radical prostatectomy: Surgery to re-move the entire prostate. The twotypes of radical prostatectomy are retro-pubic prostatectomy and perinealprostatectomy.

radioactive iodine: A radioactive formof the chemical element iodine often

used for imaging tests or as a treatmentfor cancer.

radiofrequency ablation: The use ofelectrical current to destroy tissue.

radioimmunoguided surgery: A proce-dure that uses radiolabeled substances todetect tumors for surgical removal.

radioimmunotherapy: Treatment with aradioactive substance that is linked to anantibody that will attach to the tumorwhen injected into the body.

radioisotope: An unstable element thatreleases radiation as it breaks down.Radioisotopes can be used in imagingtests or as a treatment for cancer.

radiolabeled: Any compound that hasbeen joined with a radioactive substance.

radiosensitization: The use of a drugthat makes tumor cells more sensitive toradiation therapy.

radiosensitizers: Drugs that make tu-mor cells more sensitive to radiation.

raloxifene: A drug that belongs to thefamily of drugs called selective estrogenreceptor modulators (SERMs). It is usedin the prevention of osteoporosis inpostmenopausal women. Raloxifene isalso being studied as a cancer preventiondrug.

ras gene: A gene that has been found tocause cancer when it is altered (mutated).Agents that block its activity may stopthe growth of cancer. A ras peptide is aprotein fragment produced by the rasgene.


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rebeccamycin: An anticancer drug thatbelongs to the family of drugs called an-tineoplastic antibiotics.

recurrence: The return of cancer, at thesame site as the original (primary) tumoror in another location, after it haddisappeared.

red blood cells: RBCs. Cells that carryoxygen to all parts of the body. Alsocalled erythrocytes.

Reed-Sternberg cell: A type of cell thatappears in people with Hodgkin’s dis-ease. The number of these cells increasesas the disease advances.

refractory cancer: Cancer that has notresponded to treatment.

regimen: A treatment plan that specifiesthe dosage, the schedule and the dura-tion of treatment.

regional chemotherapy: Treatment withanticancer drugs that is directed to aspecific area.

regression: A decrease in the extent orsize of cancer.

relapse: The return of signs and symp-toms of cancer after a period ofimprovement.

remission: Disappearance of the signsand symptoms of cancer. When thishappens, the disease is said to be “in re-mission.” A remission may be temporaryor permanent.

remission induction therapy: The initialchemotherapy a person receives to bringabout a remission.

renal cell cancer: Cancer that developsin the lining of the renal tubules, whichfilter the blood and produce urine.

resected: Surgical removal of part of anorgan.

resection: Surgical removal of part of anorgan.

residual disease: Cancer cells that re-main after attempts have been made toremove the cancer.

resistance: Clinical resistance is the fail-ure of a cancer to shrink after treatment.

response rate: The percentage of pa-tients whose cancer shrinks or disap-pears after treatment.

retinoblastoma: An eye cancer that mostoften occurs in children under the age offive. It occurs in both hereditary andnonhereditary (sporadic) forms.

retinoid: Vitamin A or a vitamin A-likecompound.

retinol: Vitamin A. It is essential forproper vision, healthy skin and mucousmembranes. Retinol is being studied forcancer prevention; it belongs to the fam-ily of drugs called retinoids.

retroviral vector: RNA from a virus thatis used to insert genetic material intocells.

RevM10 gene: An antiviral gene beingstudied for treatment of cancer in pa-tients who have HIV, the AIDS virus.

rhabdoid tumor: A malignant tumor ofeither the central nervous system (CNS)or the kidney. Malignant rhabdoid tu-mors of the CNS often have an abnor-mality of chromosome 22. These tumors


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usually occur in children younger thantwo years old.

rhabdomyosarcoma: A malignant tu-mor of muscle tissue.

ribonucleic acid: RNA. One of the twonucleic acids found in all cells. The otheris deoxyribonucleic acid (DNA). Ribo-nucleic acid transfers genetic informa-tion from DNA to proteins produced bythe cell.

risk factor: Anything that increases thechance of developing a disease.

rituximab: A type of monoclonal anti-body used in cancer detection or ther-apy. Monoclonal antibodies are labora-tory-produced substances that can locateand bind to cancer cells.

RNA: Ribonucleic acid. One of the twotypes of nucleic acids found in cells. Theother is DNA (deoxyribonucleic acid).RNA plays a role in sending informationfrom DNA to the protein-forming sys-tem of the cell.


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Ssarcoma: A cancer of the bone, cartilage,fat, muscle, blood vessels, or other con-nective or supportive tissue.

sargramostim: A colony-stimulatingfactor that stimulates the production ofblood cells, especially platelets, duringchemotherapy. It is a cytokine thatbelongs to the family of drugs calledhematopoietic (blood-forming) agents.Also called GM-CSF.

Schiller test: A test in which iodine isapplied to the cervix. The iodine colorshealthy cells brown; abnormal cellsremain unstained, usually appearingwhite or yellow.

schwannoma: A type of benign braintumor that begins in the Schwann cellsthat produce the myelin that protects theacoustic nerve (the nerve of hearing).

second cancer: Refers to a new primarycancer that is caused by previous cancertreatment, or a new primary cancer in aperson with a history of cancer.

second-look surgery: Surgery performedafter primary treatment to determinewhether tumor cells remain.

secondary tumor: Cancer that hasspread from the organ in which it firstappeared to another organ. For example,breast cancer cells may spread(metastasize) to the lungs and cause thegrowth of a new tumor. When thishappens, the disease is called metastaticbreast cancer, and the tumor in the lungsis called a secondary tumor. Also calledsecondary cancer.

segmental mastectomy: The removal ofthe cancer as well as some of the breast

tissue around the tumor and the liningover the chest muscles below the tumor.Usually some of the lymph nodes underthe arm are also taken out. Sometimescalled partial mastectomy.

seminoma: A type of cancer of thetesticles.

sentinel lymph node: The first lymphnode that cancer is likely to spread tofrom the primary tumor. Cancer cellsmay appear first in the sentinel nodebefore spreading to other lymph nodes.

sequential treatment: One treatmentafter the other.

Sezary syndrome: A form of cutaneousT-cell lymphoma, a cancerous diseasethat affects the skin.

shave biopsy: A procedure in which theparts of a mole that are above and justbelow the surface of the skin areremoved with a small blade. There is noneed for stitches with this procedure.

shunt: A surgically created diversion offluid, for example blood or cerebrospinalfluid, from one area of the body toanother.

side effects: Problems that occur whentreatment affects healthy cells. Commonside effects of cancer treatment arefatigue, nausea, vomiting, decreasedblood cell counts, hair loss and mouthsores.

small cell lung cancer: A type of lungcancer in which the cells appear smalland round when viewed under themicroscope. Also called oat cell lungcancer.


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small intestine: The part of the digestivetract that is located between the stomachand the large intestine.

smoldering leukemia: Disease in whichthe bone marrow does not functionnormally. Also called preleukemia ormyelodysplastic syndrome.

sodium salicylate: A drug that belongsto the family of drugs called nonsteroidalanti-inflammatory drugs. Sodium sali-cylate may be tolerated by people whoare sensitive to aspirin.

soft tissue: Refers to muscle, fat, fibroustissue, blood vessels or other supportingtissue of the body.

soft tissue sarcoma: A sarcoma that be-gins in the muscle, fat, fibrous tissue,blood vessels or other supporting tissueof the body.

solid tumor: Cancer of body tissuesother than blood, bone marrow or thelymphatic system.

somatic cells: All the body cells exceptthe reproductive (germ) cells.

somatic mutations: Alterations in DNAthat occur after conception. Somaticmutations can occur in any of the cells ofthe body except the germ cells.

spleen: An organ that is part of the lym-phatic system. The spleen produces lym-phocytes, filters the blood, stores bloodcells and destroys old blood cells. Thespleen is located on the left side of theabdomen near the stomach.

sputum: Mucus coughed up from thelungs.

squamous cell carcinoma: Cancer thatbegins in squamous cells, which are thin,

flat cells resembling fish scales. Squam-ous cells are found in the tissue thatforms the surface of the skin, the liningof the hollow organs of the body, and thepassages of the respiratory and digestivetracts. Also called epidermoid carcinoma.

squamous cells: Flat cells that look likefish scales under a microscope. Thesecells cover internal and external surfacesof the body.

stable disease: Cancer that is not de-creasing or increasing in extent orseverity.

stage: The extent of a cancer within thebody, including whether the disease hasspread from the original site to otherparts of the body. Staging refers to thedetermination of the extent of cancer.

staging: Doing exams and tests to learnthe extent of the cancer within the body,especially whether the disease has spreadfrom the original site to other parts ofthe body.

standard therapy: A currently acceptedand widely used treatment for a certaintype of cancer, based on the results ofpast research.

stem cell transplantation: A method ofreplacing immature blood-forming cellsthat were destroyed by cancer treatment.The stem cells are given to the personafter treatment to help the bone marrowrecover and continue producing healthyblood cells.

stem cells: The cells from which allblood cells come.

stent: A device placed in a body struc-ture such as a blood vessel or the gas-trointestinal tract, in order to providesupport and keep the structure open.


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stereotaxis: Use of a computer andscanning devices to create three-dimen-sional pictures. This method can be usedto direct a biopsy, external radiation orthe insertion of radiation implants.

steroid therapy: Treatment with corti-costeroid drugs to reduce swelling, painand other symptoms of inflammation.

steroids: Drugs used to relieve swellingand inflammation.

STI571: A substance that is being studiedfor its ability to inhibit the growth ofcertain leukemias. It interferes with aportion of the protein produced by thebcr/abl oncogene.

stoma: A surgically created openingfrom an area inside the body to the out-side. Colostomy and urostomy are typesof stomas. Also called an ostomy.

streptavidin: A small bacterial proteinthat binds with high affinity to the vita-min biotin. This streptavidin-biotincombination can be used to link mole-cules such as radioisotopes and mono-clonal antibodies together. These boundproducts have the property of being at-tracted, and attached, to cancer cells,rather than normal cells. The radiola-beled products are more easily removedfrom the body, thus decreasing theirtoxicity.

streptozocin: An anticancer drug thatbelongs to the family of drugs called al-kylating agents.

stromagen: A drug that is derived from apatient’s stem cells (specialized cells inthe bone marrow which form new bloodcells) and may be given back to them tohelp restore bone marrow that has beendamaged by high-dose chemotherapy.

stromal tumors (STRO-mal): Tumorsthat arise in the supporting connectivetissue of an organ.

strontium: A metal often used in a ra-dioactive form for imaging tests or as atreatment for cancer.

strontium-89: A radioactive compoundthat is absorbed by the bone. It is used totreat bone pain associated with prostatecancer.

SU5416: An anticancer drug that be-longs to the family of drugs called angio-genesis inhibitors.

subcutaneous: Beneath the skin.

subcutaneous port: A tube surgicallyplaced into a blood vessel and attachedto a disk placed under the skin. It is usedfor the administration of intravenousfluids and drugs. It can also be used toobtain blood samples.

suberoylanilide hydroxamic acid: Asubstance that is being studied as ananticancer drug.

sucralfate: A drug used to treat ulcers. Itadheres to proteins at the ulcer site andforms a protective coating over the ulcer.It is also used to treat mucositis.

sulindac sulfone: An analgesic drug thatbelongs to the family of drugs callednonsteroidal anti-inflammatory agents.It is also being studied in cancerprevention.

supraclavicular lymph nodes: Lymphnodes located above the clavicle (collarbone).


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surgical castration: Surgical removal ofthe testicles (orchiectomy) or ovaries(oophorectomy) to stop the productionof sex hormones. Decreasing the levels ofhormones may stop the growth of cer-tain cancers.

systemic: Affecting the entire body.

systemic therapy: Treatment that usessubstances that travel through thebloodstream, reaching and affecting cellsall over the body.


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TT cell: A type of white blood cell thatattacks virus-infected cells, foreign cellsand cancer cells. T cells also produce anumber of substances that regulate theimmune response.

T-cell depletion: Treatment to destroy Tcells, which play an important role in theimmune response. Elimination of T cellsfrom a bone marrow graft from anotherperson may reduce the chance of animmune reaction against the person’stissues.

T-cell lymphoma: A disease in whichcertain cells of the lymph system (calledT lymphocytes) become cancerous.

tamoxifen: An anticancer drug that be-longs to the family of drugs called anti-estrogens. Tamoxifen blocks the effectsof the hormone estrogen in the body. Itis used to prevent or delay the return ofbreast cancer or to control its spread.

taxanes: Anticancer drugs that inhibitcancer cell growth by stopping cell divi-sion. Also called antimitotic or antimi-crotubule agents, or mitotic inhibitors.

tegafur: An anticancer drug that belongsto the family of drugs calledantimetabolites.

temozolomide: An anticancer drug thatbelongs to the family of drugs called al-kylating agents.

teniposide: An anticancer drug that is apodophyllotoxin derivative and belongsto the family of drugs called mitoticinhibitors.

testosterone: A hormone that promotesthe development and maintenance ofmale sex characteristics.

thalidomide: A drug that belongs to thefamily of drugs called angiogenesis in-hibitors. It prevents the growth of newblood vessels into a solid tumor.

thioguanine: An anticancer drug thatbelongs to the family of drugs calledantimetabolites.

thiotepa: An anticancer drug that be-longs to the family of drugs calledalkylating agents.

thoracic: Pertaining to the chest.

thoracoscopy: The use of a thin, lightedtube (called an endoscope) to examinethe inside of the chest.

thrombocytes: Blood cells that help pre-vent bleeding by causing blood clots toform. Also called platelets.

thrombocytopenia: A decrease in thenumber of platelets in the blood, whichmay result in easy bruising and excessivebleeding from wounds or bleeding inmucous membranes and other tissues.

thrombophlebitis: Inflammation of avein that occurs when a blood clot forms.

thrombopoietin: A colony-stimulatingfactor that stimulates the production ofblood cells, especially platelets, duringchemotherapy. It is a cytokine thatbelongs to the family of drugs calledhematopoietic (blood-forming) agents.

thymidine: A chemical compoundfound in DNA. Also used as treatmentfor mucositis.

thymoma: A tumor of the thymus, anorgan that is part of the lymphatic sys-tem and is located in the chest, behindthe breastbone.


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thymus: An organ that is part of thelymphatic system, in which T lympho-cytes grow and multiply. The thymus islocated in the chest behind thebreastbone.

thyroid: A gland located near the wind-pipe (trachea) that produces thyroidhormone, which helps regulate growthand metabolism.

tirapazamine: A drug that makes tumorcells more sensitive to radiation therapy.

topical chemotherapy: Treatment withanticancer drugs in a lotion or creamapplied on the skin.

topoisomerase inhibitors: A family ofanticancer drugs. The topoisomeraseenzymes are responsible for the ar-rangement and rearrangement of DNAin the cell and for cell growth and repli-cation. Inhibiting these enzymes may killcancer cells or stop their growth.

topotecan: An anticancer drug that be-longs to the family drugs called topoi-somerase inhibitors.

toremifene: An anticancer drug thatbelongs to the family of drugs called an-tiestrogens. Toremifene blocks the effectof the hormone estrogen in the body. Itmay help control some cancers fromgrowing, and it may delay or reduce therisk of cancer recurrence.

total estrogen blockade: Therapy usedto eliminate estrogen in the body. Thismay be done with surgery, radiationtherapy, chemotherapy or a combinationof these.

total hysterectomy: Surgery to removethe entire uterus.

total mastectomy: Removal of thebreast. Also called simple mastectomy.

total nodal irradiation: Radiation ther-apy to the mantle field, the spleen, thelymph nodes in the upper abdomen andthe lymph nodes in the pelvic area.

total pancreatectomy: Surgery to re-move the entire pancreas.

total-body irradiation: Radiation ther-apy to the entire body. Usually followedby bone marrow or peripheral stem celltransplantation.

toxicity: Negative side effect.

trachea: The airway that leads from thelarynx to the lungs. Also called thewindpipe.

transformation: The change that a nor-mal cell undergoes as it becomesmalignant.

transfusion: The infusion of compo-nents of blood or whole may have beentaken from the person earlier and storeduntil needed.

transitional cell carcinoma: A type ofcancer that develops in the lining of thetransitional cells: cells lining someorgans.

transplantation: The replacement of anorgan with one from another person.

transrectal ultrasound: A procedureused to examine the prostate. An in-strument is inserted into the rectum, andsound waves bounce off the prostate.These sound waves create echoes, whicha computer uses to create a picture calleda sonogram.


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transurethral prostatic resection: Surgi-cal procedure to remove tissue from theprostate using an instrument insertedthrough the urethra. Also called TURP.

transurethral resection: Surgery per-formed with a special instrument in-serted through the urethra. Also calledTURP.

trastuzumab: A type of monoclonal an-tibody used in cancer detection or ther-apy. Monoclonal antibodies are labora-tory-produced substances that can locateand bind to cancer cells. Trastuzumabblocks the effects of the growth factorprotein HER2, which transmits growthsignals to breast cancer cells.

tretinoin: A drug that belongs to thefamily of drugs called retinoids. It is usedin the treatment of acne and is beingstudied in cancer prevention.

tributyrin: A triglyceride drug that mayinhibit cell growth and induce cell differ-entiation. Differentiating agents may beeffective in changing cancer cells backinto normal cells.

trimetrexate glucuronate: A drug thatbelongs to the family of drugs calledantimetabolites. It is used in the treat-ment of pneumocystis carinii pneumo-nia and is being studied in the treatmentof cancer.

triptorelin: A hormonal anticancer drugthat belongs to the family of drugs calledgonadotropin-releasing hormones.

tubal ligation: An operation to tie thefallopian tubes closed. This procedureprevents pregnancy by blocking thepassage of eggs from the ovaries to theuterus.

tumor: An abnormal mass of tissue thatresults from excessive cell division. Tu-mors perform no useful body function.They may be either benign (not cancer-ous) or malignant (cancerous).

tumor antigen vaccine: A vaccine madeof tumor antigens (proteins isolatedfrom tumor cells).

tumor debulking: Surgically removingas much of the tumor as possible.

tumor infiltrating lymphocytes: Whiteblood cells that have left the bloodstreamand migrated into a tumor.

tumor marker: A substance sometimesfound in an increased amount in theblood, other body fluids, or tissues andthat may mean that a certain type ofcancer is in the body. Examples of tumormarkers include CA 125 (ovarian can-cer), CA 15-3 (breast cancer), CEA(ovarian, lung, breast, pancreas and gas-trointestinal tract cancers), and PSA(prostate cancer). Also called biomarker.

tumor necrosis factor: A type of biologi-cal response modifier (a substance thatstimulates the body’s response to infec-tion and disease).

tumor suppressor gene: Genes in thebody that can suppress or block the de-velopment of cancer.

tumor-derived: Taken from a person’stumor tissue; may be used in the devel-opment of a vaccine that enhances thebody’s ability to build an immune re-sponse to the tumor.

tyrosinase peptide: A tumor-specificantigen used in the development of can-cer vaccines.


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Uunresectable: Unable to be surgicallyremoved.

uracil: An anticancer drug that belongsto the family of drugs called alkylatingagents.

ureter: The tube that carries urine fromthe kidney to the bladder.

urethra: The tube through which urineleaves the body. It empties urine fromthe bladder.

urinary tract: The organs of the bodythat produce and discharge urine. Theseinclude the kidneys, ureters, bladder andurethra.

uterus: The small, hollow, pear-shapedorgan in a woman’s pelvis. This is theorgan in which a fetus develops. Alsocalled the womb.


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Vvaccine: A substance or group of sub-stances designed to stimulate an immuneresponse to a tumor or to microorgan-isms, such as bacteria or viruses.

vaccine adjuvant: A substance added toa vaccine to improve the immune re-sponse so that less vaccine is needed.

vasectomy: An operation to cut or tie offthe two tubes that carry sperm out of thetesticles.

vinblastine: An anticancer drug thatbelongs to the family of plant drugscalled vinca alkaloids. It is a mitoticinhibitor.

vinca alkaloids: Anticancer drugs thatinhibit cancer cell growth by stoppingcell division. They are also called anti-mitotic or antimicrotubule agents, ormitotic inhibitors.

vincristine: An anticancer drug that be-longs to the family of plant drugs calledvinca alkaloids.

vindesine: An anticancer drug that be-longs to the family of plant drugs calledvinca alkaloids.

vinorelbine: An anticancer drug thatbelongs to the family of plant drugscalled vinca alkaloids.

viral vector: A type of virus used in can-cer therapy. The virus is changed in the

laboratory and cannot cause disease.Viral vectors produce tumor antigens(proteins found on a tumor cell) and canstimulate an antitumor immune re-sponse in the body. Viral vectors mayalso be used to carry genes that canchange cancer cells back to normal cells.

viruses: Submicroscopic organisms thatcause infectious disease. In cancer ther-apy, some viruses may be made into vac-cines that help the body build an im-mune response to kill tumor cells.

visual pathway glioma: A rare, slow-growing tumor of the eye.

vitamin A: A vitamin used in cancerprevention; it belongs to the family ofdrugs called retinoids.

vitamin E: A vitamin used in cancer pre-vention; it belongs to the family of drugscalled tocopherols.

vitamin K: A substance that promotesthe clotting of blood.

von Hippel-Lindau syndrome: A rareinherited disorder in which blood vesselsgrow abnormally in the eyes, brain, spi-nal cord, adrenal glands or other parts ofthe body. People with von Hippel-Lindau syndrome have a higher risk ofdeveloping some types of cancer.

vorozole: A hormone therapy drug usedto decrease the production of estrogen.


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W XWaldenstrom’s macroglobulinemia: Arare cancer of the lymph cells that causesthe body to produce abnormal levels ofplasma cells (plasmacytosis) and lym-phocytes (lymphocytosis) in the bonemarrow. Waldenstrom’s macroglobuli-nemia may also cause a decrease in redblood cells (anemia) and enlargement ofthe liver (hepatomegaly), spleen (sple-nomegaly), or glands (adenopathy).

white blood cell: A type of cell in theimmune system that help the body fightinfection and disease. White blood cellsinclude lymphocytes, granulocytes,macrophages and others.

Whitmore-Jewett staging system: Asystem used for the staging of prostatecancer.

whole cell vaccine: Vaccine made fromwhole tumor cells that have beenchanged in the laboratory.

Wilms’ tumor: A kidney cancer thatoccurs in children, usually before the ageof five.

xeroderma pigmentosum: A geneticcondition characterized by a sensitivityto all sources of ultraviolet radiation.

Zzoledronate: A drug that belongs to thefamily of drugs called bisphosphonates.It is used to prevent bone fractures andto reduce bone pain in people who havecancer that has spread to the bone.


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Additional information available upon request.

Prices of companies mentioned as of November 8, 2000:

ALZA Corp AZA $89.00American Home Products AHP $61.38Amgen 1 AMGN $61.63AstraZeneca AZN $49.19Aventis AVE $74.63Bristol-Myers Squibb BMY $62.31Eli Lilly & Co LLY $90.44Genentech Inc DNA $86.75Glaxo Wellcome GLX $59.50Idec Pharmaceuticals Corp IDPH $220.25Johnson & Johnson JNJ $93.44Merck & Co MRK $90.81Novartis NVS $40.25Pfizer Inc PFE $45.38Pharmacia Corp. PHA $59.44Roche ROHHY $94.68Schering-Plough SGP $51.88Smithkline Beecham 2 SBH $67.13

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The Cancer Market - UBS - Nov00