June 2009 Vol. 2 No. 4

© 2009 Green Hill Healthcare Communications, LLC

JUNE 2009 • VOL. 2, NO. 4 www.theoncologypharmacist.com

SAFE HANDLINGNational initiative highlightsrisks of occupational drugexposure

page 30

NEW IN THIS ISSUEIn the LiteratureConcise reviews of studiesrelevant to cancer care

page 6

PHARMACY PRACTICE

Continued on page 22

GASTROINTESTINAL CANCERS

HOPA President ForeseesOpportunities for GrowthAn Interview with Cindy O’Bryant, PharmD, BCOP

PROSTATE CANCER


KRAS Testing Added to Colonand Rectal Cancers Guidelines

The Leader

in News and

Meeting

Coverage

In addition to her responsibili-ties as associate professor in theDepartment of Clinical Phar-

macy at the University of ColoradoSchool of Pharmacy and director ofthe Oncology Pharmacy PracticeResidency there, Cindy O’Bryant,PharmD, BCOP, has spent the pastyear as president of the Hematology/Oncology Pharmacy Association(HOPA). Dr O’Bryant recently

spoke with The Oncology Pharmacistabout achievements during thepast year, plans for the future of theorganization, and future directionsfor oncology pharmacy in general.

How did you get involved inoncology pharmacy andHOPA in particular?When I was in pharmacy school

at Mercer University Southern

School of Pharmacy in Atlanta,Georgia, I did an oncology rotationat Emory and saw the collaborative,multidisciplinary nature of oncologypharmacy and how oncology phar-macists were well integrated intothe cancer care team. That wasexactly what I wanted to do—tohave a lot of direct patient contactand also to work collaboratively


Register online atwww.theoncologypharmacist.com toensure uninterrupted FREE delivery

of The Oncology Pharmacist

YOU COULD BE HOLDINGYOU COULD BE HOLDINGYOUR LAST ISSUE!YOUR LAST ISSUE!

AUA Counters MainstreamRecommendations withNew Position on Prostate

Cancer ScreeningCHICAGO—The American Urological Association(AUA) is lowering the recommended age for PSA(prostate-specific antigen) testing by 10 years, from age50 years to age 40 years. The AUA issued new clinicalguidance, which directly contrasts with recent recom-mendations by other major groups, at its 104th AnnualScientific Meeting in April. The new recommenda-tion by the AUA is that PSA testing should be offeredto well-informed men aged 40 years or older who havea life expectancy of at least 10 years.

HOLLYWOOD, FL—New Kirsten rat sarcoma(KRAS) testing recommendations, survivor-ship protocols, and resectability criteria are

the main highlights from the latest colon and rectalcancers guideline updates from the National Com-prehensive Cancer Network (NCCN), as reported atthe 14th Annual NCCN Conference: ClinicalPractice Guidelines & Quality Cancer Care.The guidelines were presented by Paul F. Engstrom,


BREAST CANCER

Genetic Counseling Added toBreast Cancer Guidelines

In the annual update of its breast cancer guidelines,the National Comprehensive Cancer Network(NCCN) encourages oncologists and their staff to

offer genetic counseling for patients with ductal carci-noma in situ (DCIS) and a strong family history to con-sider eliminating the “boost” after radiotherapy in olderpatients with early invasive breast cancer. The breastcancer panel lists surgical excision as an option forlocally advanced or recurrent stage IV disease, and

PROGRAM #C1K10107

PAGE 23

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Oral Biologic Therapy versusChemotherapy for PretreatedNon–small-cell Lung Cancer

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Second annual Considerations in

Multiple Myeloma newsletter series.

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*In a phase III, multicenter, randomized, double-blind, placebo-controlled trial of 99 newly diagnosed adult patients, 55 to 70 years of age, receiving induction chemotherapy with or without consolidation therapy.2

For patients 55 years and older with acute myelogenous leukemia (AML) following induction chemotherapy…

Go Beyond Neutrophil Recovery With

LEUKINE is a multilineage colony-stimulating factor that stimulates the production and activity of monocytes/macrophages and dendritic cells, as well as neutrophils1

Significantly fewer deaths due to serious infections in patients treated with LEUKINE versus placebo*2

75%DECREASE

LEUKINE,3/52 (5.8%)

vsplacebo,

11/47 (23.4%)

P=.019Fatal infections during

and within 30 days of study completion

90%DECREASE

LEUKINE,1/52 (1.9%)

vsplacebo,

9/47 (19.1%)

P=.006Death from

fungal infectionsin all patients

83%DECREASE

LEUKINE,1/8 (12.5%)

vsplacebo,

9/12 (75%)

P=.02Fatal fungal infections in patients with grade 3/4 fungal infections

73%DECREASE

LEUKINE,2/14 (14.3%)

vsplacebo,

7/13 (53.8%)

P=.046Death from

pneumonias in patients with pneumonia

References: 1. LEUKINE® (sargramostim) [package insert]. Bayer HealthCare Pharmaceuticals Inc.; April 2008. 2. Rowe JM, Rubin A, Mazza JJ, et al. Incidence ofinfections in adult patients (> 55 years) with acute myeloid leukemia treated with yeast-derived GM-CSF (sargramostim): results of a double-blind prospective studyby the Eastern Cooperative Oncology Group. In: Hiddemann W, et al, eds. Acute Leukemias V: Experimental Approaches and Management of Refractory Diseases. Berlin, Germany: Springer-Verlag; 1996:178-184.

© 2009 Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ 07470 All rights reserved. 561-10-0001-09b Printed in USA May 2009

Please see brief summary of full Prescribing Information on adjacent pages.

Drug InteractionsDrugs that can increase white blood cells (WBCs), such as lithium and corticosteroids, should be used with caution while receiving LEUKINE. Also, LEUKINE should not be used 24 hours before through 24 hours after any chemotherapy or radiation therapy. Interactions between LEUKINE and other drugs have not been fully evaluated.

Important Safety ConsiderationsLEUKINE is contraindicated in patients with excessive leukemic blasts in bone marrow or peripheral blood (≥10%); in patients with known hypersensitivity to GM-CSF, yeast-derived products, or any component of LEUKINE; and for concomitant use with chemotherapy and radiotherapy.

Serious allergic or anaphylactic reactions have been reported with LEUKINE. If any serious or anaphylactic reactions occur, LEUKINE therapy should immediately be discontinued and appropriate therapy initiated.

Liquid solutions containing benzyl alcohol (including liquid LEUKINE) or lyophilized LEUKINE reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates.

LEUKINE should be used with caution and monitored in patients with preexisting fl uid retention, pulmonary infi ltrates, or CHF; respiratory symptoms or disease; cardiac symptoms or disease; and renal or hepatic dysfunction.

Edema, capillary leak syndrome, pleural and/or pericardial effusion, supraventricular tachycardia, sequestration of granulocytes in the pulmonary circulation, and dyspnea have been reported in patients after LEUKINE administration. LEUKINE has induced the elevation of serum creatinine or bilirubin and hepatic enzymes in some patients. Monitoring of renal and hepatic function in patients with preexisting renal or hepatic dysfunction is recommended at least every other week during LEUKINE administration.

Nearly all patients reported leukopenia, thrombocytopenia, and anemia. Adverse events occurring in >10% of AML patients receiving LEUKINE in controlled clinical trials and reported in a higher frequency than placebo were: fever, skin reactions, metabolic disturbances, nausea, vomiting, weight-loss, edema, and anorexia.

If ANC >20,000 cells/mm3 or if platelet counts >500,000/mm3, LEUKINE administration should be interrupted or the dose reduced by half. Twice weekly monitoring of CBC with differential should be performed.

LEUKINE therapy should be discontinued if disease progression is detected during treatment.

6701801BS (11981)Revision date 4/08US License 1791

Rx only

BRIEF SUMMARYCONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

INDICATIONS AND USAGEUse Following Induction Chemotherapy in Acute Myelogenous Leukemia LEUKINE isindicated for use following induction chemotherapy in older adult patients with acute myelogenous leukemia(AML) to shorten time to neutrophil recovery and to reduce the incidence of severe and life-threateninginfections and infections resulting in death. The safety and efficacy of LEUKINE have not been assessed inpatients with AML under 55 years of age.

The term acute myelogenous leukemia, also referred to as acute non-lymphocytic leukemia (ANLL),encompasses a heterogeneous group of leukemias arising from various non-lymphoid cell lines which havebeen defined morphologically by the French-American-British (FAB) system of classification.Use in Mobilization and Following Transplantation of Autologous Peripheral BloodProgenitor Cells LEUKINE is indicated for the mobilization of hematopoietic progenitor cells intoperipheral blood for collection by leukapheresis. Mobilization allows for the collection of increased numbersof progenitor cells capable of engraftment as compared with collection without mobilization. Aftermyeloablative chemotherapy, the transplantation of an increased number of progenitor cells can lead to morerapid engraftment, which may result in a decreased need for supportive care. Myeloid reconstitution is furtheraccelerated by administration of LEUKINE following peripheral blood progenitor cell transplantation.Use in Myeloid Reconstitution After Autologous Bone Marrow Transplantation LEUKINE isindicated for acceleration of myeloid recovery in patients with non-Hodgkin’s lymphoma (NHL), acutelymphoblastic leukemia (ALL) and Hodgkin’s disease undergoing autologous bone marrow transplantation(BMT). After autologous BMT in patients with NHL, ALL, or Hodgkin’s disease, LEUKINE has been found tobe safe and effective in accelerating myeloid engraftment, decreasing median duration of antibioticadministration, reducing the median duration of infectious episodes and shortening the median duration ofhospitalization. Hematologic response to LEUKINE can be detected by complete blood count (CBC) withdifferential cell counts performed twice per week.Use in Myeloid Reconstitution After Allogeneic Bone Marrow Transplantation LEUKINE isindicated for acceleration of myeloid recovery in patients undergoing allogeneic BMT from HLA-matchedrelated donors. LEUKINE has been found to be safe and effective in accelerating myeloid engraftment,reducing the incidence of bacteremia and other culture positive infections, and shortening the medianduration of hospitalization.Use in Bone Marrow Transplantation Failure or Engraftment Delay LEUKINE is indicated inpatients who have undergone allogeneic or autologous bone marrow transplantation (BMT) in whomengraftment is delayed or has failed. LEUKINE has been found to be safe and effective in prolonging survivalof patients who are experiencing graft failure or engraftment delay, in the presence or absence of infection,following autologous or allogeneic BMT. Survival benefit may be relatively greater in those patients whodemonstrate one or more of the following characteristics: autologous BMT failure or engraftment delay,no previous total body irradiation, malignancy other than leukemia or a multiple organ failure (MOF)score ≤ two (see CLINICAL EXPERIENCE). Hematologic response to LEUKINE can be detected bycomplete blood count (CBC) with differential performed twice per week.

CONTRAINDICATIONSLEUKINE is contraindicated:1) in patients with excessive leukemic myeloid blasts in the bone marrow or peripheral blood (≥ 10%);2) in patients with known hypersensitivity to GM-CSF, yeast-derived products or any component of the

product;3) for concomitant use with chemotherapy and radiotherapy.

Due to the potential sensitivity of rapidly dividing hematopoietic progenitor cells, LEUKINE should notbe administered simultaneously with cytotoxic chemotherapy or radiotherapy or within 24 hours precedingor following chemotherapy or radiotherapy. In one controlled study, patients with small cell lung cancerreceived LEUKINE and concurrent thoracic radiotherapy and chemotherapy or the identical radiotherapy andchemotherapy without LEUKINE. The patients randomized to LEUKINE had significantly higher incidence ofadverse events, including higher mortality and a higher incidence of grade 3 and 4 infections and grade 3and 4 thrombocytopenia.11

WARNINGSPediatric Use Benzyl alcohol is a constituent of liquid LEUKINE and Bacteriostatic Water for Injectiondiluent. Benzyl alcohol has been reported to be associated with a fatal “Gasping Syndrome” in prematureinfants. Liquid solutions containing benzyl alcohol (including liquid LEUKINE ) or lyophilizedLEUKINE reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol)should not be administered to neonates (see PRECAUTIONS and DOSAGE ANDADMINISTRATION).Fluid Retention Edema, capillary leak syndrome, pleural and/or pericardial effusion have been reportedin patients after LEUKINE administration. In 156 patients enrolled in placebo-controlled studies usingLEUKINE at a dose of 250 mcg/m2/day by 2-hour IV infusion, the reported incidences of fluid retention(LEUKINE vs. placebo) were as follows: peripheral edema, 11% vs. 7%; pleural effusion, 1% vs. 0%; andpericardial effusion, 4% vs. 1%. Capillary leak syndrome was not observed in this limited number of studies;based on other uncontrolled studies and reports from users of marketed LEUKINE, the incidence is estimatedto be less than 1%. In patients with preexisting pleural and pericardial effusions, administration of LEUKINEmay aggravate fluid retention; however, fluid retention associated with or worsened by LEUKINE has beenreversible after interruption or dose reduction of LEUKINE with or without diuretic therapy. LEUKINE should beused with caution in patients with preexisting fluid retention, pulmonary infiltrates or congestive heart failure.Respiratory Symptoms Sequestration of granulocytes in the pulmonary circulation has beendocumented following LEUKINE infusion12 and dyspnea has been reported occasionally in patients treatedwith LEUKINE. Special attention should be given to respiratory symptoms during or immediately followingLEUKINE infusion, especially in patients with preexisting lung disease. In patients displaying dyspnea duringLEUKINE administration, the rate of infusion should be reduced by half. If respiratory symptoms worsendespite infusion rate reduction, the infusion should be discontinued. Subsequent IV infusions may beadministered following the standard dose schedule with careful monitoring. LEUKINE should beadministered with caution in patients with hypoxia.Cardiovascular Symptoms Occasional transient supraventricular arrhythmia has been reported inuncontrolled studies during LEUKINE administration, particularly in patients with a previous history ofcardiac arrhythmia. However, these arrhythmias have been reversible after discontinuation of LEUKINE.LEUKINE should be used with caution in patients with preexisting cardiac disease.Renal and Hepatic Dysfunction In some patients with preexisting renal or hepatic dysfunction enrolledin uncontrolled clinical trials, administration of LEUKINE has induced elevation of serum creatinine orbilirubin and hepatic enzymes. Dose reduction or interruption of LEUKINE administration has resulted in adecrease to pretreatment values. However, in controlled clinical trials the incidences of renal and hepaticdysfunction were comparable between LEUKINE (250 mcg/m2/day by 2-hour IV infusion) and placebo-treated patients. Monitoring of renal and hepatic function in patients displaying renal or hepatic dysfunctionprior to initiation of treatment is recommended at least every other week during LEUKINE administration.

PRECAUTIONSGeneral Parenteral administration of recombinant proteins should be attended by appropriate precautionsin case an allergic or untoward reaction occurs. Serious allergic or anaphylactic reactions have beenreported. If any serious allergic or anaphylactic reaction occurs, LEUKINE therapy should immediately bediscontinued and appropriate therapy initiated.

A syndrome characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, and/ortachycardia has been reported following the first administration of LEUKINE in a particular cycle. These signshave resolved with symptomatic treatment and usually do not recur with subsequent doses in the same cycleof treatment.

Stimulation of marrow precursors with LEUKINE may result in a rapid rise in white blood cell (WBC)count. If the ANC exceeds 20,000 cells/mm3 or if the platelet count exceeds 500,000/mm3, LEUKINEadministration should be interrupted or the dose reduced by half. The decision to reduce the dose or interrupttreatment should be based on the clinical condition of the patient. Excessive blood counts have returned tonormal or baseline levels within three to seven days following cessation of LEUKINE therapy. Twice weeklymonitoring of CBC with differential (including examination for the presence of blast cells) should beperformed to preclude development of excessive counts.Growth Factor Potential LEUKINE is a growth factor that primarily stimulates normal myeloidprecursors. However, the possibility that LEUKINE can act as a growth factor for any tumor type, particularlymyeloid malignancies, cannot be excluded. Because of the possibility of tumor growth potentiation,precaution should be exercised when using this drug in any malignancy with myeloid characteristics.

Should disease progression be detected during LEUKINE treatment, LEUKINE therapy should bediscontinued.

LEUKINE has been administered to patients with myelodysplastic syndromes (MDS) in uncontrolledstudies without evidence of increased relapse rates.13, 14, 15 Controlled studies have not been performed inpatients with MDS.

Use in Patients Receiving Purged Bone Marrow LEUKINE is effective in accelerating myeloidrecovery in patients receiving bone marrow purged by anti-B lymphocyte monoclonal antibodies. Dataobtained from uncontrolled studies suggest that if in vitro marrow purging with chemical agents causes asignificant decrease in the number of responsive hematopoietic progenitors, the patient may not respond toLEUKINE. When the bone marrow purging process preserves a sufficient number of progenitors (>1.2 x104/kg), a beneficial effect of LEUKINE on myeloid engraftment has been reported.16

Use in Patients Previously Exposed to Intensive Chemotherapy/Radiotherapy In patients whobefore autologous BMT, have received extensive radiotherapy to hematopoietic sites for the treatment ofprimary disease in the abdomen or chest, or have been exposed to multiple myelotoxic agents (alkylatingagents, anthracycline antibiotics and antimetabolites), the effect of LEUKINE on myeloid reconstitution maybe limited.Use in Patients with Malignancy Undergoing LEUKINE-Mobilized PBPC Collection Whenusing LEUKINE to mobilize PBPC, the limited in vitro data suggest that tumor cells may be released andreinfused into the patient in the leukapheresis product. The effect of reinfusion of tumor cells has not beenwell studied and the data are inconclusive.Information for Patients LEUKINE should be used under the guidance and supervision of a health careprofessional. However, when the physician determines that LEUKINE may be used outside of the hospital oroffice setting, persons who will be administering LEUKINE should be instructed as to the proper dose, and themethod of reconstituting and administering LEUKINE (see DOSAGE AND ADMINISTRATION). If homeuse is prescribed, patients should be instructed in the importance of proper disposal and cautioned againstthe reuse of needles, syringes, drug product, and diluent. A puncture resistant container should be used bythe patient for the disposal of used needles.

Patients should be informed of the serious and most common adverse reactions associated withLEUKINE administration (see ADVERSE REACTIONS). Female patients of childbearing potentialshould be advised of the possible risks to the fetus of LEUKINE (see PRECAUTIONS, PregnancyCategory C).Laboratory Monitoring LEUKINE can induce variable increases in WBC and/or platelet counts. In orderto avoid potential complications of excessive leukocytosis (WBC >50,000 cells/mm3; ANC >20,000cells/mm3), a CBC is recommended twice per week during LEUKINE therapy. Monitoring of renal and hepaticfunction in patients displaying renal or hepatic dysfunction prior to initiation of treatment is recommended atleast biweekly during LEUKINE administration. Body weight and hydration status should be carefullymonitored during LEUKINE administration.Drug Interaction Interactions between LEUKINE and other drugs have not been fully evaluated. Drugswhich may potentiate the myeloproliferative effects of LEUKINE, such as lithium and corticosteroids, shouldbe used with caution.Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conductedwith LEUKINE to evaluate the carcinogenic potential or the effect on fertility.Pregnancy (Category C) Animal reproduction studies have not been conducted with LEUKINE. It is notknown whether LEUKINE can cause fetal harm when administered to a pregnant woman or can affectreproductive capability. LEUKINE should be given to a pregnant woman only if clearly needed.Nursing Mothers It is not known whether LEUKINE is excreted in human milk. Because many drugs areexcreted in human milk, LEUKINE should be administered to a nursing woman only if clearly needed.Pediatric Use Safety and effectiveness in pediatric patients have not been established; however, availablesafety data indicate that LEUKINE does not exhibit any greater toxicity in pediatric patients than in adults. Atotal of 124 pediatric subjects between the ages of 4 months and 18 years have been treated with LEUKINEin clinical trials at doses ranging from 60-1,000 mcg/m2/day intravenously and 4-1,500 mcg/m2/daysubcutaneously. In 53 pediatric patients enrolled in controlled studies at a dose of 250 mcg/m2/day by 2-hour IV infusion, the type and frequency of adverse events were comparable to those reported for the adultpopulation. Liquid solutions containing benzyl alcohol (including liquid LEUKINE ) orlyophilized LEUKINE reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzylalcohol) should not be administered to neonates (see WARNINGS).Geriatric Use In the clinical trials, experience in older patients (age ≥65 years), was limited to the acutemyelogenous leukemia (AML) study. Of the 52 patients treated with LEUKINE in this randomized study, 22patients were age 65-70 years and 30 patients were age 55-64 years. The number of placebo patients in eachage group were 13 and 33 patients respectively. This was not an adequate database from which determinationof differences in efficacy endpoints or safety assessments could be reliably made and this clinical study wasnot designed to evaluate difference between these two age groups. Analyses of general trends in safety andefficacy were undertaken and demonstrate similar patterns for older (65-70 yrs) vs younger patients (55-64yrs). Greater sensitivity of some older individuals cannot be ruled out.

ADVERSE REACTIONSAutologous and Allogeneic Bone Marrow Transplantation LEUKINE is generally well tolerated.In three placebo-controlled studies enrolling a total of 156 patients after autologous BMT or peripheral bloodprogenitor cell transplantation, events reported in at least 10% of patients who received IV LEUKINE orplacebo were as reported in Table 6.

No significant differences were observed between LEUKINE and placebo-treated patients in the type orfrequency of laboratory abnormalities, including renal and hepatic parameters. In some patients withpreexisting renal or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of LEUKINEhas induced elevation of serum creatinine or bilirubin and hepatic enzymes (see WARNINGS). In addition,there was no significant difference in relapse rate and 24 month survival between the LEUKINE and placebo-treated patients.

In the placebo-controlled trial of 109 patients after allogeneic BMT, events reported in at least 10% ofpatients who received IV LEUKINE or placebo were as reported in Table 7.

There were no significant differences in the incidence or severity of GVHD, relapse rates and survivalbetween the LEUKINE and placebo-treated patients.

Adverse events observed for the patients treated with LEUKINE in the historically-controlled BMT failurestudy were similar to those reported in the placebo-controlled studies. In addition, headache (26%),pericardial effusion (25%), arthralgia (21%) and myalgia (18%) were also reported in patients treated withLEUKINE in the graft failure study.

In uncontrolled Phase I/II studies with LEUKINE in 215 patients, the most frequent adverse events werefever, asthenia, headache, bone pain, chills and myalgia. These systemic events were generally mild ormoderate and were usually prevented or reversed by the administration of analgesics and antipyretics suchas acetaminophen. In these uncontrolled trials, other infrequent events reported were dyspnea, peripheraledema, and rash.

Reports of events occurring with marketed LEUKINE include arrhythmia, fainting, eosinophilia, dizziness,hypotension, injection site reactions, pain (including abdominal, back, chest, and joint pain), tachycardia,thrombosis, and transient liver function abnormalities.

In patients with preexisting edema, capillary leak syndrome, pleural and/or pericardial effusion,administration of LEUKINE may aggravate fluid retention (see WARNINGS). Body weight and hydrationstatus should be carefully monitored during LEUKINE administration.

Adverse events observed in pediatric patients in controlled studies were comparable to those observed inadult patients.

Acute Myelogenous Leukemia Adverse events reported in at least 10% of patients who receivedLEUKINE or placebo were as reported in Table 8.Nearly all patients reported leukopenia, thrombocytopenia and anemia. The frequency and type ofadverse events observed following induction were similar between LEUKINE and placebo groups. Theonly significant difference in the rates of these adverse events was an increase in skin associated eventsin the LEUKINE group (p=0.002). No significant differences were observed in laboratory results, renalor hepatic toxicity. No significant differences were observed between the LEUKINE and placebo-treatedpatients for adverse events following consolidation. There was no significant difference in response rateor relapse rate.

In a historically-controlled study of 86 patients with acute myelogenous leukemia (AML), theLEUKINE treated group exhibited an increased incidence of weight gain (p=0.007), low serum proteinsand prolonged prothrombin time (p=0.02) when compared to the control group. Two LEUKINE treatedpatients had progressive increase in circulating monocytes and promonocytes and blasts in the marrowwhich reversed when LEUKINE was discontinued. The historical control group exhibited an increasedincidence of cardiac events (p=0.018), liver function abnormalities (p=0.008), and neurocorticalhemorrhagic events (p=0.025).15

Antibody Formation Serum samples collected before and after LEUKINE treatment from 214 patientswith a variety of underlying diseases have been examined for immunogenicity based on the presence ofantibodies. Neutralizing antibodies were detected in five of 214 patients (2.3%) after receiving LEUKINE bycontinuous IV infusion (three patients) or subcutaneous injection (SC)(two patients) for 28 to 84 days inmultiple courses. All five patients had impaired hematopoiesis before the administration of LEUKINE andconsequently the effect of the development of anti-GM-CSF antibodies on normal hematopoiesis could notbe assessed. Antibody studies of 75 patients with Crohn’s disease receiving LEUKINE by subcutaneousinjection with normal hematopoiesis and no other immunosuppressive drugs showed one patient (1.3%)with detectable neutralizing antibodies. The clinical relevance of the presence of these antibodies areunknown. Drug-induced neutropenia, neutralization of endogenous GM-CSF activity and diminution of thetherapeutic effect of LEUKINE secondary to formation of neutralizing antibody remain a theoretical possibility.Serious allergic and anaphylactoid reactions have been reported with LEUKINE but the rate of occurrence ofantibodies in such patients has not been assessed.

Overdosage The maximum amount of LEUKINE that can be safely administered in single or multipledoses has not been determined. Doses up to 100 mcg/kg/day (4,000 mcg/m2/day or 16 times therecommended dose) were administered to four patients in a Phase I uncontrolled clinical study bycontinuous IV infusion for 7 to 18 days. Increases in WBC up to 200,000 cells/mm3 were observed. Adverseevents reported were dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache and chills. All theseevents were reversible after discontinuation of LEUKINE.

In case of overdosage, LEUKINE therapy should be discontinued and the patient carefully monitored forWBC increase and respiratory symptoms.

REFERENCES11. Bunn P, Crowley J, Kelly K, et al. Chemoradiotherapy with or without granulocyte-macrophage colony-

stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase IIIrandomized study of the southwest oncology group. JCO 1995; 13(7):1632-1641.

12. Herrmann F, Schulz G, Lindemann A, et al. Yeast-expressed granulocyte-macrophage colony-stimulating factor in cancer patients: A phase Ib clinical study. In Behring Institute ResearchCommunications, Colony Stimulating Factors-CSF. International Symposium, Garmisch-Partenkirchen,West Germany. 1988; 83:107-118.

13. Estey EH, Dixon D, Kantarjian H, et al. Treatment of poor-prognosis, newly diagnosed acute myeloidleukemia with Ara-C and recombinant human granulocyte-macrophage colony-stimulating factor. Blood1990; 75(9):1766-1769.

14. Vadhan-Raj S, Keating M, LeMaistre A, et al. Effects of recombinant human granulocyte-macrophagecolony-stimulating factor in patients with myelodysplastic syndromes. NEJM 1987; 317:1545-1552.

15. Buchner T, Hiddemann W, Koenigsmann M, et al. Recombinant human granulocyte-macrophage colonystimulating factor after chemotherapy in patients with acute myeloid leukemia at higher age or afterrelapse. Blood 1991; 78(5):1190-1197.

16. Blazar BR, Kersey JH, McGlave PB, et al. In vivo administration of recombinant humangranulocyte/macrophage colony-stimulating factor in acute lymphoblastic leukemia patients receivingpurged autografts. Blood 1989; 73(3):849-857.

© 2008, Bayer HealthCare Pharmaceuticals Inc. All rights reserved.

U.S. Patent Nos. 5,391,485; 5,393,870; and 5,229,496. Licensed under Research Corporation TechnologiesU.S. Patent No. 5,602,007, and under Novartis Corporation U.S. Patent Nos. 5,942,221; 5,908,763;5,895,646; 5,891,429; and 5,720,952.

Manufactured by:

Bayer HealthCare Pharmaceuticals, LLC.Seattle, WA 98101

US License No. 1791 6701801BS (11981) Revised April 2008

Percent of AuBMT Patients Reporting Events

LEUKINE PlaceboEvents by Body System (n=79) (n=77)Body, GeneralFever 95 96Mucous membrane disorder 75 78Asthenia 66 51Malaise 57 51Sepsis 11 14Digestive SystemNausea 90 96Diarrhea 89 82Vomiting 85 90Anorexia 54 58GI disorder 37 47GI hemorrhage 27 33Stomatitis 24 29Liver damage 13 14Skin and AppendagesAlopecia 73 74Rash 44 38

LEUKINE PlaceboEvents by Body System (n=79) (n=77)Metabolic, Nutritional DisorderEdema 34 35Peripheral edema 11 7Respiratory SystemDyspnea 28 31Lung disorder 20 23Hemic and Lymphatic SystemBlood dyscrasia 25 27Cardiovascular SystemHemorrhage 23 30Urogenital SystemUrinary tract disorder 14 13Kidney function abnormal 8 10Nervous SystemCNS disorder 11 16

Table 6

Percent of Allogeneic BMT Patients Reporting EventsLEUKINE Placebo

Events by Body System (n=53) (n=56)Body, GeneralFever 77 80Abdominal pain 38 23Headache 36 36Chills 25 20Pain 17 36Asthenia 17 20Chest pain 15 9Back pain 9 18Digestive SystemDiarrhea 81 66Nausea 70 66Vomiting 70 57Stomatitis 62 63Anorexia 51 57Dyspepsia 17 20Hematemesis 13 7Dysphagia 11 7GI hemorrhage 11 5Constipation 8 11Skin and AppendagesRash 70 73Alopecia 45 45Pruritis 23 13Musculo-skeletal SystemBone pain 21 5Arthralgia 11 4Special SensesEye hemorrhage 11 0Cardiovascular SystemHypertension 34 32Tachycardia 11 9

LEUKINE PlaceboEvents by Body System (n=53) (n=56)Metabolic/Nutritional DisordersBilirubinemia 30 27Hyperglycemia 25 23Peripheral edema 15 21Increased creatinine 15 14Hypomagnesemia 15 9Increased SGPT 13 16Edema 13 11Increased alk. phosphatase 8 14Respiratory SystemPharyngitis 23 13Epistaxis 17 16Dyspnea 15 14Rhinitis 11 14Hemic and Lymphatic SystemThrombocytopenia 19 34Leukopenia 17 29Petechia 6 11Agranulocytosis 6 11Urogenital SystemHematuria 9 21Nervous SystemParesthesia 11 13Insomnia 11 9Anxiety 11 2Laboratory Abnormalities*High glucose 41 49Low albumin 27 36High BUN 23 17Low calcium 2 7High cholesterol 17 8

*Grade 3 and 4 laboratory abnormalities only. Denominators may vary due to missing laboratorymeasurements.

Table 7

Percent of AML Patients Reporting EventsLEUKINE Placebo

Events by Body System (n=52) (n=47)Body, GeneralFever (no infection) 81 74Infection 65 68Weight loss 37 28Weight gain 8 21Chills 19 26Allergy 12 15Sweats 6 13Digestive SystemNausea 58 55Liver 77 83Diarrhea 52 53Vomiting 46 34Stomatitis 42 43Anorexia 13 11Abdominal distention 4 13Skin and AppendagesSkin 77 45Alopecia 37 51

LEUKINE PlaceboEvents by Body System (n=52) (n=47)Metabolic/Nutritional DisorderMetabolic 58 49Edema 25 23Respiratory SystemPulmonary 48 64Hemic and Lymphatic SystemCoagulation 19 21Cardiovascular SystemHemorrhage 29 43Hypertension 25 32Cardiac 23 32Hypotension 13 26Urogenital SystemGU 50 57Nervous SystemNeuro-clinical 42 53Neuro-motor 25 26Neuro-psych 15 26Neuro-sensory 6 11

Table 8

June 2009 GREEN HILL HEALTHCARE COMMUNICATIONS 3

As this issue goes to press, cancerclinicians and researchers fromaround the world are gathering in

Orlando, Florida, for the annual meeting ofthe American Society of Clinical Oncology.The abstracts were recently released withreports of advances in cancer prevention,diagnosis, and treatment as well as in basicresearch leading to development of newtherapies. At the same time, oncology phar-macists are preparing for the 5th AnnualMeeting of the Hematology/OncologyPharmacy Association, where exciting newdevelopments in pharmacy research andpractice will be presented.The latest cancer statistics reported this

week by the American Cancer Society attestto the progress being made in the fightagainst cancer. In 2006 (the latest year forwhich statistics are available), there were181 cancer deaths per 100,000 people, down

from 184 in 2005. Although modest, thesechanges show a continuing downward trendin cancer deaths, attributed to earlier detec-tion and improved treatment.Not only are new treatments emerging for

cancers such as advanced melanoma, as dis-cussed in the article by LeAnn Norris, butnew research is leading to reevaluation ofolder agents, such as gefitinib for non–small-cell lung cancer, as discussed in the continu-ing education article by Edward S. Kim andhis colleagues. But, as their study shows, can-cer therapies not only have to be compared interms of safety and efficacy but also in termsof their impact on quality of life. As KarenOishi points out in her commentary, patientsand their families must be informed aboutthe available treatment options, and prefer-ences regarding treatments, their potentialside effects, and cost must be considered.The recent news reports of a mother and

her 13-year-old son who fled after a court-ordered treatment for the son’s lymphomaillustrate how complex these decisions maybe and how important it is to establish goodcommunication with patients and theirfamilies.The theme of the ASCO meeting this

year is personalized medicine. Advances inunderstanding of the genetics and biologyof cancer and identification of biomarkershave made it possible to tailor cancer treat-ments to the biological characteristics ofthe individual patient. But beyond this, thepatient’s values, beliefs, preferences, andlifestyle must be taken into account as well,and treatment options must be clearly com-municated to the patient and his or herfamily. In this capacity, pharmacists areessential to patient care playing an impor-tant role in counseling patients about treat-ment options and appropriate use.

A Letter from the Editors

SUSAN GOODIN,PHARMD, FCCP, BCOP

EDITORIAL CORRESPONDENCE should be addressed to EDI-TORIAL DIRECTOR, The Oncology Pharmacist®, 241 Forsgate Drive,Suite 205C,Monroe Twp, NJ 08831. E-mail: [email protected] SUBSCRIPTION RATES: United States and possessions:individuals, $105.00; institutions, $135.00; single issues $17.00. Orderswill be billed at individual rate until proof of status is confirmed. Pricesare subject to change without notice. Correspondence regarding permis-sion to reprint all or part of any article published in this journal should beaddressed to REPRINT PERMISSIONS DEPARTMENT, GreenHill Healthcare Communications, LLC, 241 Forsgate Drive, Suite205C, Monroe Twp, NJ 08831. The ideas and opinions expressed in TheOncology Pharmacist® do not necessarily reflect those of the EditorialBoard, the Editorial Director, or the Publisher. Publication of an adver-tisement or other product mention in The Oncology Pharmacist® shouldnot be construed as an endorsement of the product or the manufacturer’sclaims. Readers are encouraged to contact the manufacturer with ques-tions about the features or limitations of the productsmentioned.Neitherthe Editorial Board nor the Publisher assumes any responsibility for anyinjury and/or damage to persons or property arising out of or related toany use of the material contained in this periodical. The reader is advisedto check the appropriate medical literature and the product informationcurrently provided by the manufacturer of each drug to be administeredto verify the dosage, the method and duration of administration, or con-traindications. It is the responsibility of the treating physician or otherhealthcare professional, relying on independent experience and knowl-edge of the patient, to determine drug dosages and the best treatment forthe patient. Every effort has beenmade to check generic and trade names,and to verify dosages. The ultimate responsibility, however, lies with theprescribing physician. Please convey any errors to the Editorial Director.ISSN #1944-9607.

The Oncology Pharmacist® is published 7 times a year by Green HillHealthcare Communications, LLC, 241 Forsgate Drive, Suite 205C,Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938.Copyright ©2009 by Green Hill Healthcare Communications LLC.All rights reserved. The Oncology Pharmacist® logo is a registered trade-mark of Green Hill Healthcare Communications, LLC. No part ofthis publication may be reproduced or transmitted in any form or byany means now or hereafter known, electronic or mechanical, includ-ing photocopy, recording, or any informational storage and retrievalsystem, without written permission from the Publisher. Printed in theUnited States of America.

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For a free subscription go towww.theoncologypharmacist.com

PATRICK MEDINA,PHARMD, BCOP

CE article:Follow-up Care for Colorectal Cancer Survivors

Setting Up a Chemotherapy Prep Area in aCommunity Practice

Ixabepilone: A New Treatment forMetastatic Breast Cancer

Overcoming Barriers to AppropriateUse of Opioids for Cancer Pain

Reports from the 2009 Annual Meeting of theAmerican Society of Clinical Oncology, the 5th

Annual Conference of the Hematology/OncologyPharmacy Association

EDITORS’

LETT

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4 GREEN HILL HEALTHCARE COMMUNICATIONS June 2009

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Vol. 2, No. 4 June 2009

Feature Articles12 Skin Cancers

Recent advances in the diagnosis and treatment of melanoma

15 Cancer ComplicationsCurrent and emerging therapies for MRSA in patients with cancer

23 Continuing EducationOral biologic therapy versus chemotherapy for pretreated NSCLC

30 Safe HandlingInitiative highlights the need for increased attention, educationabout occupational drug exposure

Departments3 Editor’s Letter

5 Medical Minutes

6 In the Literature

9 News Notes

28 Recent FDA Approvals

31 Oncology Drug Codes

33 Meetings

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FREE delivery of The Oncology Pharmacist

John F. Aforismo, BSC Pharm, RPh, FASCPR. J. Health Systems, LLCWethersfield, CT

David Baribeault, RPh, BCOPBoston Medical CenterBoston, MA

Sylvia Bartel, RPh, MPHDana-Farber Cancer InstituteBoston, MA

Deborah Blamble, PharmD, BCOPThe University of Texas MD Anderson Cancer CenterHouston, TX

Marlo Blazer, RPh, PharmDJames Cancer Hospital & Solove Research InstituteColumbus, OH

Bryna Delman Ewachiw, BS, PharmDJohns Hopkins Bayview Medical CenterBaltimore, MD

Anjana Elefante, PharmD, BSc, BScPhm, RPhRoswell Park Cancer InstituteBuffalo, NY

Beth Faiman, RN, MSN, APRN, BC, AOCNCleveland Clinic Taussig Cancer CenterCleveland, OH

Christopher Fausel, PharmDIndiana University Simon Cancer CenterIndianapolis, IN

Rebecca S. Finley, PharmD, MSJefferson School of PharmacyPhiladelphia, PA

David C. Gammon, BSPharmUniversity of Massachusetts Memorial HospitalWorcester, MA

Heidi D. Gunderson, PharmD, BCOPMayo Clinic Cancer CenterRochester, MN

Sandra Horowitz, PharmD, RPhThe University of Texas MD Anderson Cancer CenterHouston, TX

Lew Iacovelli, BS, PharmD, BCOP, CPPMoses H. Cone Health SystemGreensboro, NC

Andrea A. Iannucci, PharmD, BCOPUniversity of California Davis Medical CenterSacramento, CA

Cindy Ippoliti, PharmDNew York Presbyterian Hospital/Weill Cornell Medical SchoolNew York, NY

Jim Koeller, MSUniversity of Texas at AustinSan Antonio, TX

Helen L. Leather, BPharmUniversity of FloridaGainesville, FL

Christopher J. Lowe, PharmDNovant HealthWinston-Salem, NC

Helen McFarland, PharmD, BCOPUnion Memorial HospitalBaltimore, MD

Emily Mackler, PharmD, BCOPUniversity of Michigan Health System & College of PharmacyAnn Arbor, MI

Laura Boehnke Michaud, PharmD, BCOP, FASHPThe University of Texas MD Anderson Cancer CenterHouston, TX

Deborah Moradi, PharmDThe Angeles Clinic and Research InstituteLos Angeles, CA

LeAnn Best Norris, PharmD, BCPSSouth Carolina College of PharmacyColumbia, SC

Debra L. Phillips, PharmDEast Carolina UniversityGreenville, NC

Steve Stricker, PharmD, MSSamford University McWhorter School of PharmacyBirmingham, AL

Timothy G. Tyler, PharmD, FCSHPDesert Regional Medical CenterPalm Springs, CA

John M. Valgus, PharmD, BCOPUniversity of North Carolina Hospitals and ClinicsChapel Hill, NC

Gary C. Yee, PharmD, FCCP, BCOPUniversity of Nebraska College of PharmacyOmaha, NE

EDITORIAL BOARD

CO-EDITORS-IN-CHIEF

Susan Goodin,PharmD, FCCP, BCOPCancer Institute of NewJerseyNew Brunswick, NJ

Patrick Medina,PharmD, BCOPOklahoma University Collegeof PharmacyTulsa, OK

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MED

ICALMIN

UTES

Higher doses of radiation combined with chemotherapy mayimprove survival in patients with stage III lung cancer, according toresearchers in Michigan. They have found that giving chemothera-py at the same time as radiation enhances the effect of both.Increasing the dose of radiation over the course of treatment wasalso found to increase survival.“When patients are diagnosed with stage III lung cancer, surgery

is often not an option, and survival rates are typically quite low.

Finding new ways to improve survival, even in small increments, iscrucial,” said senior study author Feng-Ming Kong, MD, PhD, whois an associate professor of radiation oncology at the University ofMichigan, Ann Arbor.Kong and his colleagues compared survival among 237 patients

treated with radiation alone, with radiation followed by chemother-apy, and with radiation and chemotherapy given at the same time.A total of 31 patients were also enrolled in a study in which the

radiation dose was increased throughoutthe course of the treatment.The researchers found that patients

treated with radiation alone had theworst overall survival rates, living onlyan average of 7.4 months after diagnosis.Adding chemotherapy increased sur-vival to 14.9 months when it was admin-istered after completion of radiation and15.8 months when administered at thesame time as radiation. After 5 years,19.4% of the patients receiving concur-rent chemotherapy were still alive, com-pared with only 7.5% of patients receiv-ing sequential chemotherapy.“Our study shows chemotherapy helps,

and high-dose radiation helps. But it’schallenging to administer these treat-ments at the same time because of thepotential toxicity associated with thehigh-dose radiation,” Kong explained.The Michigan researchers are cur-

rently assessing use of positron-emissiontomography imaging during the courseof lung cancer treatment to personalizehigh-dose radiation therapy in individ-ual patients. As the tumor becomessmaller during treatment, increasing theradiation dose will become more tolera-ble because it will be targeting a smallerarea. The researchers believe this strate-gy could lead to improved treatmentoutcomes in many patients.

Researchers are now combining a drug developed from the natu-rally occurring reovirus with chemotherapy agents to help improvesurvival rates in patients with advanced cancers. The drug, Reolysin(Oncolytics Biotech Inc), is demonstratingpromising results in combination with cer-tain chemotherapeutic agents.The reovirus preferentially replicates in

cancer cells with an activated RAS pathway,while sparing normal cells. Approximatelytwo thirds of all cancers have an activatedRAS pathway, including most metastaticdisease. Viral replication within cancer cellscauses them to burst open, releasing morevirus to infect other cells.Results from a phase 1/2 trial of Reolysin

combined with paclitaxel/carboplatin forpatients with advanced cancers showed pos-itive results. Fifteen head and neck cancer patients were treated,and all but one had prior platinum treatment. Of 12 patients evalu-

able for clinical response, five had partial response and four had hadstable disease for periods ranging from 2 to 6 months.For patients who have been followed for at least 6 months since

their initial treatment, median progression-free survival (PFS) is currently 6 monthsand overall survival is 7 months. The liter-ature suggests that platinum-refractorypatients typically have a PFS of approxi-mately 2 months and a median survivalrange of 4.5 to 6.5 months. Although thesedata look good, the overall survival figuremay, in fact, improve further as many of thepatients are still alive.These results have ledOncolytics Biotech

to announce that its first pivotal phase 3trial will use the same treatment combina-tion in head and neck cancer patients who

have failed traditional platinum-based therapies. The trial is ex-pected to get under way within the next 4 to 6 months.

Medical MinutesBY JOHN SCHIESZER

John Schieszer is anaward-winning nationaljournalist and radiobroadcaster of TheMedical Minute.He can be reached [email protected].

Combining Chemo with a Common Virus May Help Patientswith Advanced Cancer

Although aggressive therapy may be ben-eficial for some cancers, that does not appearto be the case for patients with early bladdercancer. A new study of thousands of patientswith early-stage bladder cancer has foundthat despite enduring more invasive testsand medical procedures, patients who weretreated aggressively for early-stage bladdercancer had no better survival than patientswho were treated less aggressively. In addi-tion, the aggressively treated patients weremore likely to undergo major surgery to havetheir bladder removed.In this study, researchers gathered data

from the Surveillance, Epidemiology andEnd Results (SEER) Medicare database toidentify patients who were diagnosed withearly-stage bladder cancer between 1992and 2002 and the physician primarilyresponsible for their care (Hollenbeck BK,et al. J Natl Cancer Inst. 2009;101:543-545).They identified 20,713 patients and 940physicians. Each doctor included in thestudy had treated at least 10 patients forbladder cancer. The researchers found thataverage per-patient treatment expendituresranged from $2830 for physicians in the low-

intensity treatment category to $7131 forthose in the high-intensity category.Survival rates across all intensity categorieswere similar.“What this indicates is that some doctors

are providing potentially unnecessary care,or care without measurable benefit to thepatient. It makes sense to many doctors andpatients that more would be better, but,unfortunately, there can be unintended con-sequences or unneeded care,” said studyauthor Brent Hollenbeck, MD, who is anassistant professor of urology at theUniversity of Michigan Medical School,Ann Arbor.The study found that patients treated

more aggressively had more imaging proce-dures and more invasive surgical procedures.The aggressively treated patients were alsonearly twice as likely to require major med-ical interventions, and were 2.5 times morelikely to undergo radical cystectomy.“By reducing unnecessary healthcare, we

can reduce wasteful spending, which willlessen the cost burden of bladder cancer, oneof the most expensive cancers to treat fromdiagnosis to death,” Hollenbeck explained.

High-Dose Radiation May Help Improve Lung Cancer Survival

More Intense Bladder Cancer TreatmentDoes Not Appear to Improve Survival

� Cetuximab plus FOLFIRIReduces Risk of Progression ofMetastatic Colorectal CancerBackground: Researchers investigat-

ed the efficacy of cetuximab plusFOLFIRI (irinotecan, fluorouracil, andleucovorin) as first-line treatment formetastatic colorectal cancer. The re-searchers also sought to find associationsbetween the mutation status of theKirsten rat sarcoma (KRAS) gene andclinical response to cetuximab.Design: Patients with epidermal

growth factor receptor–positive colo-rectal cancer with unresectable metas-tases were randomized to receiveFOLFIRI either alone or in combina-tion with cetuximab.Summary: This study adds to the

growing number of reports showing thesignificant association between KRASmutation status and tumor response.The researchers found that cetuximabbenefit was limited to patients withwild-type KRAS tumors. However, theyfound no significant difference in over-all survival. Grade 3/4 adverse events,which were more frequent with thecombination therapy, included skinreactions, infusion-related reactions,and diarrhea.Takeaway: Cetuximab plus FOLFIRI

increased progression-free survival by 1.2months in patients with metastatic colo-rectal cancer wild-type KRAS tumors.Van Custem E, et al. N Engl J Med.

2009;360:1408-1417.

� Addition of Casopitant MesylateReduces CINVBackground: Management of che-

motherapy-induced nausea and vomit-ing (CINV) remains an issue for pa-tients receiving highly emetogenicchemotherapy. The addition of casopi-tant mesylate to a regimen of dexa-methasone and ondansetron may helpprevent delayed-phase CINV.Design: In a multicenter, random-

ized, double-blind, placebo-controlledtrial, chemo-naïve patients with malig-nant solid tumors were randomized toreceive placebo, single oral dose (150mg) of casopitant mesylate, or 3-dayintravenous (90 mg on day 1) plus oral(50 mg on days 2 and 3) casopitantmesylate. The primary end point wasthe proportion of patients withoutvomiting, retching, or use of rescuemedications in the first 120 hours.Summary:More patients in the caso-

pitant groups achieved complete re-sponse after cycle 1 (66% in the placebogroup, 86% in the oral casopitant group,and 80% in the intravenous plus oralcasopitant group). This improvementwas sustained over multiple cycles.Adverse events included neutropenia,febrile neutropenia, and dehydration.

Takeaway: The three-drug regimen(casopitant mesylate, dexamethasone,ondansetron) significantly reducesCINV in patients receiving highlyemetogenic chemotherapy comparedwith the two-drug regimen (dexa-methasone, ondansetron). This study

was funded by GlaxoSmithKline.Grunberg SM, et al. Lancet Oncol.

May 8, 2009. Epub ahead of print.

� Cancer Survivors More Likelyto Be UnemployedBackground: Almost half of all can-

cer survivors are younger than 65 years,a group for which cancer and its treat-ment could alter employment opportu-nities. However, the association be-tween survivorship and employmentstatus is unknown.

Design: Researchers performed ameta-analysis using data found througha systematic search of studies publishedbetween 1966 and June 2008 from theMEDLINE, CINAHL, PsycINFO, andOSH-ROM databases. Meta-regressionanalysis was performed to assess associ-ations of unemployment with cancertype, country of origin, average age atdiagnosis, and background unemploy-ment rate.Summary: Cancer survivors were

1.37 times more likely to be unem-


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ERBITUX® (cetuximab): FOR PATIENTS WITH HEAD AND NECK CANCER

Important Safety Information1

Infusion Reactions� Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000—Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airwayobstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest

�Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines—Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions—Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions

Cardiopulmonary Arrest� Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiationtherapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. Fatal events occurred within 1 to 43 days after the lastERBITUX treatment—Carefully consider the use of ERBITUX in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease,congestive heart failure or arrhythmias in light of these risks

—Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy

Pulmonary Toxicity� Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in clinical trials. Interrupt ERBITUX for acute

onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX where ILD is confirmed

Dermatologic Toxicities� In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae

(eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUXtherapy. Acneform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneform rash occurred in 1-17% of patients— Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although

in nearly half, the event continued beyond 28 days— Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae— Sun exposure may exacerbate these effects

ERBITUX Plus Radiation Therapy and Cisplatin� The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established

— Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locallyadvanced squamous cell carcinoma of the head and neck

— Two of 21 patients died, one as a result of pneumonia and one of an unknown cause— Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events

E

ERBITUX + RT: 26% reduction in Risk of Death from SCCHN1,2

In theLiteratureConcise Reviews of Studies Relevant to Cancer Care

ployed than healthy controls. Sur-vivors of breast cancer, gastrointestinalcancers, and cancer of the femalereproductive organs were at anincreased risk for unemployment.Takeaway: To improve employment

outcomes, clinical and supportive serv-ices should be aimed at better manage-ment of symptoms, rehabilitation, andworkplace accommodation for disabledsurvivors.De Boer AGEM, et al. JAMA. 2009;

301:753-762.

� Gemcitabine and VinorelbineEffective in Children withHodgkin’s DiseaseBackground: Both gemcitabine and

vinorelbine have significant single-agent response rates in pediatric pa-tients with heavily pretreated re-lapsed/refractory Hodgkin’s disease.The efficacy and toxicity of a combina-tion of these two agents (ie, GV) wereassessed for this population by theChildren’s Oncology Group.Design: In a phase 2 trial, patients

received, on days 1 and 8 of each 21-day cycle, vinorelbine 25 mg/m2/dosevia intravenous (IV) push before gem-citabine 25 mg/m2/dose IV over 100minutes. Response (including com-plete response, very good partialresponse, partial response) was evaluat-ed every two cycles.Summary: In patients aged 10.7 to

29.4 years who had received at leasttwo prior chemotherapy regimens,some having undergone prior autolo-gous stem-cell transplantation, measur-

able responses were seen in 76% ofassessable patients. Hematologic toxic-ity was prominent in all treatmentcycles. Nonhematologic grade 3 and 4toxicity was less common.Takeaway: GV is an effective and

well-tolerated reinduction regimen forchildren with relapsed or refractoryHodgkin’s disease. Further evaluationof GV in this population is warranted.Cole PD, et al; for the Children’s On-

cology Group. J Clin Oncol. 2009;27:1456-1461.


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693US09AB03511 3/09

© 2009, ImClone Systems Incorporated, New York, New York 10014, U.S.A. and Bristol-Myers Squibb Company, Princeton, New Jersey 08543, U.S.A. All rights reserved. ERBITUX is a registered trademark of ImClone Systems Incorporated.

References: 1.ERBITUX® (cetuximab) Package Insert. ImClone Systems Incorporated, New York, NY 10014 and Bristol-Myers Squibb Company, Princeton, NJ 08543; November 2008. 2.Bonner JA, Harari PM, Giralt J, et al.Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med.2006;354:567-578. 3.Data on file, Bristol-Myers Squibb, ERBI 001.

I Electrolyte Depletion� Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX® (cetuximab) and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of

hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy— Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Replete electrolytes as necessary

Late Radiation Toxicities� The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone.

The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively— The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

Pregnancy� In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of

ERBITUX. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus

Adverse Events� The most serious adverse reactionsassociated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation

dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus� The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes),

headache, diarrhea, and infection� The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus

radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). Themost common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), andweight loss (11%)

For more information, please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

Please see brief summary of Full Prescribing Information includingboxed WARNINGSregarding infusion reactions and cardiopulmonary arrest on adjacent page.

ERBITUX + RT (%) RT Alone (%)(n = 208) (n = 212)

Grades Grade Grades Grade1-4 3/4 1-4 3/4

Mucositis/stomatitis 93 56 94 52

Dysphagia 65 26 63 30

Xerostomia 72 5 71 3

Radiation dermatitis 86 23 90 18

INDICATIONSHead and Neck Cancer� ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck1

�ERBITUX, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of thehead and neck for whom prior platinum-based therapy has failed1

SCCHN = squamous cell carcinoma of the head and neck; RT = radiation therapy.

† No difference in radiation dose delivered between the 2 treatment groups in a randomized trial comparing ERBITUX + RT versus RT alone in patients with locally or regionally advanced SCCHN.2

� The incidences of grades 3/4 xerostomia, mucositis/stomatitis, and radiation dermatitis were more frequent in the ERBITUX plus RT arm

E

No. (%) of Patients

ERBITUX + RT RT Alone(n = 211) (n = 213)

Delivery of planned RT dose

Adequate delivery per protocol 184 (87.2) 187 (87.8)

Inadequate delivery per protocol 27 (12.8) 26 (12.2)

6

� Adjuvant ChemotherapyImproves Survival in OlderWomen with Early-StageBreast CancerBackground: In the United States,

the average age at diagnosis of breastcancer is approximately 63 years, andmost deaths occur in women 65 years orolder. However, older women are under-represented in clinical trials.Design: Patients with stage I, II, IIIA,

or IIIB breast cancer were randomizedto receive either standard chemothera-

py or capecitabine. Endocrine therapywas recommended when applicable. ABayesian statistical design was used totest the noninferiority of capecitabineas compared with standard chemothera-py. The primary end point was relapse-free survival.Summary: At 2 years, patients who

received capecitabine were twice aslikely to have a relapse and almosttwice as likely to die as patients whoreceived standard chemotherapy. At 3years, the rate of relapse-free survival

was 68% for patients who re-ceived capecitabine and 85%in those who received stan-dard chemotherapy.Takeaway: Standard ad-

juvant chemotherapy is supe-rior to capecitabine in pa-tients with early-stage breastcancer who are 65 years ofage or older.MussHB, et al; for the CALB

Investigators. N Engl J Med.2009;360:2005-2065.


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Erbitux® (cetuximab)Solution for intravenous useBrief Summary of Prescribing Information. For complete prescribing information consult official package insert.

INDICATIONS AND USAGESquamous Cell Carcinoma of the Head and Neck (SCCHN)Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally orregionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in FullPrescribing Information.]Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cellcarcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1)in Full Prescribing Information.]Colorectal CancerErbitux, as a single agent, is indicated for the treatment of EGFR-expressing metastatic colorectal cancer afterfailure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for thetreatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-basedregimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.]Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectalcarcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux incombination with irinotecan is based on objective response rates. Currently, no data are available thatdemonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combinationwith irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Clinical Studies(14.2) in Full Prescribing Information and Warnings and Precautions.]

CONTRAINDICATIONSNone.

WARNINGS AND PRECAUTIONSInfusion ReactionsSerious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbituxincluded rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss ofconsciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactionsoccurred in 2–5% of 1373 patients in clinical trials, with fatal outcome in 1 patient. Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication withantihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agentsnecessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators,and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusionreactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warningand Dosage and Administration (2.4) in Full Prescribing Information.]Cardiopulmonary ArrestCardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapyand Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlledtrial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, withmyocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one hadcongestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with noprior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use ofErbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary arterydisease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes,including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning andWarnings and Precautions.]Pulmonary ToxicityInterstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux inclinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinueErbitux for confirmed ILD. Dermatologic ToxicityDermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectioussequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis,cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneform rash occurred in 76–88%of 1373 patients receiving Erbitux in clinical trials. Severe acneform rash occurred in 1–17%of patients. Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patientsafter cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patientsreceiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposureduring Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.]Use of Erbitux in Combination With Radiation and CisplatinThe safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death andserious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin(100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumoniaand one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of thesediscontinuations were due to cardiac events.Hypomagnesemia and Electrolyte AbnormalitiesIn patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receivingErbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanyingelectrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients forhypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion ofErbitux. Replete electrolytes as necessary. Epidermal Growth Factor Receptor (EGFR) Expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in thehead and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumorexpression prior to study entry.

Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidenceof EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomationEGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR andintensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentageof positive cells or the intensity of EGFR expression.

ADVERSE REACTIONSThe following adverse reactions are discussed in greater detail in other sections of the label:• Infusion reactions [See Boxed Warning and Warnings and Precautions.]• Cardiopulmonary arrest [See Boxed Warning and Warnings and Precautions.]• Pulmonary toxicity [See Warnings and Precautions.]• Dermatologic toxicity [See Warnings and Precautions.]• Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.]The most common adverse reactions with Erbitux (cetuximab) (incidence 25%) are cutaneous adverse reac-tions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologictoxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus. Across all studies, Erbitux was discontinued in 3–10% of patients because of adverse reactions.

Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in theclinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may notreflect the rates observed in practice. The data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomizedPhase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedulefor a median of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.]Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm,angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient.Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in1–4% of patients. Renal: Renal failure occurred in 1% of patients with colorectal cancer. Squamous Cell Carcinoma of the Head and Neck Table 1 contains selected adverse events in 420 patients receiving radiation therapy either alone or with Erbituxfor locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose andschedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions(range 1–11).

Table 1: Incidence of Selected Adverse Events ( 10%) in Patients with LocoregionallyAdvanced SCCHN

Erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212)

Body System Grades Grades Grades GradesPreferred Term 1–4 3 and 4 1–4 3 and 4

% of PatientsBody as a WholeAsthenia 56 4 49 5Fever1 29 1 13 1Headache 19 <1 8 <1Infusion Reaction2 15 3 2 0Infection 13 1 9 1Chills1 16 0 5 0DigestiveNausea 49 2 37 2Emesis 29 2 23 4Diarrhea 19 2 13 1Dyspepsia 14 0 9 1Metabolic/NutritionalWeight Loss 84 11 72 7Dehydration 25 6 19 8Alanine Transaminase, high3 43 2 21 1Aspartate Transaminase, high3 38 1 24 1Alkaline Phosphatase, high3 33 <1 24 0RespiratoryPharyngitis 26 3 19 4Skin/AppendagesAcneform Rash4 87 17 10 1Radiation Dermatitis 86 23 90 18Application Site Reaction 18 0 12 1Pruritus 16 0 4 0

1 Includes cases also reported as infusion reaction. 2 Infusion reaction is defined as any event described at any time during the clinical study as “allergic

reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as“allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”.

3 Based on laboratory measurements, not on reported adverse events, the number of subjects with testedsamples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone.

4 Acneform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustularrash”, “dry skin”, or “exfoliative dermatitis”.

The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study.

Late Radiation ToxicityThe overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiationtherapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%),esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicitieswas similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARRESTInfusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings andPrecautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion forserious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in FullPrescribing Information.]Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients withsquamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitorserum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [SeeWarnings and Precautions.]

According to new American Cancer Society statistics,about 562,340 American men and women will die ofcancer in 2009. The most common fatal cancers arecancers of the lung and bronchus, prostate, and colo-rectum in men and cancers of the lung and bronchus,breast, and colorectum in women.

Did you

Know?

� BRCA1 and BRCA2 PatentsChallengedA potential landmark lawsuit was

filed on May 12, 2009, in the federalcourt of New York against MyriadGenetics Laboratories, the manufactur-er of BRACAnalysis, and the US Patent

Office. The suit challenges the deci-sion to grant a patent on a gene to asingle company. Plaintiffs argue thatBRCA testing would improve if marketforces were allowed to work, and thatthe restriction on competition blocksother companies to develop alterna-

tives, as well as to interpret or comparegene sequences that involve thepatented genes. Myriad has not yetresponded publicly to the suit. TheAmerican Civil Liberties Union,which organized the lawsuit, pointedout that the problem is with the USPatent Office, not Myriad specifically.Single companies also hold patentson the HFE gene, which is linked tohereditary hemochromatosis, the CFTRgene, which is linked to cystic fibrosis,and a genetic test on long QT syn-

drome, which can lead to heart arrhyth-mias and sudden death (New YorkTimes. May 12, 2009).

� Sleep Problems May Lead toIncreased Cancer PainPain and fatigue may be reduced by

interventions to help patients with can-cer deal with sleep problems anddepressed mood. Further, pain manage-ment may help alleviate trouble sleep-ing. Stepanski and colleagues analyzeddemographic, clinical, and patient-re-ported outcomes data from 11,445 can-cer patients undergoing treatment in alarge community oncology practiceusing structural equation modeling. Thedata were split so that a model was con-structed using half of the patients; thismodel was then cross-validated on theremaining patients. Although fatiguewas best represented as a latent variable,significant direct effects were found fortrouble sleeping, depressed mood, andpain (J Sleep Med. April 15, 2009).

� Risk for False-positive Findingswith Multiple CancerScreeningsAs the number of cancer screening

tests increases, the likelihood for false-positives may also increase, along withdiagnostic interventions. Researchersexamined this cumulative risk, by ana-lyzing data from patients participatingin the ongoing Prostate, Lung, Colo-rectal, and Ovarian Cancer ScreeningTrial. Croswell and colleagues foundthat after 14 tests, the cumulative riskof having at least one false-positive is60.4% and the cumulative risk ofundergoing an invasive diagnostic pro-cedure prompted by a false-positiveresult is 28.5% for men and 22.1% forwomen. Based on this likelihood,physicians should educate their pa-tients about these risks during cancerscreening discussions (Ann Fam Med.2009;7:212-222).

� FDA Invests in Product SafetyThe US Food and Drug Administra-

tion (FDA) has requested a budget of$3.2 billion to protect and promote thepublic health—a 19% increase overthe current year’s budget. The 2010request proposes two major initiatives:protecting America’s food supply andsafer medical products. The safer med-ical products effort ($166.4 million)provides resources to improve the safe-ty of human and animal drugs, medicaldevices, vaccines, blood, and othermedical products by strengthening thesafety and security of the supply chainfor medical products. Included in thiseffort is the follow-on biologics anddrug importation initiative ($5 mil-lion), which proposes a new authorityfor the FDA to approve follow-on bio-logics and provides funding for theFDA to develop policies to allowAmericans to buy drugs approved inother countries (www.fda.gov/bbs/topics/NEWS/ 2009/NEW02013.html).


NEW

SNOT

ES

Colorectal CancerTable 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or withErbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at therecommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly).Table 2: Incidence of Selected Adverse Events Occurring in 10% of Patients with Advanced

Colorectal Carcinoma1 Treated with Erbitux MonotherapyErbitux plus BSC BSC alone

(n=288) (n=274)Body System Any Grades Any GradesPreferred Term Grades2 3 and 4 Grades 3 and 4

% of Patients

DermatologyRash/Desquamation 89 12 16 <1Dry Skin 49 0 11 0Pruritus 40 2 8 0Other-Dermatology 27 1 6 1Nail Changes 21 0 4 0Body as a WholeFatigue 89 33 76 26Fever 30 1 18 <1Infusion Reactions3 20 5Rigors, Chills 13 <1 4 0PainAbdominal Pain 59 14 52 16Pain-Other 51 16 34 7Headache 33 4 11 0Bone Pain 15 3 7 2PulmonaryDyspnea 48 16 43 12Cough 29 2 19 1GastrointestinalConstipation 46 4 38 5Diarrhea 39 2 20 2Vomiting 37 6 29 6Stomatitis 25 1 10 <1Other-Gastrointestinal 23 10 18 8Mouth Dryness 11 0 4 0InfectionInfection without neutropenia 35 13 17 6NeurologyInsomnia 30 1 15 1Confusion 15 6 9 2Anxiety 14 2 8 1Depression 13 1 6 <1

1 Adverse reactions occurring more frequently in Erbitux treated patients compared with controls.2 Adverse events were graded using the NCI CTC, V 2.0. 3 Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest

tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus,sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusionrelated.

BSC = best supportive care

The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trialswere acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most commonGrades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneformrash (14%). ImmunogenicityAs with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximabwere assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assayperformance and sampling timing, the incidence of antibody development in patients receiving Erbitux has notbeen adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) ofevaluable patients without apparent effect on the safety or antitumor activity of Erbitux.The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may beinfluenced by several factors including assay methodology, sample handling, timing of sample collection,concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodiesto Erbitux with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONSA drug interaction study was performed in which Erbitux was administered in combination with irinotecan. Therewas no evidence of any pharmacokinetic interactions between Erbitux and irinotecan.

USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category CThere are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animalmodels, EGFR has been implicated in the control of prenatal development and may be essential for normalorganogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross theplacental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has thepotential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancyonly if the potential benefit justifies the potential risk to the fetus.Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose ofcetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48).Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetalmalformations or other teratogenic effects occurred in offspring. However, significant increases inembryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human doseof cetuximab (based on total body surface area).Nursing MothersIt is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted inhuman milk. Because many drugs are excreted in human milk and because of the potential for serious adversereactions in nursing infants from Erbitux, a decision should be made whether to discontinue nursing or todiscontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted,based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information],nursing should not be resumed earlier than 60 days following the last dose of Erbitux.Pediatric UseThe safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics ofcetuximab have not been studied in pediatric populations. Geriatric UseOf the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advancedcolorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy wereobserved between these patients and younger patients.Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number ofsubjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years ofage or older.

OVERDOSAGEThe maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events werereported for this patient.

NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of FertilityLong-term animal studies have not been performed to test cetuximab for carcinogenic potential, and nomutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assayor in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receivingweekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area).Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to controlanimals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured malefertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) ascompared to control male monkeys. It is not known if cetuximab can impair fertility in humans.Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weeklyhuman exposure (based on total body surface area), resulted in dermatologic findings, including inflammation atthe injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosaof the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renaltubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highestdose level beginning after approximately 13 weeks of treatment.

PATIENT COUNSELING INFORMATIONAdvise patients:• To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems.• Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate

contraception in both males and females during and for 6 months following the last dose of Erbitux therapy. • That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose

of Erbitux.

Erbitux® is a registered trademark of ImClone Systems Incorporated.Manufactured by ImClone Systems Incorporated, Branchburg, NJ 08876Distributed and Marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543

Copyright ©2008 by ImClone Systems Incorporated and Bristol-Myers Squibb Company. All rights reserved.

1236886A4ER-B0001A-11-08 Rev November 2008

News NotesNews Updates of Relevance to Everyday Oncology Practice


PHARMACY

PRACTICE

with others on the healthcare team.Then I did my pharmacy practice resi-dency at the University of CaliforniaSan Diego Medical Center and myoncology pharmacy practice residencyat the University of Colorado. In 2004,I attended the Making a Difference inOncology meeting and heard aboutHOPA, which was just being formed. Ijoined and immediately got involvedin committee work within HOPA.That evolved into serving in leadershippositions as secretary, president-elect,and now as president.

What have been some of thehighlights of your year as HOPApresident?This has been a year of laying the

foundation for the organization andwatching the initial parts of the strate-gic plan come to fruition. HOPA is stilla relatively young organization, andwe’re still very much a member volun-teer organization. As we grow, we relyon our members to take time out oftheir busy lives to get everything done.HOPA has accomplished so manythings this year it is hard to pick out thehighlights. Last year when Jim Koellerwas president, HOPA University wasestablished; this year, the education andstandards committee has developed pro-gramming that allowed our membershipto have online access to continuing edu-cation programs. As HOPA Universtiyexpands, we will be able to provide rel-evant and high-quality continuing edu-cation not only at annual meetings butalso throughout the year.As the organization moves forward, it

is important that we are able to providefunding opportunities so the member-ship can do research, especially in areaswere there are gaps in knowledgeregarding oncology patient care andoncology pharmacy. The research com-mittee has worked hard to establish anInvestigator Research Award for whichwe hope to award sometime this year.

We’ve also been working collaborative-ly with several outside organizations,such as the American Society ofHealth-System Pharmacists and theAmerican College of Clinical Pharma-cy, on how we can improve and stream-line the oncology pharmacy board certi-fication process. As a result, HOPA willnow provide the testing and continuingeducation credit for the BCOP [board-certified oncology pharmacist] specialty

sessions offered at each organization’sannual meeting. In addition, we’ve beenworking with other oncology profes-sional groups, including the AmericanSociety of Clinical Oncology and theOncology Nursing Society, on develop-ing standards for the safety of theadministration of chemotherapy.We arelooking to work with the AmericanAssociation of Colleges of Pharmacy onthe development of an oncology phar-macy curriculum guide to provide somestandardization of what we as practi-tioners feel is important and needs to becommunicated to pharmacy students.The hope here is that students areexposed early and really understandwhat oncology pharmacy involves andwhat opportunities it offers.

Are there any plans to establishregional chapters of HOPA?There is nothing formally set up with-

in HOPA to provide regional chapters,but some regional or state societies haveasked for input in some of their pro-gramming and meetings. This is part ofHOPA’s strategic plan and, as we moveforward, we are looking at the viabilityof regional or local chapters within ourown organization to allow exchange ofideas and education between memberson a more frequent basis. At this point,with HOPA’s rapid growth, we’re spend-ing a lot of time establishing necessaryinfrastructure within the organization,getting policies and procedures set up,and making sure committees have direc-tions and are functioning at a high level.

What are some of the highlightsthat we can look forward to atthis year’s meeting?This year is going to be another great

meeting with many learning opportuni-ties. It’s been organized by an active pro-gram committee, with the goal ofinvolving the membership more in theeducation process by having moredebates, case discussions, and more

diverse workshops with hands-on typeactivities to meet the needs of our dif-ferent types of members. We’re trying toget to the nitty gritty of what we do ashematology/oncology pharmacists andhow we do it and to get a lot of inputfrom our membership. Our members arevery talented and active, and we’re try-ing to tap into their expertise. At theopening session, Ernest Anderson fromthe Association of Community Cancer

Centers will present the keynote ad-dress, providing us with a global, cost-effectiveness perspective on cancer care,which is something we may not thinkabout on a daily basis when we are tak-ing care of patients. We will be having atown hall meeting to give the membersa voice and allow them to discuss issuesthat are important to HOPA and hema-tology/oncology pharmacy. Additionally,HOPA is sponsoring the Run from theSun, our first annual run/walk and char-ity drive benefiting the Richard DavidKann Melanoma Foundation.

Does HOPA get involved inpolicy and legislative issues onthe state or national level?We have a legislative affairs commit-

tee, and they have been quite active thisyear, mostly at the federal level. Forinstance, they have written letters tothe Centers for Medicare & MedicaidServices regarding funding for Medicareservices and to the FDA regarding drugshortages. We are working with a groupof 11 pharmacy organizations to supportpayment systems within pharmacy andto assess what impact the new fundingthat is going to be coming through withthe federal stimulus package will haveon pharmacy in general and on oncolo-gy pharmacy in particular. We’ve beenlooking at ways that pharmacists can beincluded as a provider of services andable to bill for their cognitive and otherservices. The president-elect of HOPA,Philip Johnson from Moffitt, has a pas-sion for legislative issues, so I foresee thatin the coming years there will be evenmore work done in the legislative realm.

Does HOPA have any plans toaddress the predicted oncologyworkforce shortage?The HOPA board has just begun

thinking about what this shortage willbe and what impact it will have ononcology pharmacy. We’ve started talk-ing about forming task forces to providerecommendations on how HOPAshould approach this shortage. Theshortage appears to be one that mostlyaffects physicians, physician assistants,nurse practitioners, and others who pro-vide more direct, basic care more thansome pharmacists. It may actually pro-vide opportunities for oncology pharma-cists to become more integrated into

patient care, allowing us to be moreactive mid-level practitioners. There’sgoing to be a need for that, and oncolo-gy pharmacists can provide high-qualitydirect patient care if given the opportu-nity. Another area where oncologypharmacy may see some gains would bein the area of research. If there are fewerpractitioners to see patients, that meansfewer people with time to do research,which opens a door for oncology phar-macists to do some rigorous research inthe area of oncology pharmacy.

Does HOPA offer any researchsupport or other programs forpharmacy students or residents toencourage them to get involvedin oncology pharmacy?HOPA has done a good job of reach-

ing out to the residents. At our meetingevery year we have a resident posterreception, which is very well attended.A large majority of the oncology phar-macy practice residents across the coun-try come to HOPA and present theirresidency projects. We offer merit-basedtravel grants to some of the residents sothey can attend the meeting. We’vetried to incorporate residents on everycommittee as well as several new prac-titioners so they can get involved inthe organization early in their careerand become part of the committeestructure. HOPA realizes that it isimportant to train the future of ourorganization. This year, students fromNOVA Southeastern University willserve as volunteers at the meeting, andwe hope that once they see the greatthings we do on a daily basis, it willencourage them to consider a career inoncology pharmacy.

Any final comments?I think HOPA is a great organization

with wonderful and talented people.Although we are relatively young, weare quite poised to become a leader inoncology care. We are working to devel-op standards and guidelines that willimpact oncology patient care and out-comes. It has been a great honor to serveas president. I look forward to HOPA’sfuture successes and being a part of thisoutstanding organization throughoutmy career.

—Karen Rosenberg

HOPA President Foresees OpportunitiesContinued from cover

We are having students do some volunteerwork at the meeting, and we hope thatonce they see the great things we do ona daily basis, it will encourage them toconsider a career in oncology pharmacy.

We’ve been looking at ways thatpharmacists can be included as a providerof services and able to bill for theircognitive and other services.

© 2009 Genentech USA, Inc. All rights reserved. 9708100 Printed in USA.

www.BioOncology.com

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At Genentech BioOncology, we’re leading the fi ght against cancer withinnovative science and are working to transform cancer treatment.

A family of firsts—Our proven therapeutics are standards of care in 5 of the 6 leading causes of cancer mortality in the United States.

A robust pipeline—Our molecules in development target the fundamental mechanisms of cancer growth and include a HER dimerization inhibitor, a Hedgehog pathway inhibitor, an antibody–drug conjugate, and antibodies targeting cancer cell-surface antigens.

A commitment to patients—We actively pursue ways to ensure patient access to therapeutics through a variety of patient support programs so healthcare providers can remain focused on patient care.

Our goal is to fundamentally change the way cancer is treated — not just with incremental advances, but with new standards of care.


SKINCA

NCER

S More than 75% of all skin can-cer deaths are from melanoma.Although this cancer is cur-

able in early stages, treatment foradvanced melanoma continues to be achallenge.1 Recently, significant ad-vances were made in the areas of diag-nostics, immunotherapy, and targetedtherapies. This review examines studiespresented at several national meetingsin 2008, including the AmericanSociety of Clinical Oncology (ASCO)and the European Society for MedicalOncology (ESMO) Congress, in addi-tion to significant advances publishedin the literature.

New diagnostic testsPatient prognosis in melanoma is

highly dependent on early diagnosis. Infact, 5-year survival rates are 45% inpatients with an ulcerated melanoma>4-mm thick as compared with 95% inpatients with thin melanoma (<1 mm).2Early detection and surgical excision iscurrently the best treatment option inpatients with thin melanoma. Opti-mization of early diagnosis is needed,however, as most pigmented skinlesions are hard to assess with thenaked eye.3Dermoscopy is one option that allows

for cross-polarization of light, whichmakes the epidermis translucent andpermits visualization of the epidermisand superficial epidermis.4,5 A meta-analysis of studies performed in the clin-ical setting was conducted to evaluatethe accuracy of dermoscopy comparedwith the naked eye for diagnosis of cuta-neous melanoma.6 The findings sup-ported previous data that indicated thatdermoscopy is indeed significantly bet-ter at differentiating between mela-noma and nonmelanoma lesions. Likeother techniques, appropriate use of der-moscopy requires training, but whenused correctly, it can be extremely ben-eficial in identifying patients who needfurther evaluation.

New drugs/drug regimensImmunotherapy has been a mainstay

in both adjuvant treatment formelanoma and metastatic disease. Inthe United States, interferon alfa-2band interleukin-2 (IL-2) are currentlythe only two approved immunothera-peutic agents for melanoma. Disap-pointing response rates and undesirabletoxicities, however, affect adherencerates and limit use of these agents.

During the 2008 ASCO meeting,promising data pertaining to new andcurrent immunologic agents were pre-sented supporting the future role ofimmunotherapy as the primary treat-ment for melanoma.

Antagonistic monoclonal antibodiesThe discovery of agents that block

cytotoxic T lymphocyte antigen-4(CTLA-4) has already demonstratedpromising results in T-cell–mediatedkilling, antitumor T-cell immune func-tion, and subsequent inhibition oftumor recurrence.7 Immune-relatedadverse events (IRAEs) are a uniquephenomenon associated with CTLA-4

blockade. Unlike the current approvedimmunotherapeutic agents, CTLA-4blockade and subsequent IRAEs havebeen linked to tumor efficacy. O’Dayand associates presented data froma large multicenter phase 2 trial ofipilimumab in patients with advancedmelanoma who had failed priorchemotherapy and/or IL-2. Patientsreceived 10 mg/kg of this agent intra-venously (IV) every 3 weeks for fourcycles followed by maintenance treat-ment for patients with stable or re-sponding disease every 12 weeks.Overall median survival was 10.2months, and 24 (57%) of 42 patientsexperienced stable disease that had notprogressed at the time of presentation.Of 155 patients, overall rate of diseasecontrol (stable disease + partial response+ partial response) exceeded 27%(42/155). IRAEs occurred in 22% ofpatients (grade 3 or 4), with gastroin-testinal and hepatic toxicities occurringin 8% and 7% of patients, respectively.These data are encouraging when look-ing at overall survival and period of dis-ease control.8Another study sought to determine

whether prophylactic budesonide wouldprevent IRAEs associated with anti-CTLA-4 agents. Weber and colleaguespresented results of a phase 2 trial eval-uating the safety and efficacy of ipili-

mumab with or without budesonide.This study included treatment-naïveand previously treated patients withadvanced melanoma. Study end pointsincluded overall survival, response rates,and grade 2 diarrhea or higher. Overallsurvival at 10.5 months was notreached, but 1-year survival rates were58% (ipilimumab + budesonide) and59.1% (ipilimumab + placebo). Treat-ment-naïve patients had a 1-year sur-vival rate of 71%. Response rates wereseen in both groups (ipilimumab +budesonide, 12.1%; ipilimumab +placebo, 15.8%), but no differenceswere seen in the incidence of grade 2-4diarrhea in the 2 groups. One of the

most interesting findings was thattumors stopped growing in 30% ofpatients at the end of the 12-week peri-od, with another 10% to 20% showingresponses later.9At ASCO, data were also presented

on the other anti-CTLA-4 agent,tremelimumab, being studied for treat-ment of melanoma. Ribas and col-leagues presented a late-breakingabstract that evaluated the role ofchemotherapy (temozolamide or dacar-bazine) versus tremelimumab alone asfirst-line therapy. This large, random-ized trial included 655 patients withstage IIIc-IV melanoma. Tremelimumab,15 mg/kg, was administered every dayfor 90 days in the treatment group com-pared with oral temozolamide, 200mg/m2 on days 1 to 5 every 28 days, ordacarbazine, 1000 mg/m2 IV every 21days, in the chemotherapy arm. Primaryend points included overall survival,with secondary end points evaluatingresponse, durable tumor response, 6-month progression-free survival (PFS),and safety. Unfortunately, tremelimu-mab failed to demonstrate a significantimprovement in overall survival com-pared with standard chemotherapy.Overall survival with tremelimumabwas 11.76 months versus 10.71 monthsfor chemotherapy (with overlappingconfidence intervals and hazard ratio =

1.04). Therefore, the data and safetymonitoring board recommended earlydiscontinuation after two thirds of theevents had occurred. Response rateswere similar at 9.1 versus 10.1. Addi-tionally, 6-month PFS was similar (18.6and 14.1) in the two arms. Diarrhea(43% overall), pruritus (25%), and rash(23%) were the most common toxici-ties in the tremelimumab arm. Theauthors concluded that tremelimumabfailed to show overall survival benefitsin stage IIIc-IV melanoma patients asfirst-line therapy.10

Agonistic monoclonal antibodiesSeveral new immunologic agents are

currently under investigation for thetreatment of melanoma. A phase 1/2study of BMS-663513 (4-1BB), a fullyhumanized anti-CD137 nonblockingagonist monoclonal IgG4 antibody, wasconducted in patients with melanoma.CD137 is expressed on a variety of cellsand is thought to have several mecha-nisms of action. Additionally, synergis-tic activity has been seen preclinicallywith anti-CD137 agents and other treat-ment options, such as chemotherapy,radiation, and anti-CTLA-4 therapy. Inboth dose-finding phases of this study,patients with melanoma were enrolledand experienced minor dose-limitingtoxicities and partial response rates ofsignificant duration. Ongoing studiesare investigating use of this agent inpatients with metastatic melanoma.11A phase 1 study of CD40, a novel

target found on B-cell malignanciesand many solid tumors, was conductedin patients with melanoma. Partialresponses were seen in four (27%) of15 patients, with one near-completeresponse that lasted for 18 months.Unfortunately, CD40 activity may belost as tumors become metastatic.Therefore, studies are evaluating thepotential of using CD40 therapy afterinitial therapy for optimal immuneactivation.12Other phase 1 data were presented

on an anti-programmed death (PD)-1monoclonal antibody, PD-1(CD279).PD-1 blockade augments the prolifera-tion of melanoma-specific CD8 T cells.Antitumor activity was found in onepatient with a partial response, andfour patients experienced tumor regres-sions. Interestingly, the one patientwho experienced a partial response hadfailed chemotherapy, bevacizumab, and

Recent Advances in the Diagnosis andTreatment of Melanoma

BY LEANN B. NORRIS, PHARMD, BCPS, BCOPSOUTH CAROLINA COLLEGE OF PHARMACY, COLUMBIA

Skin Cancers

Synergistic activity has been seenpreclinically with anti-CD137 agentsand other treatment options, such aschemotherapy, radiation, and anti-CTLA-4 therapy.


ALOXI® (palonosetron HCl) injection 0.25 mg is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy.

Important Safety Information

ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. Most commonly reported adverse reactions include headache (9%) and constipation (5%).

Please see the following brief summary of prescribing information.

REFERENCES: 1. The Italian Group for Antiemetic Research. Dexamethasone alone or in combination with ondansetron for the prevention of delayed nausea and vomiting induced by chemotherapy. N Engl J Med. 2000;342:1554-1559. 2. Hickok JT, Roscoe JA, Morrow GR, et al. 5-Hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial. Lancet Oncol. 2005;6:765-772. Epub September 13, 2005. 3. Cohen L, de Moor CA, Eisenburg P, Ming EE, Hu H. Chemotherapy-induced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings. Support Care Cancer. 2007;15:497-503. Epub November 14, 2006. 4. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 5. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved Prevention of Moderately Emetogenic Chemotherapy-induced Nausea and Vomiting with Palonosetron, a Pharmacologically Novel 5-HT3 Receptor Antagonist: Results of a Phase III, Single-Dose Trial Versus Dolasetron. Cancer. 2003;98:2473-2482. 6. ALOXI® (palonosetron HCl) injection full prescribing information.

When patients experience acute chemotherapy-induced nausea and vomiting (CINV) during their fi rst cycle ofchemotherapy, they may have an increased risk of CINV on subsequent days and in subsequent cycles.1-3

ALOXI®:

A single IV dose lasts up to 5 days after MEC4,5*

The only IV 5-HT3 antiemetic specifically approved for prevention of both acute and delayed CINV associated with MEC6*

Can be used with multiple-day chemotherapy regimens6†

FOR A SUCCESSFUL CINVPREVENTION STRATEGY FROM THE FIRST CYCLE

* Moderately emetogenic chemotherapy.† Based on sNDA approval in August 2007, the restriction on repeated dosing of ALOXI (palonosetron HCl) injection within a

7-day interval was removed.

www.ALOXI.com

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license.

Distributed and marketed by Eisai Inc.

© 2008 Eisai Inc.

All rights reserved. Printed in USA. AL349 A 10/08

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cetuximab. Major toxicities with thisagent were similar to toxicities associ-ated with anti-CTLA-4 therapy.13

Tyrosine kinase inhibitorsTwo phase 2 studies presented at

ASCO involved multitargeted kinaseinhibitors. Axitinib, a vascular endo-thelial growth factor receptor (VEGFR)

and platelet-derived growth factorreceptor (PDGFR) inhibitor, was ad-ministered to 32 patients with refracto-ry advanced melanoma. An objectiveresponse rate of 19% (6/32) wasachieved. Stable disease occurred in28% of patients, and 30% were pro-gression free at 6 months. This studyproved that further research is needed

to evaluate the effects of axitinib bothalone and in combination with otheragents for melanoma.14 Sunitinib, a c-kit(CD117) and multitargeted tyrosinekinase inhibitor, was evaluated in aphase 2 trial in pretreated metastaticuveal melanoma patients. Tumors werestained for c-kit activity. Overall, 15patients, who had at least 10% c-kit

staining, were treated with sunitinib.One patient had an objective responserate and 10 patients had documentedstable disease. PFS exceeded 5 months,and response durations and stable dis-ease were >4 months. Although thesedata are preliminary, the study offerspromising results and supports poten-tial research in patients with hard-to-treat uveal melanoma.15

Large clinical trialsInterferon therapy has been a main-

stay in the treatment of melanoma todecrease disease recurrence and slowdisease progression. Pegylated interfer-on has a unique molecular structure thatallows for a longer half-life, extendedaction, and once-weekly dosing. Al-though studied in other disease states,pegylated interferon use has not beenestablished in the treatment of mel-anoma. In 2008, Eggermont and associ-ates published data evaluating the ben-efit of pegylated interferon alfa-2b inresected stage III melanoma patientscompared with observation. Peg-inter-feron was administered as 6 µg/kg perweek for 8 weeks then 3 µg/kg per weekfor an intended duration of 5 years. Theprimary end point was recurrence-freesurvival with secondary end pointsincluding distant metastasis-free sur-vival, overall survival, and safety. Morethan 1200 patients were enrolled in thestudy—608 patients in the interferongroup and 613 in the observation group.Pegylated interferon alfa-2b was admin-istered for an overall median of 12months. The 4-year rate of recurrence-free survival was 45.6% in the interfer-on group compared with 38.9% in theobservation group. There was no signif-icant difference, however, in overall sur-vival between the two groups. Grade3/4 adverse events occurred more fre-quently in the treatment group than inthe observation group. The most com-mon toxicities in patients treated withpegylated interferon alfa-2b includedfatigue, hepatotoxicity, and depression.Therefore, the toxicity profile is similarto the profile for interferon alfa-2b. Thedata suggest that pegylated interferonalfa-2b may have a role in the treatmentof patients with resected stage IIImelanomas.16In a phase 2 trial, McDermott and

associates evaluated the efficacy andsafety of the sorafenib/dacarbazine com-bination in patients with advancedmelanoma.17 Patients enrolled in thestudy had stage III unresectable or stageIV melanoma. Patients received dacar-bazine 1000 mg/m2 either with placeboor in combination with sorafenib, 400mg, twice a day for a maximum of 16cycles. The primary end point was PFS.Time to progression, response rate, andoverall survival were secondary end


ALOXI® (palonosetron HCl) injection

BRIEF SUMMARY OF PRESCRIBING INFORMATION

INDICATIONS AND USAGE

Chemotherapy-Induced Nausea and VomitingALOXI is indicated for:• Moderately emetogenic cancer chemotherapy – prevention of acute and delayed nausea and vomiting associated with initial and repeat courses• Highly emetogenic cancer chemotherapy – prevention of acute nausea and vomiting associated with initial and repeat coursesDOSAGE AND ADMINISTRATIONRecommended DosingChemotherapy-Induced Nausea and VomitingDosage for Adults - a single 0.25 mg I.V. dose administered over 30 seconds. Dosing should occur approximately 30 minutes before the start of chemotherapy.Instructions for I.V. AdministrationALOXI is supplied ready for intravenous injection. ALOXI should not be mixed with other drugs. Flush the infusion line with normal saline before and after administration of ALOXI.Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.CONTRAINDICATIONSALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. [see Adverse Reactions (6) in full prescribing information]WARNINGS AND PRECAUTIONSHypersensitivityHypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other 5-HT3receptor antagonists.ADVERSE REACTIONSBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not refl ect the rates reported in practice.In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374 adult patients received palonosetron. Adverse reactions were similar in frequency and severity with ALOXI and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by ≥ 2% of patients in these trials (Table 1).Table 1: Adverse Reactions from Chemotherapy-Induced Nausea and Vomiting Studies ≥ 2% in any Treatment Group

In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of approximately 0.75 mg, three times the recommended dose. One patient received a 10 mcg/kg oral dose in a postoperative nausea and vomiting study and one healthy subject received a 0.75 mg I.V. dose in a pharmacokinetic study.In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of ALOXI to adult patients receiving concomitant cancer chemotherapy:Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension, < 1%: hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. In many cases, the relationship to ALOXI was unclear.Dermatological: < 1%: allergic dermatitis, rash.Hearing and Vision: < 1%: motion sickness, tinnitus, eye irritation and amblyopia.Gastrointestinal System: 1%: diarrhea, < 1%: dyspepsia, abdominal pain, dry mouth, hiccups and fl atulence.

General: 1%: weakness, < 1%: fatigue, fever, hot flash, fl u-like syndrome.Liver: < 1%: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy.Metabolic: 1%: hyperkalemia, < 1%: electrolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia.Musculoskeletal: < 1%: arthralgia.Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia, paresthesia.Psychiatric: 1%: anxiety, < 1%: euphoric mood.Urinary System: < 1%: urinary retention.Vascular: < 1%: vein discoloration, vein distention.Postmarketing ExperienceThe following adverse reactions have been identifi ed during postapproval use of ALOXI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Very rare cases (<1/10,000) of hypersensitivity reactions and injection site reactions (burning, induration, discomfort and pain) were reported from postmarketing experience of ALOXI 0.25 mg in the prevention of chemotherapy-induced nausea and vomiting.DRUG INTERACTIONSPalonosetron is eliminated from the body through both renal excretion and metabolic pathways with the latter mediated via multiple CYP enzymes. Further in vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. Therefore, the potential for clinically signifi cant drug interactions with palonosetron appears to be low.Coadministration of 0.25 mg I.V. palonosetron and 20 mg I.V. dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone.In an interaction study in healthy subjects where palonosetron 0.25 mg (I.V. bolus) was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not signifi cantly altered (AUC: no change, Cmax: 15% increase).A study in healthy volunteers involving single-dose I.V. palonosetron (0.75 mg) and steady state oral metoclopramide (10 mg four times daily) demonstrated no signifi cant pharmacokinetic interaction.In controlled clinical trials, ALOXI injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents.Palonosetron did not inhibit the antitumor activity of the fi ve chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models.USE IN SPECIFIC POPULATIONSPregnancyTeratogenic Effects: Category BTeratology studies have been performed in rats at oral doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) and rabbits at oral doses up to 60 mg/kg/day (3789 times the recommended human intravenous dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to palonosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, palonosetron should be used during pregnancy only if clearly needed.Labor and DeliveryPalonosetron has not been administered to patients undergoing labor and delivery, so its effects on the mother or child are unknown.Nursing MothersIt is not known whether palonosetron is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric UseSafety and effectiveness in patients below the age of 18 years have not been established.Geriatric UsePopulation pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ≥ 65 years of age and younger patients (18 to 64 years). Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were ≥ 65 years old, while 71 (5%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and the younger subjects, but greater sensitivity in some older individuals cannot be ruled out. No dose adjustment or special monitoring are required for geriatric patients.Of the 1520 adult patients in ALOXI PONV clinical studies, 73 (5%) were ≥65 years old. No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded. No differences in effi cacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients. However, ALOXI effi cacy in geriatric patients has not been adequately evaluated.Renal ImpairmentMild to moderate renal impairment does not signifi cantly affect palonosetron pharmacokinetic parameters. Total systemic exposure increased by approximately 28% in severe renal impairment relative to healthy subjects. Dosage adjustment is not necessary in patients with any degree of renal impairment.Hepatic ImpairmentHepatic impairment does not signifi cantly affect total body clearance of palonosetron compared to the healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic impairment.RaceIntravenous palonosetron pharmacokinetics was characterized in twenty-four healthy Japanese subjects over the dose range of 3 – 90 mcg/kg. Total body clearance was 25% higher in Japanese subjects compared to Whites, however, no dose adjustment is required. The pharmacokinetics of palonosetron in Blacks has not been adequately characterized.OVERDOSAGEThere is no known antidote to ALOXI. Overdose should be managed with supportive care. Fifty adult cancer patients were administered palonosetron at a dose of 90 mcg/kg (equivalent to 6 mg fi xed dose) as part of a dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg. This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed.Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose. A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse.PATIENT COUNSELING INFORMATIONSee FDA-Approved Patient Labeling (17.2) in full prescribing informationInstructions for Patients• Patients should be advised to report to their physician all of their medical conditions, any pain, redness, or swelling in and around the infusion site [see Adverse Reactions (6) in full prescribing information].• Patients should be instructed to read the patient insert.

Rx OnlyMfd by OSO Biopharmaceuticals, LLC, Albuquerque, NM, USA or Pierre Fabre, Médicament Production, Idron, Aquitaine, France and Helsinn Birex Pharmaceuticals, Dublin, Ireland.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license.Distributed and marketed by Eisai Inc., Woodcliff Lake, NJ 07677.© 2008 Eisai Inc.All rights reserved. Printed in USA. AL350 10/08

EventALOXI

0.25 mg (N=633)

Ondansetron 32 mg I.V. (N=410)

Dolasetron 100 mg I.V.

(N=194)Headache 60 (9%) 34 (8%) 32 (16%)

Constipation 29 (5%) 8 (2%) 12 (6%)Diarrhea 8 (1%) 7 (2%) 4 (2%)Dizziness 8 (1%) 9 (2%) 4 (2%)Fatigue 3 (< 1%) 4 (1%) 4 (2%)

Abdominal Pain 1 (< 1%) 2 (< 1%) 3 (2%)Insomnia 1 (< 1%) 3 (1%) 3 (2%)

Diagnosis and Treatment of MelanomaContinued from page 12


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Current and Emerging Therapies for MRSAin Patients with Cancer

BY KATHRYN SCHULTZ, PHARMD, BCPS; AND EMILY MACKLER, PHARMD, BCOPUNIVERSITY OF MICHIGAN HEALTH SYSTEM, ANN ARBOR

There are many factors to consid-er when selecting a therapy formethicillin-resistant Staphylo-

coccus aureus (MRSA) in patients withcancer, including, but not limited to:severity of illness, site of infection,presence of chemotherapy side effects,such as neutropenia and mucositis,drug interactions, adverse events,recent antibiotic therapy, previousinfections and susceptibilities, and pres-ence of indwelling catheters. Formalguidelines have not been published forthe management of MRSA in cancerpatients; however, the management ofneutropenic fever and cancer-relatedinfections has been addressed by theInfectious Diseases Society of America(IDSA) and the National Comprehen-sive Cancer Network (NCCN) in theirpublished guidelines released in 2002and 2008, respectively.1,2In recent years, selection of anti-

biotics to treat MRSA has come intoquestion. Glycopeptide-resistant MRSAwas not recognized until 1996, almost40 years after the introduction of van-comycin.3 However, concern for apotential vancomycin minimum inhib-itory concentration (MIC) creep, clini-cal failure of vancomycin in the treat-ment of susceptible MRSA infectionswith increased MICs, and increasingincidence of vancomycin-resistant or-ganisms, especially enterococci, hasincreased the need to consider alterna-tive therapies.2-4 The repertoire of ther-apies to combat MRSA has increasedover the past decade, and new therapiesare continually in development.3-6Organizations such as IDSA have

made efforts to enhance appropriateprescribing of vancomycin by publish-ing guidelines for its use in neutropenicfever and catheter-related infections.1,7The Centers for Disease Control andPrevention (CDC) also launched theCampaign to Prevent AntimicrobialResistance in Healthcare Settings,which encourages thoughtful prescrib-ing of vancomycin.8 The purpose of thiscampaign is to improve antimicrobialstewardship and prevent emergence ofvancomycin-resistant organisms. Theseguidelines and the CDC campaignemphasize that vancomycin should beinitiated only in specific situations andrecommend deescalating empiric thera-py by discontinuing vancomycin after

72 hours based on clinical and micro-biological data.1,2,7

MRSA prophylaxisThe most common sites for MRSA

infections are the skin and skin struc-ture, the bloodstream, and the respira-tory tract.2 Patients with cancer fre-quently have central venous catheters(CVCs) and thus are at a higher riskfor CVC-related infection. Vancomycinis frequently used in regions wheremethicillin-resistant staphylococci arefound in high incidence. In an effort toprevent CVC-related infections, theuse of antibiotic lock therapy in certaincases to allow retention of a tunneledCVC (TCVC) or implantable devicehas been studied.7,9 Van de Weteringand van Woensel evaluated the effica-cy of antibiotics in the prevention ofearly TCVC infections in oncology pa-tients.9 Early TCVC infections aredefined as those that develop within 45days after placement of the catheter.The researchers concluded that admin-istration of teicoplanin or vancomycin

(two studies each) did not significantlydecrease the incidence of gram-posi-tive bacteremia when compared withplacebo. However, when the TCVCwas flushed with a vancomycin andheparin solution, the incidence of bac-teremia was reduced compared withheparin flushing alone (odds ratio[OR] = 0.43; confidence interval [CI]:0.21-0.87).9 Thus, prophylactic flush-ing of TCVC with a vancomycin/heparin solution may prevent gram-positive infections in oncologypatients. It should be noted, however,that flushes were used in only five stud-ies included in the systematic review.Additionally, the NCCN does notendorse the use of vancomycin/heparin solution flushes because ofconcerns that bacterial resistancewould increase if this method werewidely practiced.2The value of other prophylactic regi-

mens in preventing gram-positive infec-tions has also been investigated.10-13None of these regimens were specifical-ly evaluated in patients with cancer, butdecolonization has been evaluated as apreventive means of decreasing theincidence of MRSA infection. Intra-nasal mupirocin was evaluated with orwithout whole-body washing withchlorhexidine in all MRSA-colonizedhospital and nursing home patients, andboth agents were evaluated in MRSA-colonized intensive care unit (ICU)patients.10,11 In these studies, intranasalmupirocin with chlorhexidine bodywash reduced skin colonization com-pared with mupirocin and placebo solu-tion, but did not eradicate MRSA fromother body sites. Therefore there wasnot a significant difference in the num-ber of patients who were MRSA-free 30days after treatment.10In ICU patients, combination intra-

nasal mupirocin and chlorhexidinebathing reduced the incidence ofMRSA colonization during the hospital-ization, but evaluation did not include

longer time points for evaluation.11 Asecond body-wash solution, octenidinedihydrochloride, in combination withmupirocin was evaluated in hospitalizedpatients colonized with MRSA.12 Thiscombination decreasedMRSA coloniza-tion of tested body sites during the hos-pital stay. The degree of reduction variedby body site, nasal carriage showing thegreatest reduction (88.5%).12In the above-mentioned studies, the

value of the therapeutic agents used forMRSA decolonization was determinedby rates of skin decolonization, but oneagent has been studied to determinewhether it would prevent MRSA pneu-monia.13 In a study by Silvestri and asso-ciates, oral vancomycin administered asa 4% gel to the oropharynx every 6hours was evaluated in ICU patientswho were expected to be intubated for>72 hours. The study found that over a1-year period, there were significantly

fewer nosocomial lower airway infec-tions in the vancomycin group com-pared with the control group (OR =0.26; 95% CI: 0.08-0.88; P <.001). OneMRSA infection was prevented forevery seven patients treated with van-comycin gel.13Although the efficacy of various

MRSA prophylaxis regimens has beenstudied in the general hospital popula-tion and in ICU patients, the utility ofthese agents to prevent MRSA infec-tions in patients with cancer has notspecifically been studied, and their rou-tine use is not recommended in cancerpatients at this time.

MRSA treatmentMRSA has historically been associ-

ated with patients in the hospital set-ting. More recently, however, commu-nity-associated strains of MRSA haveemerged. As mentioned earlier, themost common sites for MRSA infec-tions are the skin and skin structure,the bloodstream, and the respiratorytract.2 Therapeutic agents for treatmentof MRSA include both intravenous(IV) and oral antibiotics. Many of theavailable oral antibiotics are options forpatients with less-severe skin and skin-structure infections (SSSIs)or as step-down therapy after a course of IV treat-ment. Oral agents that are available forthe treatment of MRSA include doxy-cycline, trimethoprim-sulfamethoxa-zole (cotrimoxazole), clindamycin, andlinezolid. Of the IV antibiotics avail-able for treatment of MRSA infections,vancomycin has been the gold stan-dard. Second-line therapies includelinezolid, an oxazolidinone; dapto-mycin, a cyclic lipopeptide; and tigecy-cline, a glycylcycline. Because of itsadverse event profile, quinupristin-dal-fopristin, a streptogramin, is usuallythird-line (Table 1).1,3-5,7,14-19When neutropenia confounds the

clinical scenario, current guidelines rec-ommend adding vancomycin to a neu-tropenic fever antibiotic regimen after72 hours of continuing fever if gram-positive cocci in clusters are found on agram stain, MRSA is identified by cul-ture, or if a patient is at high risk forinfection with MRSA.1Localized MRSA cellulitis in cancer

patients is treated with recommendedtherapies for SSSIs as indicated by the

The repertoire of therapies to combatMRSA has increased over the past decade,and new therapies are continually indevelopment.

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Table 1. Available Therapies for MRSA

Therapy Mechanism of actionRecommended dosageand administration Supporting literature Special considerations

Vancomycin Tricyclic glycopeptide inhibitsbacterial cell wall synthesis,alters permeability ofbacterial cell membrane andinterferes with RNA synthesis

Bactericidal; slow, time-dependent

15 mg/kg IV q12h

Renal dose adjustment

MRSA bacteremia: first-line per IDSA guidelines1,7 Increasing resistance3,4

Quinupristin-dalfopristin (Q-D)

Inhibits early and late phases of protein synthesis of 50S ribosomal subunit,respectively

Bactericidal

cSSSIs: 7.5 mg/kg IV q12h

VRE bacteremia: 7.5 mg/kg IV q8h

Not FDA approved forMRSA bacteremia

Catheter-related bacteremia: 1 g IV q12h vancomycin vs7.5 mg/kg IV q8h Q-D15

• 62% cancer patients • Combined all staphylococcal infections (only 2 MRSA) • Phase 2 trial • 1/2 Staphylococcus aureus in vancomycin group and

2/5 in 7.5-mg/kg Q-D group showed clinical response • MRSA not segregated from MSSA • Safety profiles comparable

MRSA infections: Q-D 7.5 mg/kg IV q8h16

• Culture-proven MRSA • Various sources (bacteremia, catheter-related

bacteremia, respiratory, etc) • All patients failed/intolerant to previous therapy • Administration adverse events led to discontinuation of

therapy (20%) • Overall success 71.1% (n = 90) and 66.7% in patients

clinically and bacteriologically evaluable

Q-D 7.5 mg/kg IV q8h vs vancomycin 1 g IV q12h17

• Gram-positive nosocomial pneumonia • Patients with significant neutropenia

(ANC <500/mm3) were excluded • Clinical success 56.3% vs 58.3% • Tendency for drug-related venous adverse events

28/145 vs 16/138 (P = .056)

Myalgia and arthralgia

Venous reactions (50%) andchange in infusion siterequired (70%)

Inhibits 3A4

Linezolid Oxazolidinone inhibitsbacterial protein synthesis bybinding to the 70S initiationcomplex

Bacteriostatic

Pneumonia or cSSSIs:600 mg IV or PO q12h

Linezolid 600 mg IV q12h vs vancomycin 1g IV q12h18

• Neutropenic patients with cancer • No significant difference in clinical efficacy • Increased drug-related adverse events in vancomycin

group (52/303 vs 72/300; P <.04)

Linezolid 600 mg IV or PO q12h vs comparator group(vancomycin, oxacillin, dicloxacillin)14

• Increased risk of mortality in linezolid-treated catheter-related bloodstream infections in seriously ill patients(78/363 vs 58/363) in 84 days after first dose

IV and PO available

Thrombocytopenia,specifically in treatmentcourses ≥14 days

Risk of serotonin syndromewhen concomitantly usedwith agents that increaseserotonin concentrations suchas serotonin agonists andselective serotonin reuptakeinhibitors

Daptomycin Cyclic lipopeptide rapidlydepolarizes bacterial cellmembrane via formation ofpotassium efflux channels

Bactericidal; rapid,concentration-dependent

cSSSIs: 4 mg/kg IV q24h

Bacteremia: 6 mg/kg IVq24h

Renal dose adjustment

Daptomycin 6 mg/kg IV daily vs low-dose gentamicin + antistaphylococcal penicillin or vancomycin19

• Staphylococcus aureus bacteremia ± endocarditis • Successful outcome 42 days after therapy: 44.2% vs

41.7% • Clinically significant renal dysfunction: 11% vs 26.3%

(P = .004) • Successful outcome in patients with MRSA: 44.4% vs

31.8% (NS) • Any drug-related adverse events: 35% vs 42.2% (P = .29) • Serious adverse events: 51.7% vs 44.8% (P = .3)

Poor lung penetration andbinds to lung surfactant

Increased creatinephosphokinase 2.8%-6.7%

Rhabdomyolysis: case reportswith 6 mg/kg IV q24h dosing

Increased risk with acuterenal failure or concomitantuse of drugs that may causerhabdomyolysis (ie, statins)

Tigecycline Glycycline inhibits 30Sribosomal subunit to inhibitprotein translation

Bacteriostatic

cSSSIs: Initial dose: 100mg IV once, then 50 mgIV q12h

In vitro activity against MRSA5

No clinical studies evaluating use in the treatment ofMRSA

Time-dependent killing

Drug achieves poor serumconcentration—notrecommended for treatmentof bacteremia2

ANC indicates absolute neutrophil count; cSSSIs, complicated skin and skin-structure infections; FDA, US Food and Drug Administration; IDSA, Infectious Diseases Society of America; IV, intravenous; MRSA, methicillin-resistantStaphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus; NS, not significant; PO, by mouth; RNA, ribonucleic acid; VRE, vancomycin-resistant enter ococci.


TOP June Issue 6/5/09 11:44 AM Page 16

Teva is #1inOncology Products

19 Hughes • Irvine, California 92618800.729.9991 • www.tevausa.com

Data derived from the use of information under license from the following IMS HealthInformation Service: IMS NSP Audit, MAT 9/08. Data is proprietary to IMS Health.

©2009, Teva Pharmaceuticals USA 8349 A

ViewTeva’s complete line of oncologyproducts at www.tevausa.com/oncology

1


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IDSA guidelines.20 For initial therapy,IV vancomycin is used empirically, buttreatment may be changed to oral ther-apies such as linezolid or clindamycindepending on sensitivities of the par-ticular strain, if available, and if thepatient’s condition is improved. How-ever, patients are treated differently ifthey are immunocompromised (neu-tropenic, recent chemotherapy, cell-mediated immunodeficiency). Treat-ment of an immunocompromisedpatient changes drug selection for SSSIto broad-spectrum empiric therapythat includes coverage of resistantgram-positive bacteria, such as MRSA.The therapy selected is typically van-comycin, but linezolid, daptomycin, orquinupristin/dalfopristin are alterna-tive options.2,20Treatment of community-acquired

pneumonia in cancer patients followsthe IDSA guidelines, but may be com-plicated by recent antibiotic therapy,increasing severity of illness, history ofMRSA infection, or known coloniza-tion, thus necessitating the addition ofvancomycin or linezolid and considera-tion of hospitalization for pneumo-nia.2,21 Hospital-acquired pneumonia incancer patients, whether early or late-onset, tends to necessitate treatment asfor late-onset pneumonia, especially ifthe patient has received antibiotics inthe past 90 days, has had a recent hospi-talization, or is from a healthcare-associ-ated facility.2,22The third common site of MRSA

infections in cancer patients is thebloodstream. These infections are com-monly associated with vascular accessdevices (VADs), because the deviceprovides a potential site of infection.The course of action for VAD infectionsdepends on whether it is categorized asan entry-site or exit-site infection.2VAD exit-site infections may be treatedwith antimicrobial therapy without theremoval of the catheter. However,patients with a serious, catheter-relatedinfection (tunnel or port pocket) shouldhave the catheter removed immediate-ly.2 Whether the MRSA infection iscategorized as community-acquired orhospital-acquired, vancomycin is thefirst-line treatment for bacteremia inthis population. Doxycycline and clin-damycin are not recommended mono-therapies for MRSA bacteremia becauseof increasing resistance.5 Additionally,linezolid is not recommended forcatheter-related infections in light ofthe US Food and Drug Administration(FDA) alert (Table 1). Also, it is notFDA approved for bacteremia, thusadding to the limitations of drug selec-tion for MRSA bacteremia.23

MRSA emerging therapiesThe increasing incidence of MRSA

infections has led to a need for develop-

ment of new therapeutic options forMRSA (Table 2).23-28 There are a fewnew glycopeptides: teicoplanin, tela-vancin, dalbavancin, and oritavancin.Teicoplanin is not currently available inthe United States. In a study of patientswith hematologic malignancies whopresented with neutropenic fever, eitherteicoplanin or vancomycin was addedafter documentation of bacteremia dueto gram-positive cocci.29 Therapeuticsuccess was seen in 55 (87.3%) of 63patients in the teicoplanin 6 mg/kg IVtwice daily for 2 days, then once-dailyarm and 56 (91.8%) of 91 patients inthe vancomycin 15 mg/kg every 12hours arm (P = .560). In bacteremiacaused by staphylococci, successful out-come was seen in 45 (86.5%) of 52

patients treated with teicoplanin com-pared with 45 (93.8%) of 48 patientstreated with vancomycin.Telavancin, a lipoglycopeptide anti-

biotic, is active against MRSA. It hastwo mechanisms of action, which con-tribute to its bactericidal activityagainst MRSA. It inhibits cell-wall syn-thesis and depolarizes the bacterial cellmembrane.6 In two recently publishedphase 3 trials, telavancin was at least aseffective as vancomycin (91% vs 86%)in curing MRSA SSSIs.30 Adverseevents of telavancin and vancomycinled to withdrawal from the study in 8%and 6% of patients, respectively. Phase3 trials comparing telavancin with van-comycin for hospital-acquired pneumo-nia due to MRSA were completed in

May and June of 2007, respectively.23,24Dalbavancin is a semisynthetic lipo-

glycopeptide effective against gram-positive organisms including MRSA.31The half-life of dalbavancin is longerthan that of other glycopeptides at 9 to12 days. A phase 2 prospective trialcompared the safety and efficacy of twodoses of dalbavancin given 1 weekapart compared with vancomycintwice daily for 14 days in patients withcatheter-related bloodstream infec-tions. Of note, patients with prolongedneutropenia or those who had receivedimmunosuppressant therapy were ex-cluded. The overall success rate (com-bined clinical and microbiologicresponse) was greater with dalbavancin

Table 2. Pipeline Drug Status

Drug class Agent Approval status

Glycopeptide Teicoplanin Approved in Europe

Lipoglycopeptides Telavancin 1/26/09: NDA submitted for nosocomial pneumonia

3/5/08: FDA accepted for review Theravance’s complete response toapprovable letter for cSSSIs

12/7/06: NDA submitted for cSSSIs

Dalbavancin 9/9/08: Pfizer withdrew all marketing applications for cSSSIs in adults

12/21/07: Pfizer received an FDA approvable letter; working with the FDAto provide additional data on dalbavancin in regard to the noninferioritydraft guidance for approval of antibiotics published by the FDA

Oritavancin 10/9/08: FDA sent a complete response letter stating that the company’sNDA did not demonstrate safety and efficacy for treatment of cSSSIs.FDA requested that a sufficient number of patients with MRSA as thecause of the cSSSI be enrolled to determine efficacy in that subset

12/8/08: FDA said insufficient data had been provided

02/08: NDA submitted for cSSSIs

Phase 2 for catheter-related bacteremia

Cephalosporins Ceftobiprole 11/26/08: FDA sent a complete response letter stating that the NDA forceftobiprole could not be approved at this time and requested thecompany to audit work at the clinical sites

11/08: In the week prior to the FDA’s complete response letter, theCommittee for Medicinal Products for Human Use of the EuropeanMedicines Agency recommended to the European Union thatceftobiprole be approved for cSSSIs

3/19/08: FDA requested more information about how ceftobiprole works

3/18/08: FDA issued approvable letter for cSSSIs and diabetic footinfections

Ceftaroline 10/27/08: Phase 3 results were presented at the 48th Annual InterscienceConference on Antimicrobial Agents and Chemotherapy/InfectiousDiseases Society of America 46th Annual Meeting in Washington, DC. Theabstract stated that ceftaroline was noninferior to vancomycin/aztreonamfor the treatment of cSSSIs

02/07: Two phase 3 studies initiated for cSSSIs

Zinc metalloenzyme Lysostaphin No trials under way

cSSSIs indicates complicated skin and skin-structure infections; FDA, US Food and Drug Administration; NDA, new drug application.

Sources: References 23-28.

Current and Emerging Therapies for MRSAContinued from page 16


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CANCER

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NS

than with vancomycin (87% vs 50%; P<.05). Adverse events (oral candidiasisand diarrhea) were similar for the twodrugs. No patients discontinued dalba-vancin therapy, whereas two patientsin the vancomycin arm withdrew fromthe study because of adverse events,including one with acute renal failurepossibly related to vancomycin. Dal-bavancin is a lipoglycopeptide, whichmay contribute to its efficacy incatheter-related bloodstream infec-tions when staphylococcal organismsare imbedded in biofilms. Phase 3 stud-ies are under way to further evaluatethe safety of dalbavancin.Oritavancin is a third lipoglycopep-

tide, for which a new drug application

was filed in 2008 for complicated skinand skin-structure infections (cSSSI).26Phase 2 trials to demonstrate safety andefficacy of a once-daily agent versus aninfrequent dosing schedule for the treat-ment of cSSSI were completed in May2008. Although teicoplanin has beenstudied in treatment of bacteremia inneutropenic patients with hematologiccancers, the three lipoglycopeptideshave not been studied in cancer popula-tions. The FDA released a letter inDecember 2008 to the manufacturers oforitavancin requesting additional phase3 studies that would include morepatients with cSSSI that have MRSAidentified as the causative organism inorder to exhibit efficacy in this patientpopulation.26Cephalosporins have historically not

been a therapeutic choice for treatingMRSA. New cephalosporins, such asceftobiprole and ceftaroline, however,are currently under development. Thesenew agents provide broad-spectrumcoverage that includes gram-positive,gram-negative, and anaerobic organ-isms with the added benefit of activityagainst MRSA and vancomycin-resis-tant staphylococci. The added coverageof MRSA is due to the high level ofbinding of these new cephalosporins tothe penicillin-binding protein 2a.Ceftobiprole has been evaluated in

two phase 3 clinical trials for the treat-ment of cSSSIs and will be evaluatedin phase 3 trials for hospital-acquiredpneumonia, community-acquired pneu-monia requiring hospitalization, andneutropenic fever in patients receivingchemotherapy.32 Ceftobiprole was foundto be noninferior to vancomycin intreatment of cSSSIs. Similar safety andadverse event profiles were seen

between ceftobiprole and vancomycin,the only significant difference being ahiger incidence of nausea in the cefto-biprole group (14% vs 8%; P <.05).32A phase 2 study of ceftaroline evalu-

ated its safety and efficacy comparedwith standard therapy, which includedvancomycin, for treatment of cSSSIs.33Ceftaroline was well tolerated, with61.2% of the ceftaroline group experi-encing an adverse event, similar to the56.3% rate in the standard therapygroup. Test of cure (TOC) was evaluat-ed at predetermined time points aftercompletion of therapy. Clinical cures atTOC were achieved in 96.7% of cef-taroline patients and 88.9% of standardtherapy patients. Of microbiologic cul-

tures that identified pathogens, 10patients had MRSA, five in each treat-ment group. Clinical cure was achievedin 80% (4 of 5) of ceftaroline patientsand 100% (5 of 5) of standard (van-comycin)-therapy patients.While both new cephalosporins show

promise for being effective againstMRSA, it should be noted that trials todate have been of their use in treatingcSSSIs; studies of their use in bac-teremia and pneumonia have not beenreported on or published. Interestingly,Ortho-McNeil withdrew its phase 2study of ceftobiprole in the treatment ofhospitalized patients with S aureus bac-teremia because of lack of an appropri-ate patient population.28 At this point,no published studies are available thatevaluate the use of MRSA-active ceph-alosporins in patients with cancer, butthe manufacturers of ceftobiprole planto conduct a study of its use in cancerpatients with neutropenic fever.Another agent under investigation,

lysostaphin, is a zinc metalloenzyme thatwas first identified in 1964. The S aureuspeptidoglycan cell wall contains a high-er amount of glycine than other staphy-lococcal species, mainly because of thepentaglycine bridges, which provide theadditional strength to the cell wall ofS aureus.34 This structural differencemakes lysostaphin a novel therapeuticagent for S aureus and, more important-ly, antibiotic-resistant S aureus. Lyso-staphin has the added advantage ofbeing active against actively growingand nondividing cells, such as staphylo-cocci in biofilms. Its activity is due tothree enzymes: glycylglycine endopepti-dase, endo-β-N–acetyl glucosamidaseand N-acetyl-muramyl-L-alanine ami-dase. Lysostaphin has been studied for

the treatment of endocarditis synergisti-cally with aminoglycosides, but it hasthe potential to be used for MRSAinfections because of its unique speci-ficity and activity against S aureusbiofilms. However, it has not yet beenevaluated in patients with cancer.

ConclusionPatients with cancer are prone to

MRSA infections in the bloodstream,skin and skin structures, and respirato-ry tract. Selection of initial antibiotictherapy should take into considerationthe local antimicrobial susceptibilities,site of infection, clinical condition ofpatient, drug allergies, and recentantibiotic use.2 There are no publishedguidelines for the management ofMRSA infections in patients with can-cer, but there are resources availablefrom the IDSA and the NCCN to helpguide antibiotic selection and prudentuse of vancomycin.1,2,7,20 As moreagents are developed to be effectiveagainst MRSA, it is important that wecontinue to evaluate them specificallyfor their place in treatment of patientswith cancer.

References1. Hughes WT, Armstrong D, Bodey GP, et al.

2002 Guidelines for the use of antimicrobialagents in neutropenic patients with cancer. ClinInfect Dis. 2002;34:730-751.

2. National Comprehensive Cancer Network I.Prevention and treatment of cancer-relatedinfections (1.2008). www.nccn.org/professionals/physician_gls/PDF/infections.pdf. Accessed July30, 2008.

3. Sakoulas G, Moellering RC Jr. Increasing anti-biotic resistance among methicillin-resistantStaphylococcus aureus strains. Clin Infect Dis.2008;46(suppl 5):S360-S367.

4. Tverdek FP, Crank CW, Segreti J. Antibiotictherapy of methicillin-resistant Staphylococcusaureus in critical care. Crit Care Clin. 2008;24:249-260, vii-viii.

5. Cosgrove SE, Fowler VG Jr. Management ofmethicillin-resistant Staphylococcus aureus bac-teremia. Clin Infect Dis. 2008;46(suppl 5):S386-S393.

6. Naber CK. Future strategies for treatingStaphylococcus aureus bloodstream infections.Clin Microbiol Infect. 2008;14(suppl 2):26-34.

7. Mermel LA, Farr BM, Sherertz RJ, et al.Guidelines for the management of intravascularcatheter-related infections. Clin Infect Dis. 2001;32:1249-1272.

8. Centers for Disease Control and Prevention.December 5, 2003. Fact sheet: 12 steps to pre-vent antimicrobial resistance among hospitalizedadults. www.cdc.gov/drugresistance/healthcare/ha/12steps_HA.htm. Accessed August 12, 2008.

9. van de Wetering MD, van Woensel JB.Prophylactic antibiotics for preventing earlycentral venous catheter gram positive infec-tions in oncology patients. Cochrane DatabaseSystem Rev. 2007;(1):CD003295.

10. Wendt C, Schinke S, Württemberger M, et al.Value of whole-body washing with chlorhexi-dine for the eradication of methicillin-resistantStaphylococcus aureus: a randomized, placebo-controlled, double-blind clinical trial. InfectControl Hosp Epidemiol. 2007;28:1036-1043.

11. Ridenour G, Lampen R, Federspiel J, et al.Selective use of intranasal mupirocin andchlorhexidine bathing and the incidence ofmethicillin-resistant Staphylococcus aureus colo-nization and infection among intensive care unitpatients. Infect Control Hosp Epidemiol. 2007;28:1155-1161.

12. Rohr U, Mueller C, Wilhelm M, et al. Meth-icillin-resistant Staphylococcus aureus whole-body decolonization among hospitalized pa-tients with variable site colonization by usingmupirocin in combination with octenidine dihy-drochloride. J Hosp Infect. 2003;54:305-309.

13. Silvestri L, van Saene HK, Milanese M, et al.

Prevention of MRSA pneumonia by oral van-comycin decontamination: a randomized trial.Eur Respir J. 2004;23:921-926.

14. US Food and Drug Administration. March 16,2007. Information for healthcare professionals:Linezolid (marketed as Zyvox). www.fda.gov/cder/drug/InfoSheets/HCP/linezolidHCP.pdf.Accessed August 12, 2008.

15. Raad I, Bompart F, Hachem R. Prospective, ran-domized dose-ranging open phase II pilot studyof quinupristin/dalfopristin versus vancomycinin the treatment of catheter-related staphylococ-cal bacteremia. Eur J Clin Microbiol Infect Dis.1999;18:199-202.

16. Drew RH, Perfect JR, Srinath L, et al. Treatmentof methicillin-resistant Staphylococcus aureusinfections with quinupristin-dalfopristin inpatients intolerant of or failing prior therapy.J Antimicrob Chemother. 2000;46:775-784.

17. Fagon JY, Patrick H, Haas DW, et al. Treatmentof gram-positive nosocomial pneumonia: pro-spective randomized comparison of quin-upristin/dalfopristin versus vancomycin. Nosoco-mial Pneumonia Group. Am J Respir Crit CareMed. 2000;161:753-762.

18. Jaksic B, Martinelli G, Perez-Oteyza J, et al.Efficacy and safety of linezolid compared withvancomycin in a randomized, double-blind studyof febrile neutropenic patients with cancer. ClinInfect Dis. 2006;42:597-607.

19. Fowler VG Jr, Boucher HW, Corey GR, et al.Daptomycin versus standard therapy for bac-teremia and endocarditis caused by Staphylococ-cus aureus. N Engl J Med. 2006;355:653-665.

20. Stevens DL, Bisno AL, Chambers HF, et al.Practice guidelines for the diagnosis and man-agement of skin and soft-tissue infections. ClinInfect Dis. 2005;41:1373-1406.

21. Mandell LA, Wunderink RG, Anzueto A, et al.Infectious Diseases Society of America/American Thoracic Society consensus guide-lines on the management of community-acquired pneumonia. Clin Infect Dis. 2007;44(suppl 2):S27-S72.

22. American Thoracic Society; Infectious DiseasesSociety of America. Guidelines for the manage-ment of adults with hospital-acquired, ventila-tor-associated, and health-care associated pneu-monia. Am J Respir Crit Care Med. 2005;171:388-416.

23. ClinicalTrials.gov. Comparison of Telavancinand Vancomycin for Hospital-Acquired Pneu-monia Due to Methicillin-Resistant Staphylo-coccus aureus (ATTAIN 1). www.clinicaltrials.gov/ct2/show/NCT00107952?term=telavancin&rank=2. Accessed August 12, 2008.

24. ClinicalTrials.gov. Comparison of Telavancinand Vancomycin for Hospital-Acquired Pneu-monia Due to Methicillin-Resistant Staphylo-coccus aureus (ATTAIN 2). www.clinicaltrials.gov/ct2/show/NCT00124020?term=telavancin&rank=3. Accessed August 12, 2008.

25. Drugs.com. Pfizer to Withdraw Global Market-ing Applications for Dalbavancin. www.drugs.com/nda/dalbavancin_080909.html. AccessedFebruary 8, 2009.

26. Drugs.com. Complete Response Letter for Orita-vancin. www.drugs.com/nda/oritavancin_081209.html. Accessed February 8, 2009.

27. Drugs.com. FDA Issues Approvable Letter forCeftobiprole. www.drugs.com/nda/ceftobiprole_080318.html. Accessed August 12, 2008.

28. Drugs.com. FDA Issues Complete Response Let-ter for Ceftobiprole. www.drugs.com/nda/ceftobiprole_080318.html. Accessed August 12, 2008.

29. D’Antonio D, Staniscia T, Piccolomini R, et al.Addition of teicoplanin or vancomycin for thetreatment of documented bacteremia due togram-positive cocci in neutropenic patients withhematological malignancies: microbiological,clinical and economic evaluation.Chemotherapy.2004;50:81-87.

30. Stryjewski ME, Graham DR, Wilson SE, et al.Telavancin versus vancomycin for the treatmentof complicated skin and skin-structure infectionscaused by gram-positive organisms. Clin InfectDis. 2008;46:1683-1693.

31. Raad I, Darouiche R, Vazquez J, et al. Efficacyand safety of weekly dalbavancin therapy forcatheter-related bloodstream infection caused bygram-positive pathogens. Clin Infect Dis. 2005;40:374-380.

32. Anderson SD, Gums JG. Ceftobiprole: anextended-spectrum anti-methicillin-resistantStaphylococcus aureus cephalosporin. AnnPharmacother. 2008;42:806-816.

33. Talbot GH, Thye D, Das A, et al. Phase 2 studyof ceftaroline versus standard therapy in treat-ment of complicated skin and skin structureinfections. Antimicrob Agents Chemother. 2007;51:3612-3616.

34. Kumar JK. Lysostaphin: an antistaphylococcalagent.Appl Microbiol Biotechnol. 2008;80:555-561.

This structural difference makeslysostaphin a novel therapeutic agentfor S aureus and, more importantly,antibiotic-resistant S aureus.

Current and Emerging Therapies for MRSAContinued from page 18

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MD, Fox Chase Cancer Center, Phila-delphia, Pennsylvania, and head of theNCCN committee for colon, rectal, andanal cancer guidelines.“I think the KRAS story is probably

the number one story of the guide-lines,” Engstrom said during an inter-view. “I think the second one is theaddition of the survivorship guidelinesto our panel. I think other than lungcancer, really we’re the only cancerright now to have a full inclusion inthe guidelines of survivorship. Andthen I think third is judging who’sresectable for liver metastasis.”Several studies published in 2008

demonstrated that the status of thetumor KRAS gene is highly predictiveof outcome with anti–epidermal growthfactor receptor agents, such as cetux-imab and panitumumab. However,these agents have been found to beeffective only in colorectal cancerpatients with tumors that express thenormal (or wild-type) KRAS gene andnot with tumors that express KRASgene mutations.So the colon and rectal cancers guide-

line updates include the recommenda-tion that KRAS testing should be donefor all patients diagnosed with metastat-ic colorectal cancer before finalizingtheir treatment plan, with these agentsused only for those who have tumorswith wild-type KRAS genes.Said Engstrom, “I think the finding

[from those studies] was an eye-openerto oncologists because we didn’t knowwhy some patients didn’t respondbefore. Just like we have a lot of otheragents that we don’t know whypatients don’t respond to, such asirinotecan. Some of our patients do[respond] and some don’t. And nowwe’re starting to tease this apart withthese molecular tests. I think this is animportant new direction in the man-agement of colorectal cancer.”The guidelines’ new section on sur-

vivorship outlines principles for long-term follow-up care for patients in remis-sion. In addition to monitoring thesepatients for disease-specific recurrence,the new guidelines stress the need forscreening and monitoring for other can-cers. Specifically, the guidelines state

that special attention should be paid toprevention of breast and cervical can-cers among women survivors, while sur-veillance for prostate cancer should bestressed to male cancer survivors.In addition, the survivorship section

describes healthy lifestyle recommenda-tions (especially exercise), the manage-ment of long-term treatment side effects,wellness counseling, and transferringcare to a primary care physician.“There are many survivors in the

group of colorectal patients, and they’rea little bit neglected,” said Engstrom.“Some of them have had colono-scopies. Many of them have had radio-therapy along with chemotherapy. Ihave patients that are out 20, 25, 30years from their treatment of [colorec-tal] cancer and they still have somesequelae that they are living with. Andnobody’s ever really talked to themabout that. So I think these survivor-ship guidelines are important. Thebreast cancer patients are usually themodel that we go by, but I think thereare as many survivors in colorectal can-cer as there are in breast cancer.”

The guideline updates also include arecommendation for the reevaluationof patients with initially unresectablemetastatic colorectal disease to deter-mine whether they would be suitablefor resection following chemotherapy.Specifically, the guidelines now in-clude the words “potentially convert-ible” or “unconvertible,” which havebeen added to the definition of unre-sectable disease.An up-front multidisciplinary team

evaluation is now recommended, in-cluding a surgeon with resection expert-ise. “Before, we defined ‘resectable’ bywhat comes out, asking how many me-tastases are there and how large?” saidEngstrom during his presentation. “Nowwe’re defining it by what stays in, suchas preserving liver segments.”In addition, the guideline updates

provide new data on using cetuximab intreatment of patients with metastaticcolorectal cancer, including in combina-tion with specific chemotherapy drugs asan initial therapy option.

—Deborah Brauser

Colon and Rectal Cancers GuidelinesContinued from cover

advocates skin-sparing mastectomy,when possible, for breast reconstruction.The updates were presented at the

NCCN Annual Conference by BerylMcCormick, MD, of Memorial Sloan-Kettering Cancer Center, New York, andStephen B. Edge, MD, of Roswell ParkCancer Institute, Buffalo, New York.

DCIS and early breast cancerFamily history suggestive of heredi-

tary breast cancer is a reason to offergenetic counseling to patients withDCIS or early invasive breast cancer,the NCCN panel decided. Data suggestthat women at high risk are increasing-ly opting for prophylactic mastectomy.A Surveillance, Epidemiology and EndResults (SEER) analysis of DCIS pa-tients found the rate of bilateral mastec-tomy to be 6% in 1998 but 18% in 2005(Tuttle TM, et al. J Clin Oncol. 2009;1362-1367).Patients with DCIS should also

undergo mammography after excision,when there is uncertainty about theadequacy of excision, the panel said.

Radiotherapy recommendationsReflecting trends in whole breast ir-

radiation, the panel included a recom-mendation for computed tomography(CT)-based treatment planning, andgave the option for radiotherapy dosesof 45 Gy to 50 Gy in 1.8 Gy to 2 Gy perfraction or a hypofractionated dose of42.5 Gy at 2.66Gy per fraction (ie, lowerdose over a shorter period).Trials have suggested that faster

courses of radiotherapy will decreasethe time to treatment initiation, reducethe cost of healthcare, and increase theproportion of women who completeradiotherapy after breast-conservingsurgery. “We offer hypofractionation toour patients, and 60% opt for it,”McCormick said.Radiotherapy should be considered

after mastectomy in patients with oneto three positive nodes, as this has beenshown to reduce local recurrence andincrease survival, the panel added.The updated guidelines also contain

an option for radiotherapy withoutadditional radiation (boost) in earlyinvasive breast cancer (stage I, IIA, orIIB or T3N1M0). The previous recom-mendation was for radiotherapy to thewhole breast with boost. A EuropeanOrganisation for Research and Treat-

ment of Cancer (EORTC) study of5318 stage I and II patients found sig-nificant advantages to the boost exceptin patients aged 60 years and older(Bartelink H, et al. N Engl J Med. 2001;345:1378-1387).“Based on this study, the panel

believed the boost had little biologicalvalue in older patients and should beoptional for older patients with negativemargins,” she said, adding that she oftendoes include the boost for patients over60 who have positive margins.

Local therapy for stage IV diseaseAnother addition to the guidelines is

the option for surgical resection andradiation therapy to the chest wall andinternal mammary nodes for patientswith stage IV or recurrent disease whowere initially treated with mastectomywithout radiation therapy.This is supported by a database from

EORTC 10801 and Danish BreastCancer Cooperative Group 82TM ofsalvage treatment for local recurrence,which compared breast-conservingtherapy (n = 66) to mastectomy (n =67) in stage I and II patients (with themajority also receiving radiotherapy).

Out to 10 years, no difference in sur-vival has emerged, with approximately50% of both groups still alive,McCormick noted.The panel also concluded that

women who are diagnosed initially withmetastatic disease may benefit fromlocal breast surgery with or withoutradiation therapy. Generally, this pallia-tive local therapy should be consideredonly after a response to initial systemictherapy, Edge said.Studies have suggested that excision

of a primary tumor (with negative mar-gins) can impact survival in stage IVpatients. For example, in a recent study,surgery reduced the risk of death by 51%(Bafford AC, et al. Breast Cancer ResTreat. 2009;115:7-12).“Some 3% to 5% of women present

with metastases at diagnosis, and their5-year survival is 5% to 15%,” henoted. “Local therapy has historicallybeen reserved for palliation in thosewith local progression of tumor, but formany patients, metastases are discov-ered only after surgery, on postopera-tive imaging.”Increased survival after radiation as

Breast Cancer GuidelinesContinued from cover


BREAST CANCERBREAST CANCER

GASTROINTESTINAL CANCERSGASTROINTESTINAL CANCERS


Complimentary

Oral Biologic Therapy versus Chemotherapyfor Pretreated Non–small-cell Lung Cancer

HOW TO RECEIVE CREDITTo receive continuing education credit, learners must:• Read the article in its entirety• Take the CE self-assessment test and complete the evaluation test:1. Log on to www.theoncologypharmacist.com.2. Click on UNMC logo on homepage.3. Register to participate.4. Enter program number # C1K10107

• The learner must answer at least 70% of the questions on the post-test correctly.• The estimated time to complete this activity is 1 hour. Your continuing educationcertificate can be printed by following the directions online after successful com-pletion of the post-test.

DISCLAIMERSThe opinions or views expressed in this continuing education activity are those of thefaculty and do not necessarily reflect the opinions or recommendations of theUniversity of Nebraska Medical Center (UNMC), Center for Continuing Education.

While the University of Nebraska Medical Center, Center for Continuing Education isan ACPE-accredited organization, this does not imply endorsement by the UNMC or

ACPE of any commercial products affiliated with this activity.

LEARNING OBJECTIVESAfter completing this activity, the reader should be better able to:• Describe findings of phase 2 and phase 3 trials of gefitinib in non–small-cell lungcancer (NSCLC).

• Discuss the potential clinical implications of the INTEREST trial.

• Explain how patient characteristics such as race, sex, smoking history, and bio-markers such as epidermal growth factor receptor-gene-copy number may affectresponse to NSCLC therapy.

• Discuss management of skin toxicities associated with epidermal growth factorreceptor inhibitor therapy

TARGET AUDIENCERegistered pharmacists and other interested healthcare professionals, especiallythose caring for cancer patients.

COSTThis program is complimentary for all learners.

EDITORIAL BOARDEdward S. Kim, MDThe University of Texas M.D. AndersonCancer Center1515 Holcombe Blvd.Houston, TX 77030

Karen Oishi, RN, MSN, GNP, ANP, OCNAdvanced Practice Nurse/Clinical NursePractitionerThe University of Texas M.D. AndersonCancer Center1515 Holcombe Blvd.Houston, TX 77030

Katie Tipton, PharmD, BCOPClinical Pharmacy SpecialistThe University of Texas M.D. AndersonCancer Center1515 Holcombe Blvd.Houston, TX 77030

PLANNING COMMITTEELois ColburnExecutive DirectorCenter for Continuing EducationUniversity of Nebraska MedicalCenter986800 Nebraska Medical CenterOmaha, NE 68198-6800

Brenda Ram, CMPCoordinator Center for ContinuingEducationUniversity of Nebraska MedicalCenter986800 Nebraska Medical CenterOmaha, NE 68198-6800

Dawn LagrosaAssociate EditorGreen Hill HealthcareCommunications, LLC241 Forsgate DriveMonroe Twp, NJ 08831

Lara J. ReimanManaging EditorGreen Hill HealthcareCommunications, LLC241 Forsgate DriveMonroe Twp, NJ 08831

Karen RosenbergEditorial DirectorGreen Hill HealthcareCommunications, LLC241 Forsgate DriveMonroe Twp, NJ 08831

Jill Stein22 rue MalherParis, France 75004FACULTY/PLANNER DISCLOSURES

It is the policy of the University of Nebraska Medical Center,Center for Continuing Education that all planners and facul-ty participating in continuing education activities providedby the University of Nebraska Medical Center, Center forContinuing Education are to disclose to the audience anyreal or apparent conflicts of interest with providers of com-mercial products and/or devices relating to the topics ofthis educational activity and also disclose discussion oflabeled/unapproved uses of drugs or devices discussed intheir presentation. The planners and faculty have beenadvised that this activity must be free from commercial biasand based upon all the available scientifically rigorous datafrom research that conforms to accepted standards ofexperimental design, data collection, and analysis.

The authors, reviewers, and planning committee members list-ed below have stated they have no significant or substantialrelationship with providers of commercial products and/ordevices discussed in this activity and/or with any commercialsupporter of this activity.

• Lois Colburn• Edward S. Kim, MD• Dawn Lagrosa• Brenda Ram, CMP• Lara J. Reiman• Karen Rosenberg• Jill Stein• Katie Tipton, PharmD, BCOP

The following author has stated that she has the followingfinancial relationships:

• Karen Oishi, RN, MSN, GNP, ANP, OCN, has received hono-raria from sanofi-aventis, Genentech, and Novartis.

ACCREDITATION AND CONTACT HOURS STATEMENTThe University of Nebraska Medical Center, Centerfor Continuing Education is accredited by the Ac-creditation Council for Pharmacy Education as aprovider of continuing pharmacy education. The

ACPE provider number is 447-000-09-068-H04-P.To receive the1 contact hour of continuing education credit, pharmacistsshould complete the activity requirements and evaluation at theconclusion of the activity. Approval is valid from the initialrelease date of June 15, 2009. The expiration date is June 15,2010. A statement of credit will be available for printing onlineupon completion of the post-test with a score of 70% or betterand the evaluation instrument.

BY EDWARD S. KIM, MDThe University of Texas M.D. Anderson Cancer Center, Houston

Program #C1K10107 • RELEASE DATE: June 15, 2009 • EXPIRATION DATE: June 14, 2010

Lung cancer remains a leading cause of cancer-related deathsworldwide and in the United States accounts for more cancerdeaths than breast, colorectal, and prostate cancer combined.

The rate of lung cancer deaths is alarmingly high because patients usu-ally present with advanced metastatic disease, which has limited treat-ment options. Standard treatment involves chemotherapy and sup-portive care, albeit with modest response rates and a high recurrencerate after standard first-line platinum-based doublet therapy.

BackgroundThe taxane docetaxel, at a dose of 75 mg/m2, is approved by the US

Food and Drug Administration (FDA) for second-line treatment ofadvanced non–small-cell lung cancer (NSCLC). The pivotal trialsthat led to docetaxel’s approval for this indication demonstrated animproved survival and quality of life with docetaxel compared withbest supportive care and compared with vinorelbine or ifosfamidechemotherapy. Side effects may include diarrhea, neuropathy, and

severe neutropenia. Other agents such as pemetrexed and erlotinib arealso indicated for second-line treatment of NSCLC.Two randomized phase 2 trials (known as Iressa Dose Evaluation in

Advanced Lung Cancer, or IDEAL 1 and 2) in patients with previ-ously treated advanced NSCLC suggested that gefitinib—an epider-mal growth factor receptor (EGFR)-tyrosine kinase inhibitor that istaken orally—was efficacious and less toxic than chemotherapy inpatients who had undergone prior treatment for NSCLC.1,2Based on the data from these trials, gefitinib received accelerated

approval by the FDA in 2003 as a single agent for patients withadvanced lung cancer that progressed despite treatment with plat-inum-based and docetaxel chemotherapy. In 2005, however, a phase 3trial (Iressa Survival Evaluation in Lung Cancer [ISEL]) showed thatgefitinib compared with placebo did not improve survival in patientswith NSCLC.3 The FDA subsequently altered gefitinib’s labeling, lim-iting its use to patients who were already receiving the drug andappeared to be benefitting from it.

CONTINUING EDUCATIONAT WWW.THEONCOLOGYPHARMACIST.COM


INTEREST study findingsThe Iressa in NSCLC Trial Evaluating Response

and Survival versus Taxotere (INTEREST) was anopen-label, phase 3 study that compared gefitinib withdocetaxel in patients with locally advanced ormetastatic NSCLC who had received at least oneprior platinum-based chemotherapy regimen.4 Overall,1466 patients were recruited from 149 centers in 24countries and then randomized to gefitinib, 250mg/day orally, or docetaxel, 75 mg/m2, administered asa 1-hour intravenous infusion every 3 weeks. The two treatment groups were well matched in

terms of demographic and clinical characteristics andwere generally representative of a pretreated popula-tion with advanced NSCLC.There were two primary survival end points: sur-

vival in all treated patients and in those whose tumorshad high EGFR-gene-copy number.In the 1433 patients whose results were analyzed,

efficacy rates were similar for gefitinib and docetaxel.That is, gefitinib-treated patients had a median over-all survival of 7.6 months versus 8.0 months in doc-etaxel-treated patients, while 32% of gefitinib and

34% of docetaxel patients were alive at 1 year, con-firming noninferiority of gefitinib. The median pro-gression-free survival (2.2 vs 2.7 months) and objec-tive response rates (9.1% vs 7.6%) were also similarfor the two groups. The similar rates of overall survival were seen across

multiple preplanned subgroups except in patients whoreceived third-line treatment. In fact, patients whoreceived third-line treatment had significantly longersurvival with docetaxel than with gefitinib. Gefitinib was better tolerated than docetaxel.

Overall, gefitinib-treated patients experienced fewertreatment-related adverse events than docetaxel-treated patients (72% vs 82%), overall events (72% vs82%), serious adverse events (4% vs 18%), adverse

events prompting withdrawal from therapy (4% vs11%), grade 3 to 4 adverse events (9% vs 41%), andadverse events resulting in death (1% vs 2%). Thetype of adverse event also differed between the twotreatment groups.Rash, acne, and diarrhea were more common with

gefitinib, while hematologic toxic effects, asthenic disor-ders, and alopecia were more common with docetaxel.Researchers also found that more gefitinib-treated

patients had sustained and clinically relevant im -provement in quality of life as assessed by Functional

Assessment of Cancer Therapy-Lung (FACT-L) totalscore. The FACT-L is a widely validated tool thatmeasures quality of life in patients being treated forlung cancer using a patient-completed questionnaire.


Complimentary


Oral Biologic Therapy versus Chemotherapy for PretreatedNon–small-cell Lung Cancer: A Pharmacist’s PerspectiveBY KATIE TIPTON, PHARMD, BCOPThe University of Texas M.D. Anderson Cancer Center, Houston

COMMENTARYCOMMENTARY

Recurrent disease after primary therapy of non–small-cell lung cancer (NSCLC) has feweffective treatment options. In patients with

poor performance status or multiple comorbidities,practitioners must often choose between best sup-portive care and potential harm to the patient asso-ciated with treatment that offers poor response rates.Docetaxel, pemetrexed, and erlotinib are the onlydrugs currently approved for second-line treatment ofrecurrent or metastatic lung cancer with responserates rarely reported to be greater than 10%. An opti-mal second-line treatment would have a mild sideeffect profile, increase quality of life, and provideimproved response compared with traditional agents.Treatments such as the oral tyrosine kinase inhibitors(TKIs) erlotinib and gefitinib are generally well tol-erated, but provide similar rates of response aschemotherapy.Despite promising data from the phase 2 studies

Iressa Dose Evaluation in Advanced Lung Cancer 1and 2 (IDEAL 1; IDEAL 2),1,2 gefitinib was removedfrom the US drug market in June 2005 because of alack in evidence of improved survival versus placeboas second-line therapy for NSCLC. The Iressa

Survival Evaluation in Lung Cancer (ISEL) trialshowed median survival of 5.6 and 5.1 months, respec-tively, for gefitinib and placebo.3 The study did showsignificant improvement in never-smokers and Asianpatients for gefitinib, but no advantage for patientswith adenocarcinoma or women. There has beenmuch discussion of the issues that may have affectedthe trial’s outcomes. Specifically, 90% of the patientpopulation was chemotherapy-refractory, and possibleunderdosing of gefitinib may have altered the out-comes of the trial.Currently, the availability of gefitinib in the

United States is limited. The drug is availablethrough clinical trials and to patients who have andcontinue to benefit from gefitinib therapy. Recently,US trials have reexamined the use of gefitinib inNSCLC. The Iressa in NSCLC Trial EvaluatingResponse and Survival versus Taxotere (INTEREST)investigated the effectiveness of gefitinib in recurrentor metastatic NSCLC versus docetaxel, a standardtreatment in the setting.4The INTEREST study compared gefitinib with

docetaxel in previously treated NSCLC patients.Primary outcomes were noninferiority of gefitinib on

overall survival (OS) for the entire population andsuperiority of gefitinib in patients with high epider-mal growth factor receptor (EGFR)-gene-copy num-ber by fluorescence in situ hybridization. Secondaryoutcomes included objective response rates and pro-gression-free survival (PFS). All patients were previ-ously treated with platinum-based regimens, withapproximately 16% of patients in each arm havinghad received more than one treatment for metastaticor recurrent disease. At baseline, 53.8% and 56.3%of patients were chemotherapy-refractory to plat-inum-based chemotherapy, and 9.3% and 7.8% wererefractory to paclitaxel-based regimens in the gefi-tinib and docetaxel arms, respectively.2 Fifty-sevenpercent of patients in the gefitinib arm and 59.6% ofthose in the docetaxel arm were refractory to theirmost recent chemotherapy. Nearly 55% of all pa -tients had adenocarcinoma, and approximately 60%had a performance status of 1.Median OS was similar in the two arms (8 months

for gefitinib and 7.8 months for docetaxel), and thenoninferiority hazard ratio for OS was 1.020 (96%confidence interval [CI]: 0.905-1.150). PFS andresponse rates were also similar.2 Superiority in OS

More gefitinib-treated patients had sustained andclinically relevant improvement in quality of life asassessed by FACT-L total score.


Program #C1K10107• RELEASE DATE: June 15, 2009 • EXPIRATION DATE: June 14, 2010

Complimentary



The two treatment groups had similar improvementsin lung cancer symptoms.The study additionally showed that individuals who

had never smoked, women, persons of Asian ethnicorigin, and those with adenocarcinoma lived longerthan smokers, men, people of non-Asian ethnic ori-gin, and those without adenocarcinoma. However,contrary to expectation, patients with these factorshad a similarly long survival whether they were treat-ed with gefitinib or docetaxel. Earlier research hadsuggested that docetaxel chemotherapy provided sim-ilar survival benefit in all patients. Several biomarkers had been reported to help predict

which patients are more likely to respond to EGFRinhibitor treatment. The INTEREST study found, forthe most part, no link between treatment outcome andbiomarkers.It is important to note that the study differed in sev-

eral respects from the ISEL study, which found no sig-nificant improvement in overall survival in gefitinib-treated patients with advanced NSCLC compared withplacebo-treated patients. The ISEL trial enrolled a largenumber of patients who were refractory to chemothera-

py. This population is notoriously difficult to treat andhas a poor prognosis, which may account for the lack ofsignificant improvement in the gefitinib group.

Clinical implicationsThe management of advanced NSCLC remains a

clinical challenge. However, an oral agent that rivalsintravenous chemotherapy in terms of efficacy but hasbetter tolerability and improves quality of life repre-sents an important shift in the treatment paradigm forthis disease and also offers patients an attractive treat-ment alternative.

What we now know:• Lung cancer is a key cause of cancer deaths world-wide. Standard therapy involves chemotherapyand supportive care, but response rates are subop-timal and disease recurrence is common.

• Docetaxel is widely used for second-line treat-ment of advanced NSCLC.

• The molecularly-targeted oral agent gefitinib andcytotoxic intravenous chemotherapy with docetax-el are equally effective in advanced NSCLC. The

two treatments provide similar overall survival,tumor response, and progression-free survival.

• Gefitinib decreases toxicity compared with do -cetaxel.

• Gefitinib improves quality of life more than doce -taxel. In fact, it is the first agent that has beenshown to improve quality of life more than achemotherapy agent.

Jill Stein contributed to the preparation of this manuscript.

References1. Fukuoka M, Yano S, Giannone G, et al. Multi-institutional ran-

domized phase II trial of gefitinib for previously treated patientswith advanced non-small-cell lung cancer. J Clin Oncol. 2003;21:2237-2246.

2. Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, aninhibitor of the epidermal growth factor receptor tyrosine kinase, insymptomatic patients with non-small-cell lung cancer. A random-ized trial. JAMA. 2003;290:2149-2150.

3. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best support-ive care in previously treated patients with advanced non-small-celllung cancer: results from a randomized, placebo-controlled, multi-centre study (Iressa Survival Evaluation in Lung Cancer). Lancet.2005;366:1527-1537.

4. Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previ-ously treated non-small-cell lung cancer (INTEREST): a random-ized phase III trial. Lancet. 2008;372:1809-1818.

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was not observed for gefitinib in patients with a highEGFR-gene-copy number or any other subgroup.Patients previously reported to have favorableresponse rates to EGFR inhibitors, such as those withadenocarcinoma, those of Asian ethnic origin,women, and never-smokers, had comparable out-comes regardless of treatment group. Such patients inboth groups also experienced higher survival ratesthan those with other NSCLC histologies, those ofnon-Asian ethnic origin, men, and smokers. Patientswith other NSCLC histologies, those of non-Asianethnic origin, men, and smokers had similar survivalrates with gefitinib and docetaxel treatment.2 Thesefindings indicate that gefitinib is not inferior to USFood and Drug Adminstration–approved second-linetreatments for NSCLC docetaxel in response rate,OS, or PFS.Although the findings from the INTEREST study

raise questions about the ability to predict response toEGFR inhibitors, they offer evidence that gefitinib isa viable option for second-line treatment of metasta-tic/recurrent NSCLC. If reapproved, gefitinib willjoin the approved second-line options of docetaxel,pemetrexed, and erlotinib as well as unapproved alter-natives of gemcitabine and vinorelbine. Choice ofavailable second-line therapies is primarily dictatedby a patient’s previous exposure to chemotherapy,comorbidities, hepatic and renal function, and per-formance status. Dosing convenience, potential druginteractions, and toxicities should also be considered.Gefitinib may be offered to patients with poor per-formance status, renal dysfunction, and mild hepatic

dysfunction or moderate-to-severe hepatic dysfunc-tion due to liver metastases. Concomitant medica-tions should be reviewed, however, to avoid druginteractions resulting in toxicities.Oral TKIs such as gefitinib and erlotinib also pre -

sent new challenges in toxicity management. Earlyintervention and management are instrumental toimproving tolerability of the EGFR inhibitors gefi-tinib, erlotinib, and cetuximab. Most notably, derma-tologic toxicity may affect a patient’s tolerance oftherapy. Forty-three percent to 86% of patients expe-rience dermatologic toxicities with EGFR inhibitors,and up to 16% may have grade 3 rash. In addition toappropriate dosing reductions, familiarity with treat-ment algorithms for management of dry skin andacnelike and maculopapular rash are necessary toassist oncologists in managing these toxicities.5,6Little experimental evidence exists to support der-

matologic toxicity management. A study by Scopeand colleagues aimed to determine whether minocy-cline or tazarotene could reduce and prevent cetux-imab-induced acnelike rash in patients withmetastatic colorectal cancer.7 Forty-eight patientswere randomized to receive either placebo orminocycline in addition to either topical tazaroteneor placebo applied to one side of the face for a totalof 8 weeks starting on day 1 of cetuximab therapy.Fewer patients receiving minocyclines reportedmoderate-to-severe itching or rash. A significant dif-ference in the number of facial lesions was observed,with a maximal effect near week 4 and a decline ineffect by week 8. Although four patients receiving

placebo required dose interruptions in cetuximabdue to grade 3 rash, no patients receiving minocy-cline required interruptions. Tazarotene treatmenthad no benefit and caused significant skin irritation.Nearly 33% of patients discontinued tazarotenetherapy because of irritation. These data suggestbenefit with approximately 1 month of prophylacticminocycline treatment and no advantage to use oftazarotene in management of EGFR-related rash.

References1. Fukuoka M, Yano S, Giannone G, et al. Multi-institutional ran-

domized phase II trial of gefitinib for previously treated patientswith advanced non-small-cell lung cancer. J Clin Oncol. 2003;21:2237-2246.

2. Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, aninhibitor of the epidermal growth factor receptor tyrosine kinase,in symptomatic patients with non-small-cell lung cancer. A ran-domized trial. JAMA. 2003;290:2149-2150.

3. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best sup-portive care in previously treated patients with refractoryadvanced non-small-cell lung cancer: results from a randomisedplacebo-controlled, multicentre study (Iressa Survival Evaluationin Lung Cancer). Lancet. 2005;366:1527-1537.

4. Kim ES, Hirsch V, Mok T, et al. Gefitinib versus docetaxel in pre-viously treated non-small-cell lung cancer (INTEREST): a ran-domised phase III trial. Lancet. 2008;372:1809-1818.

5. Chou LS, Garey J, Oishi K, Kim E. Managing dermatologic tox-icities of epidermal growth factor receptor inhibitors. Clin LungCancer. 2006;8(suppl 1):S15-S22.

6. Hu JC, Sadeghi P, Pinter-Brown LC, Yashar S, Chiu MW.Cutaneous side effects of epidermal growth factor receptorinhibitors: clinical presentation, pathogenesis, and management.J Am Acad Dermatol. 2007;56:317-326.

7. Scope A, Agero AL, Dusza SW, et al. Randomized double-blindtrial of prophylactic oral minocycline and topical tazarotene forcetuximab-associated acne-like eruption. J Clin Oncol. 2007;25:5390-5396.


Oral Biologic Therapy versus Chemotherapy for Pretreated Non–small-cell Lung Cancer: A Nurse’s PerspectiveBY KAREN OISHI, RN, MSN, GNP, ANP, OCNThe University of Texas M.D. Anderson Cancer Center, Houston

Lung cancer is the cause of approximately onethird of all cancer-related deaths and is thenumber one cause of cancer deaths in the

United States and worldwide.1,2 Traditionally, it hasbeen a difficult disease to manage and treat, becauselung cancer is usually diagnosed at an advancedstage and because we have a limited number ofeffective drugs. The oncology community constant-ly strives to better understand the biology of the dis-ease and to develop better drugs. Several phase 3 tri-als indicate that current doublet chemotherapyregimens yield equivalent efficacies and similar tox-icity profiles,3 and new-generation molecularly tar-geted therapies are emerging. Gefitinib, the first epidermal growth factor recep-

tor (EGFR)-tyrosine kinase inhibitor to reach themarket, targets the specific physiologic pathway oftumor survival and proliferation. Later-introducedEGFR inhibitors approved for treatment of non–small-cell lung cancer (NSCLC) after at least oneprior chemotherapy regimen include erlotinib, doc-etaxel, and pemetrexed. Since the negative resultsof the Iressa Survival Evaluation in Lung Cancer(ISEL) trial were reported in 2005,4 gefitinib hasbeen slowly fading away from the domain ofNSCLC treatment options. The surprising results of the Iressa in NSCLC Trial

Evaluating Response and Survival versus Taxotere(INTEREST) reported late last year has caused theoncology community to rethink the options for lungcancer therapy. This trial showed the statistical non-inferiority of gefitinib compared with the previouslyapproved second-line agent docetaxel.5 In light ofthese findings, the role of gefitinib is now beingreassessed, and we are all asking what the study out-

comes will mean in clinical management of patientswith NSCLC. The INTEREST study examined quality-of-life

(QOL) measures, as well as the safety and tolerabil-ity of gefitinib and docetaxel.5 QOL is often over-looked in clinical trials, because the primary endpoint tends to evaluate the survival advantagesexclusively. In NSCLC, achieving QOL is a veryimportant goal, because most lung cancer patientsexperience many symptoms related to their disease.Trial participants who received gefitinib and do -cetaxel showed improvements in their lung cancersymptoms, but significantly more patients had sus-tained and clinically relevant improvement in QOLwith gefitinib.5The results of the INTEREST study have raised

more questions than answers for the lung cancercommunity. Will gefitinib be US Food and DrugAdministration–approved and available as a second-line therapy? Will the positive INTEREST data haveany influence on our selection of specific agents fortreatment? Do second-line chemotherapy agents,such as docetaxel or pemetrexed, show efficacy equiv-alent to that of molecularly targeted agents, such aserlotinib and gefitinib? Is there a need for a head-to-head trial comparing erlotinib with gefitinib? How dowe sequence second-line therapies to best benefitpatients? Is there a need for molecular marker testingin patients receiving chemotherapy agents as well astargeted agents? Answers to these and other ques-tions, will, I believe, lead in the next 5 or 10 years tomore sophisticated and less controversial treatmentalgorithms for the NSCLC community.As oncology nurses, we have the responsibility to

inform and educate the public as well as patients

and their families about significant new findingsthat may potentially provide new options for lungcancer treatment. This enables patients to choosemore suitable options from those that are availableto them. If it gets the necessary approval, gefitinibwill be among the options available to treat lungcancer, and we must be prepared for the possibilityof a need to educate the oncology community aboutits use and potential side effects. Oncology nursesnot only educate patients about available therapyoptions, but also help them decide which side effectsthey are willing to tolerate, for example, dermato-logic (rash with EGFR inhibitors) versus gastroin-testinal (nausea/vomiting with chemotherapies)toxicities. The INTEREST study shows the need forfurther study of QOL measures. Oncology nursesshould be encouraged to pursue research on thesemeasures, as we are advocates for our patients.

References1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics,

2002. CA Cancer J Clin. 2005;55:74-108.2. American Cancer Society. Cancer Statistics 2008 [PowerPoint

presentation]. www.cancer.org/docroot/PRO/content/PRO_1_1_Cancer_Statistics_2008_Presentation.asp. Accessed May 15,2009.

3. Fossella FV, Devore R, Kerr RN, et al; for The TAX 320 Non-Small Cell Lung Cancer Study Group. Randomized phase IIItrial of docetaxel versus vinorelbine or ifosfamide in patientswith advanced non-small-cell lung cancer previously treatedwith platinum-containing chemotherapy regimens. J Clin Oncol.2000;18:2354-2362.

4. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best sup-portive care in previously treated patients with refractoryadvanced non-small-cell lung cancer: results from a randomisedplacebo-controlled, multicentre study (Iressa Survival Evalua -tion in Lung Cancer). Lancet. 2005;366:1527-1537.

5. Kim ES, Hirsch V, Mok T, et al. Gefitinib versus docetaxel inpreviously treated non-small-cell lung cancer (INTEREST): arandomised phase III trial. Lancet. 2008;372:1809-1818.



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local therapy in stage IV disease wasalso recently documented in a series inwhich overall survival at 3 years was43% with treatment, versus 27% in theuntreated arm (Le Scodan R, et al. JClin Oncol. 2009;27:1375-1381).

Imaging issues addressedThe panelists did not advocate the

use of positron-emission tomogra-phy/CT scanning in the evaluation ofnewly diagnosed patients with early-stage disease, except in those clinicalsituations where other staging studiesare equivocal or suspicious. Even then,biopsy is recommended, as always foraccurate staging. They further maintained that the

value of magnetic resonance imaging(MRI) remains unclear, but theyrevised the guidelines to address theutility of dedicated breast MRI. Thepanel noted that MRI has a role inscreening women at high risk, detect-ing disease in dense breasts, evaluatingextent of disease, defining response toneoadjuvant therapy, and evaluatingcases of axillary nodal adenocarcinomabut normal mammography. Edge advised physicians, however,

not to make surgical decisions on thebasis of MRI findings, due to the highrate of false positives. Instead, biopsyand tissue sampling should help guidetreatment decisions. He noted that MRIoutperforms mammography in detectingsecond cancers. In one study, MRIfound contralateral tumors in 3% ofbreast cancer patients (Lehman CD, etal. N Engl J Med. 2007;356:1295-1303).MRI also helps select patients forbreast-conserving therapy after neoad-juvant therapy by evaluating responseto treatment and defining the extent ofcancer; however, it also underestimatesthe amount of residual disease. The use of MRI does lead to a change

in therapy for some patients, Edgenoted. In a meta-analysis of all retro-spective literature on the topic,Houssami and colleagues showed that11% of patients underwent more exten-sive surgery than originally planned,and 8% converted from lumpectomy tomastectomy (J Clin Oncol. 2008;26:3248-3258). It is still unclear whetherthe rate of mastectomies is increasing inparallel with increased use of MRI,however. In an NCCN database, rateshave been stable despite rising MRI use,according to Edge.Evidence is also lacking to show that

MRI actually affects outcomes, henoted. Although MRI does pick uplesions not seen on mammography,80% are determined to be benign. “Wemay identify more lesions on MRI, butthey may not be clinically significantor they may be controlled by the radia-tion we give,” he commented.

The NCCN’s bottom line on MRI isthat its value remains uncertain, thepractice of obtaining MRI varies (andshould meet standards for performance),and the downsides are real.

New reconstruction guidelines New guidelines have been added for

postsurgical reconstruction usingbreast implants, autologous tissue(flaps), or a combination of the two (eg,latissimus/implant composite recon-struction). The options are to performreconstruction in conjunction withmastectomy (immediate) or after thecompletion of cancer treatment (de -

layed). The preference for one over theother is based on factors such as theneed for radiotherapy (delayed) anduse of implants (immediate) McCormicknoted. “Women who need radiothera-py should be identified at diagnosis,and reconstruction in those casesshould be delayed,” she said. ™

™

Breast Cancer GuidelinesContinued from page 22

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PROSTATE CA

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The PSA test, as well as how it is usedto guide patient care (ie, at what agemen should begin regular testing, inter-vals at which the test should be repeat-ed, and at what point a biopsy is neces-sary), are highly controversial. TheAUA believes, however, that whenoffered and interpreted appropriately thePSA test may provide essential informa-tion for the diagnosis, pretreatment stag-ing or risk assessment, and posttreat-ment monitoring of prostate cancer.

The new Best Practice Statementupdates the AUA’s previous guidance,which was issued 9 years ago. Majorchanges to the AUA statement includenew recommendations aboutwho should be considered forPSA testing, as well as whena biopsy is indicated follow-ing an abnormal PSA read-ing. According to the AUA,early detection and riskassessment of prostate cancershould be offered to well-informed men 40 years of ageor older who have a lifeexpectancy of at least 10 years. A base-line PSA level above the median for age40 is a strong predictor of prostate can-cer. Such testing may not only allow forearlier detection of more curable can-cers, but may also allow for more effi-cient, less frequent testing, according tothe AUA.Men who wish to be screened for

prostate cancer should have both a PSAtest and a digital rectal examination.The statement by the AUA also notesthat other factors, such as family histo-ry, age, overall health, and ethnicity,should be combined with the results ofPSA testing and physical examinationto better determine the risk of prostatecancer. The statement recommendsthat the benefits and risks of screeningfor prostate cancer should be discussed,including the risk of overdetection(detecting some cancers which may notneed immediate treatment).“The single most important message

of this statement is that prostate cancertesting is an individual decision thatpatients of any age should make in con-junction with their physicians and urol-ogists. There is no single standard thatapplies to all men, nor should there be atthis time,” said Peter Carroll, MD, chairof the panel that developed the state-

ment. “[The] panel carefully reviewedthe most recently reported trials of PSAtesting in both the United States andEurope before finalizing its guidelines.The strengths and limitation of these tri-als are reviewed in the guidelines.”In regard to biopsy, a continuum of

risk exists at all values, and major studieshave demonstrated that there is no safePSA value below which a man may bereassured that he does not have biopsy-detectable prostate cancer. Therefore,

the AUA does not recommend a singlePSA threshold at which a biopsy shouldbe obtained. Rather, the decision to per-form a biopsy should take into account

additional factors, includingfree and total PSA levels,PSA velocity and density,patient age, family history,race/ethnicity, biopsy history,and comorbidities. In addi-tion, the AUA statementemphasizes that not allprostate cancers require ac -tive treatment and that notall prostate cancers are life-

threatening. The decision to proceed toactive treatments is one that menshould discuss in detail with theirphysician to determine whether activetreatment is necessary, or whether sur-veillance may be an option for theirprostate cancer.“Prostate cancer comes in many

forms, some aggressive and some not,”said Carroll, who is professor and chairof urology at the University of Califor -nia, San Francisco. “The AUA is com-mitted to timely, expert, and appropri-ate care for men either with or at riskof getting prostate cancer and is pre-pared to revise these guidelines contin-uously as new information becomesavailable.”

Key pointsThe Best Practice Statement by the

AUA also clarifies a number of keypoints about the use of PSA in treat-ment selection and posttreatment fol-low-up of prostate cancer patients:• Serum PSA predicts the response ofprostate cancer to local therapy.

• Routine use of a bone scan is notrequired for staging asymptomaticmen with clinically localized pros -tate cancer when their PSA level is≤20.0 ng/mL.

• Computed tomography or magnet-ic resonance imaging scans may beconsidered for the staging of menwith high-risk clinically localizedpros tate cancer when the PSAlevel is >20.0 ng/mL or when local-ly ad vanced or when the Gleasonscore is ≥8.

• Pelvic lymph node dissection forclinically localized prostate cancermay not be necessary if the PSAlevel is <10.0 ng/mL and the Glea -son score is ≤6.

• Periodic PSA determinationsshould be offered to detect diseaserecurrence.

• Serum PSA should decrease andremain at undetectable levels afterradical prostatectomy.

• Serum PSA should fall to a lowlevel following radiation therapy,high-intensity focused ultrasound,and cryotherapy and should not riseon successive occasions.

• PSA nadir after androgen suppres-sion therapy predicts mortality.

• Bone scans are indicated for thedetection of metastases followinginitial treatment for localized dis-ease, but the PSA level that shouldprompt a bone scan is uncertain.Additional important prognostic in -formation can be obtained by evalu-ation of PSA kinetics (velocity).

• The kinetics of PSA rise after localtherapy for prostate cancer can helpdistinguish between local and dis-tant recurrence.“What is also important in this docu-

ment is that we clearly acknowledge therisks of overdetection and overtreat-ment. I think that brings us in line withother groups,” Carroll said in an inter-view with The Oncology Pharmacist. “Weare no longer recommending a singlePSA cut point but to use PSA in con-junction with age, digital rectal exami-nation, ethnicity, family history, andother PSA parameters. This is a moresensitive and specific way of diagnosingprostate cancer.” William Catalona, MD, who is a

professor of urology at NorthwesternUniversity, Chicago, said dropping theage for a baseline PSA to age 40 maybe an important new approach becauseit can better guide clinicians by poten-tially providing significantly moreinformation.“I think it is important. Not so much

for diagnosing prostate cancer at age40, but for establishing a baseline sothat you can get data for PSA velocity.So, if you start at age 40, their PSAshould be less than 1.0 ng/mL. Afterthat, you can track it,” said Catalona inan interview with The OncologyPharmacist. “I think early PSA velocityis a promising new marker for identify-ing men destined to die of prostate

cancer. It can help detect cancer earli-er than we can now detect it using anyother method. Perhaps we can nowtreat them and save their lives. Thisadds to our ability to identify the worsecancers early.”

—John Schieszer

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™

AUA Counters Mainstream RecommendationsContinued from cover

Peter Carroll, MD

According to the AUA, early detection andrisk assessment of prostate cancer shouldbe offered to well-informed men 40 yearsof age or older who have a life expectancyof at least 10 years.

• Bevacizumab forGlioblastomaThe US Food and Drug Adminis -

tration (FDA) has granted acceleratedapproval of bevacizumab (Avastin,Genentech) for treatment of glioblas-toma that has progressed followingprior therapy. The accelerated ap -proval is based on data from an open-label phase 2 study of 167 patientswith glioblastoma that had pro-gressed following initial treatmentwith temozolomide and radiation. Ofthe 167 patients, 26% had a tumorresponse to bevacizumab, and themedian duration of response was 4.2months. The first antiangiogenesistherapy approved by the FDA, beva-cizumab is also indicated for certaintypes of metastatic colorectal cancer,non–small-cell lung cancer, andHER2-negative breast cancer.

• Laser Surgery for InoperableBrain TumorsThe FDA has cleared the AutoLITT

System (Monteris Med ical) for use inneurosurgery. The first application ofthe technology is expected to be intreatment of otherwise inoperablebrain tumors. The system uses amagnetic resonance imaging–guidedlaser probe, delivered through a smallbur hole in the skull, to deliver laserinterstitial thermal therapy (“LITT”) toheat and coagulate the tumor fromthe inside. Once coagulated, thetreated tumor mass is dead.

• Full Approval for Dasatinibfor CMLThe FDA has granted full approval

for dasatinib (Sprycel, Bristol-MyersSquibb) for treatment of all phases ofchronic myeloid leukemia (CML) inadults who are resistant or intolerantto prior therapies including imatinib.The oral tyrosine kinase inhibitor wasoriginally approved under acceleratedapproval regulations. The full approvalwas based in part on a phase 3 studyshowing 80% progression-free sur-vival at 2 years in patients resistant orintolerant to imatinib. The drug is alsoapproved for treatment of adults withPhiladelphia chromosome–positiveacute lymphoblastic leukemia.

Recent FDAApprovals


points. Median PFS was 21.1 weeks inthe dacarbazine + sorafenib arm versus11.7 weeks in the placebo + dacarbazinearm; however, this did not reach statisti-cal significance. There were statisticallysignificant differences, however, in thePFS rates at 6 and 9 months. In addition,time to progression was 21.1 weeks ver-sus 11.7 weeks in the placebo group. Nodifferences in overall survival were seen,and the toxicity profile was manageablein both arms. Therefore, if phase 3results are similar, sorafenib could poten-tially have a role in the treatment ofstage III-IV melanoma.At the ESMO Congress in 2008,

results from the largest randomizedphase 3 trial ever conducted in stage IVmelanoma were presented.18 Patientswere included in the study if they hadeither unresectable metastatic mela -noma previously untreated with either acytokine or chemotherapy for stage IVdisease. Patients were treated witheither temozolamide 150 mg/m2/day for7 days, then 7 days off, or standard-dosedacarbazine progression. The primaryend point was overall survival. Second -ary end points included PFS, overallresponse rate, duration of objectiveresponse, and safety and tolerability.Median overall survival failed to meetstatistical significance at 9.13 months inthe temozolamide arm and 9.36 monthswith dacarbazine. Median PFS was alsounimpressive at 2.3 and 2.17 months,respectively. Response rates were higherin the temozolamide arm (14.5% vs9.8%), but the duration of response waslonger in the dacarbazine arm. The tox-icity profile was worse in the temozo-lamide treatment arm, with more grade3 and 4 toxicities. The authors conclud-ed that temozolamide is an alternativeto dacarbazine in unresectable metasta-tic melanoma patients. Toxicity profiles,however, may be more significant withtemozolamide without any additionalsurvival benefits.18

References1. Ries LAG, Melbert D, Krapcho M, eds. SEER

Cancer Statistics Review, 1975-2005. Bethesda,MD: National Cancer Institute. http://seer.cancer.gov/csr/1975_2005/, based on November 2007SEER data submission, posted to the SEER Website, 2008.

2. Balch CM, Buzaid AC, Soong SJ, et al. Final ver-sion of the American Joint Committee onCancer staging system for cutaneous melanoma.J Clin Oncol. 2001;19:3635-3648.

3. Tsao H, Atkins MB, Sober AJ. Management ofcutaneous melanoma. N Engl J Med. 2004;351:998-1012.

4. Menzies SW, Crotty KA, Ingvar C, McCarthyWH. An Atlas of Surface Microscopy of PigmentedSkin Lesions Dermoscopy. 2nd ed. Sydney,Australia: McGraw-Hill Australia; 2003.

5. Malvehy J, Puig S, Argenziano G, Marghoob AA,Soyer HP. International Dermoscopy SocietyBoard. Dermoscopy report: proposal for stan-dardization. Results of a consensus meeting ofthe International Dermoscopy Society. J AmAcad Dermatol. 2007;57:84-95.

6. Vestergaard ME, Macaskill P, Holt PE, MenziesSW. Dermoscopy compared with naked eyeexamination for the diagnosis of primary mela -noma: a meta-analysis of studies performed in aclinical setting. Br J Dermatol. 2008;159: 669-676.

7. Peggs KS, Quezada SA, Korman AJ, Allison JP.Principles and use of anti-CTLA4 antibody inhuman cancer immunotherapy. Curr Opin

Immunol. 2006;18:206-213.8. O’Day SJ, Ibrahim R, DePril V, et al. Efficacy and

safety of ipilimumab induction and maintenancedosing in patients with advanced melanoma whoprogressed on one or more prior therapies. J ClinOncol. 2008;26:488s. Abstract 9021.

9. Weber JS, Berman D, Siegel J, et al. Safety andefficacy of ipilimumab with or without prophylac-tic budesonide in treatment-naive and previouslytreated patients with advanced melanoma. J ClinOncol. 2008;26:485s. Abstract 9010.

10. Ribas A, Hauschild A, Kefford R, Gomez-Navarro J, Pavlov D, Marshall M. Phase III,open-label, randomized, comparative study oftremelimumab (CP-675,206) and chemotherapy(temozolomide [TMZ] or dacarbazine [DTIC]) inpatients with advanced melanoma. J Clin Oncol.2008;26:485s. Abstract LBA9011.

11. Sznol M, Hodi FS, Margolin K, et al. Phase Istudy of BMS-663513, a fully human anti-

CD137 agonist monoclonal antibody, in patients(pts) with advanced cancer (CA). J Clin Oncol.2008;26:133s. Abstract 3007.

12. Vonderheide RH, Flaherty KT, Khalil M, et al.Clinical activity and immune modulation incancer patients treated with CP-870,893, anovel CD40 agonist monoclonal antibody. J ClinOncol. 2007;25:876-883.

13. Brahmer JR, Topalian S, Wollner I, et al. Safetyand activity of MDX-1106 (ONO-4538), ananti-PD-1 monoclonal antibody, in patientswith selected refractory or relapsed malignan-cies. J Clin Oncol. 2008;26:133s. Abstract 3006.

14. Fruehauf JP, Lutzky J, McDermott DF, et al.Axitinib (AG-013736) in patients with metasta-tic melanoma: a phase II study. J Clin Oncol.2008;26:484s. Abstract 9006.

15. Chan KR, Gundala S, Laudadio M, MastrangeloM, Yamamoto A, Sato T. A pilot study usingsunitinib malate as therapy in patients with stage

IV uveal melanoma. J Clin Oncol. 2008;26:494s.Abstract 9047.

16. Eggermont AM, Suciu S, Santinami M, et al.Adjuvant therapy with pegylated interferonalfa-2b versus observation alone in resectedstage III melanoma: final results of EORTC18991, a randomized phase III trial. Lancet.2008;372:117-126.

17. McDermott DF, Sosman JA, Gonzalez R, et al.Double-blind randomized phase II study of thecombination of sorafenib and dacarbazine inpatients with advanced melanoma: a report fromthe 11715 Study Group. J Clin Oncol. 2008;26:2178-2185.

18. Patel PM, Suciu S, Mortier L, et al. Extendedschedule, escalated dose temozolamide versusdacarbazine in stage IV maligant melanoma:final results of the randomized phase II study(EORTC 18032). Ann Oncol. 2008;19(suppl8):viii1-viii4. Abstract LBA8.

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Diagnosis and Treatment of MelanomaContinued from page 14

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National Safe Handling Month Calls Attention to Need for IncreasedAwareness, Education about Occupational Drug Exposure

Safe Handling

For additional information on the safehandling of hazardous drugs and tohear more from Byron Peters andMiKaela Olsen, please view the ar -chived Safe Handling Awareness DayCE webinar at www.carmelpharmausa.com/CE. Free CE credit for thisarchived webinar presentation is avail-able for pharmacists, pharmacy techni-cians, nurses, and risk managers.

April 2009 was designated thefirst-ever National Safe Han -dling Awareness Month in an

effort to increase awareness of the risksof occupational exposure to chemothera -peutic agents and other hazardous drugsand educate healthcare providers onguidelines and safety measures that canminimize the risks. The initiative, sup-ported by an unrestricted educationalgrant provided by Carmel Pharma, Inc.,the maker of PhaSeal, included regionaland national continuing education ac -tivities. The Oncology Pharma cist recent-ly spoke with Byron Peters, RPh, andMiKaela Olsen, RN, MS, OCN, aboutways to ensure safe handling of haz-ardous drugs in the clinical setting. MrPeters is director of pharmacy, SitemanCancer Center, Wash ington UniversitySchool of Medicine, St. Louis, Missouri.Ms Olsen is an oncology and hematol-ogy clinical nurse specialist, at JohnsHopkins Hospital, Baltimore, Maryland.

The National Institute forOccupa tional Safety and Health,the Oncology Nursing Society,the American Society of Health-System Pharmacists, and otherorganizations have issued guide-lines on safe handling. Why isthis campaign to increaseawareness needed?Byron Peters (BP): Many people

think that measures such as use of bio-logical safety cabi-nets and personalprotective equip-ment are enough.But when we con-ducted an environ-mental wipe samplestudy some yearsago, it was striking

to see that despite doing everything wethought we were supposed to be doing,there was still surface contamination ina relatively new work environment(Harrison BR, et al. Am J Health-SystPharm. 2006;63:1763-1744). More andmore studies are showing contamina-tion in all areas of the workplace. MiKaela Olsen (MO): Workplace

health is becomingmore of a concernin general acrossthe country, andhazardous drugs area part of that. Haz -ardous drugs arebeing increasinglyused for nonmalig-nant diseases, and

nononcology providers may not beaware of the hazards of these drugs.Another concern is the increasing useof potentially hazardous oral drugs thatmay carry risks similar to intravenouslyadministered agents. We need to recognize and take hold

of this problem and ensure safe han-dling. Unfortu nately, not everyone usesthe recommended personal protectiveequip ment when handling these agents.There’s a huge knowledge deficit, andmaybe peer pressure issues too. If moreexperienced staff in the departmentchoose not to use protective equipment,their less experienced colleagues maynot realize how important it is to do soor may feel it is not a priority.

How can institutions be sure thatemployees are following safe han-dling procedures?MO: Monitoring of employees to

determine whether they are experienc-ing any symptoms that may be related tohazardous drug exposure is important.Employees may be experiencing non-specific symptoms, such as headache,nausea, and eye or skin irritation, andmay not necessarily associate them withexposure to a particular substance. BP: We do need heightened aware-

ness because people have been exposed,either knowingly or unknowingly.Fifteen years ago, we did not have someof the environmental controls or engi-neering devices that we now have toprotect us. We are making great strides.We have containment isolators, betterbiological safety cabinets, and we knowhow frequently we have to inspectthem. We also use a closed-systemtransfer device (CSTD) that has beenclinically proven to reduce the risk ofdrug exposure (the PhaSeal System).Studies have shown that when two lev-els of protection were implemented,subjects’ urine became negative for drugtraces (Wick C, et al. Am J Health-SystPharm. 2003;60:2314-2320). We don’tknow if we have the perfect solution,but at least based on what we knownow, there are some additional stepsthat people can take to ensure safety.The problem is that not everyone isusing all the levels of protection we nowhave; some are not even at the mini-mum level.

What are some of the barriersto more widespread use of safehandling measures?MO: I think that sometimes stems

partly from the leadership of the facility.

We have to educate our leadershipabout the hazards of these drugs and thepotential risks to employees. They needto develop policies to protect everyonein the environment from hazardousdrugs, and implement those policies.This shows that they are committed toprotecting their employees.BP:Unfortunately, I think part of the

problem is probably financially motivat-ed. Interventions cost money and maynot be reimbursed. Costs, however,should not be a reason for not imple-menting safeguards. Providing a safework environment is the cost of doingbusiness and something that you justhave to do.

What can nurses and pharmacistsdo to ensure proper handling oforal chemotherapy agents by pa -tients and healthcare providers?MO: There is less regulation safety

measures for oral versus intravenouschemotherapy. In the Oncol ogyNursing Society Chemo therapy andBiotherapy course, we cover handling oforal chemotherapy drugs in the homeand we discuss that in our teaching tonurses. Many institutions have patienteducation materials that they provide tothe family about how to handle thesedrugs and to dispose of body excretionsat home. BP: When we as pharmacists dis-

pense drugs to patients, part of theprocess involves counseling. We shareinformation about safe handling, suchas not breaking tablets in half, and howto dispose of the drugs. Interestingly,there are no regulations about packag-ing of hazardous drugs when dispensing.Oral chemotherapy agents are packagedthe same way as drugs like amoxicillin.

What practical steps can hospitalsand other institutions take toensure adherence to safe handling guidelines? MO: It is the employee’s right to be

informed about the risks, and they needto receive annual training about how toprotect themselves. Women who aretrying to conceive are pregnant orbreast feeding and men who are tryingto conceive need to be informed about

the risks and should be offered alternateduty if requested. BP: Frequently we talk about special-

ly trained and experienced nurses andpharmacists, but there are also otherlevels of people who come in contactwith hazardous drugs, such as techni-cians, students, housekeeping staff, andthose who ship and receive drugs. Theseindividuals need to be trained on safehandling as well. Studies have shownthat vials can come from the manufac-turer with hazardous drugs on the out-side of the container even when theyare properly sealed.MO:When these drugs are given, we

may be unknowingly exposing staff, vis-itors, and caregivers. We have to thinkabout the whole continuum and protecteveryone in the environment. We haveto look at this problem from the timethe drug is delivered all the way to itsproper disposal.BP: The work surface contamination

study we conducted got management’sattention. We’ve implemented a CSTD,the PhaSeal product. People realize thatthis is an added cost, but they under-stand that we are willing to do what isneeded to do to protect our staff, ourpatients, and our visitors and to protectthe environment. We try to take a lead-ing role in our community showing thatwe understand the problem and will dowhatever it takes to provide the utmostsafety. The leadership has to make safehandling a priority. If you start at thetop, it sends a good message to heightenawareness about the hazards of handlingthese drugs. You need to continue toreinforce policies with training pro-grams, annual recertification, annualassessment of technique and competen-cy, and in-service training. ™

™

Byron Peters, RPh

MiKaela Olsen, RN,MS,OCN

Costs should not be a reason for notimplementing safeguards. Providing asafe work environment is the cost ofdoing business.


Colorectal cancer is a term used to refer tocancer that starts in either the colon orthe rectum. Colon cancer and rectal

cancer have many features in common. The fol-lowing sections will assist healthcare profession-als and payers by providing appropriate coding,billing, and reimbursement information associ-ated with the management of colo rectal cancer.

The following sections include:• Associated ICD-9-CM codes used for theclassification of colorectal cancer

• Drugs that have been FDA-approved inthe treatment of colorectal cancer Please note: if a check mark appears inthe FDA column it will NOT appear inthe Compendia section even if a drug isincluded in the NCCN (NationalComprehensive Cancer Network) Drugs &Biologics Compendium

• Drugs included in the NCCN Drugs &Biologics Compendium for off-label use incolorectal cancer. NCCN is recognized bythe Centers for Medicare & MedicaidServices (CMS) as a referencing source

• Corresponding HCPCS/CPT codes andcode descriptions

• Current code price (AWP-based pricing)• Most recent ASP plus 6% (Medicareallowable)

• Possible CPT administration codes foreach medication.

Medications Used for the Treatment of Colorectal Cancer

Oncology Drug Codes

ONCO

LGY DRUG

CODES

Associated ICD-9-CM Codes Used for Colorectal Cancer

153 Malignant neoplasm of colonExcludes: benign carcinoid tumor of colon (209.50-209.56)

malignant carcinoid tumor of colon (209.10-209.16)153.0 Hepatic flexure153.1 Transverse colon153.2 Descending colon

Left colon153.3 Sigmoid colon

Sigmoid (flexure)Excludes: rectosigmoid junction (154.0)

153.4 CecumIleocecal valve

153.5 Appendix153.6 Ascending colon

Right colon153.7 Splenic flexure153.8 Other specified sites of large intestine

Malignant neoplasm of contiguous or overlapping sites of colon whose pointof origin cannot be determined

Excludes: ileocecal valve (153.4) rectosigmoid junction (154.0)

153.9 Colon, unspecifiedLarge intestine NOS

154 Malignant neoplasm of rectum, rectosigmoid junction, and anusExcludes: benign carcinoid tumor of rectum (209.57)

malignant carcinoid tumor of rectum (209.17)154.0 Rectosigmoid junction

Colon with rectumRectosigmoid (colon)

154.1 RectumRectal ampulla

154.2 Anal canalAnal sphincter

Excludes: skin of anus (172.5, 173.5)154.3 Anus, unspecified

Excludes: anus:margin (172.5, 173.5)skin (172.5, 173.5)perianal skin (172.5, 173.5)

154.8 OtherAnorectumCloacogenic zoneMalignant neoplasm of contiguous or overlapping sites of rectum, rectosigmoid junction, and anus whose point of origin cannot be determined

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ONCO

LOGY D

RUG

CODES

NCCN Drugs Current MedicareFDA- & Biologics code price allowableapproved Compendium (AWP- (ASP + 6%), CPT

Generic (brand) HCPCS code: for colorectal off-label use for based effective administrationname code description cancer colorectal cancer pricing) 4/1/09-6/30/09 codes

bevacizumab J9035: injection � $68.75 $57.40 96413, 96415 (Avastin) bevacizumab, 10 mg

capecitabine J8520: capecitabine, � $7.35 $5.28 N/A (Xeloda) oral, 150 mg

capecitabine J8521: capecitabine, � $24.50 $17.51 N/A(Xeloda) oral, 500 mg

cetuximab J9055: injection, � $60.00 $49.73 96413, 96415(Erbitux) cetuximab, 10 mg

floxuridine J9200: injection, � $121.50 $58.08 96422, 96423, (FUDR) floxuridine, 500 mg 96425

fluorouracil J9190: injection, � $3.44 $1.55 96409(Adrucil) fluorouracil, 500 mg

irinotecan J9206: injection, � $32.82 $18.30 96413, 96415(Camptosar) irinotecan, 20 mg

leucovorin J0640: injection, � $3.75 $0.87 96372, 96374, calcium leucovorin calcium, per 50 mg 96409

oxaliplatin J9263: injection, � $12.26 $9.54 96413, 96415(Eloxatin) oxaliplatin, 0.5 mg

panitumumab J9303: injection, � $106.09 $84.29 96413, 96415(Vectibix) panitumumab, 10 mg

References• HCPCS Level II Expert; 2009 • CPT 2009; 2008 • ICD-9-CM for Professionals, Volumes 1 & 2; 2009 • The Drug Reimbursement Coding and Pricing Guide, Vol 6, No 2; RJ Health Systems International LLC; 2nd Quarter 2009 •FDA-approved indication (from products’ prescribing information) • NCCN • American Cancer Society • www.ReimbursementCodes.com powered by RJ Health Systems International, LLC., Wethersfield, Connecticut • CMS-Medicareallowable 2nd Quarter 2009 (effective dates 4/1/09-6/30/09).

Prices listed herein are effective as of May 1, 2009.

ASP indicates average sales price; AWP, average wholesale price; CMS, Centers for Medicare & Medicaid Services; CPT, Current Procedural Terminology; FDA, US Food and Drug Administration; HCPCS, Healthcare CommonProcedure Coding System; NCCN, National Comprehensive Cancer Network.

This information was supplied by:

The Most Comprehensive HCPCS/CPT Drug and Product Reimbursement Coding and Pricing Service Available!

ReimbursementCodes.com is an online HCPCS/CPT reimbursement coding and pricing service that provides up-to-date reimbursement information.

You have the ability to accurately match reimbursement to the corresponding date of service for every claim!• Drugs which are injected subcutaneously, intramuscularly, or intravenously• Selected orally administered chemotherapeutic and antiemetic agents• Nutritional agents and ostomy care products• Drugs administered via nebulizers or other DME equipment• Radiopharmaceuticals

Plus a fast and efficient avenue to HCPCS/CPT coding and reimbursement information!• In billable units matching the CMS- and AMA-established reimbursement code description• A validated pricing methodology• Includes all price changes that have occurred for each code, along with the effective date of the change(s)

Does your revenue stream run as productively as possible? Contact RJ Health Systems, and mention The Oncology Pharmacist.

PO BOX 290616, Wethersfield, CT 06109 • T: (860) 563-1223 • F: (860) 563-1650 • www.RJHealthSystems.com


MEE

TINGS

8-11 TORONTO, CANADAInternational Academy of OralOncology 2nd World Congresswww.iaoo2009.com

9-10 SAN FRANCISCO, CALIFORNIANCCN Academy for Excellence andLeadership in Oncologywww.nccn.org

11-12 BOSTON, MASSACHUSETTSUnderstanding New Technologiesand Managing Oncology Care Needswww.cancerlearning.com

21-23 WASHINGTON, DC8th International Congress onTargeted Therapies in Cancerwww.cancerlearning.com

11-12 ST. LOUIS, MISSOURITranslational Advances in RadiationOncology and Cancer ImagingSymposiumwww.astro.org

OCTOBER 2009JULY 2009

Meetings1-4 CHICAGO, ILLINOISLynn Sage Breast Cancer Symposiumwww.lynnsagebreastcancer.org

4-7SAN DIEGO, CALIFORNIA29th Annual Oncology NursesSymposiumwww.scripps.org

8-9 DALLAS, TEXAS2009 Cancer Center Business Summitwww.cancerbusinesssummit.com

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AUGUST 2009

SEPTEMBER 2009

RITUXAN® (Rituximab) Brief summary—Please consult full prescribing information.

INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan®

(rituximab) is indicated for the treatment of patients with: Relapsed or refractory,low-grade or follicular, CD20-positive, B-cell NHL as a single agent; Previouslyuntreated follicular, CD20-positive, B-cell NHL in combination with CVPchemotherapy; Non-progressing (including stable disease), low-grade, CD20-positive B-cell NHL, as a single agent, after first-line CVP chemotherapy;Previously untreated diffuse large B-cell, CD20-positive NHL in combination withCHOP or other anthracycline-based chemotherapy regimens. WARNINGS ANDPRECAUTIONS Infusion Reactions Rituxan can cause severe, including fatal,infusion reactions. Severe reactions typically occurred during the first infusion withtime to onset of 30–120 minutes. Rituxan-induced infusion reactions andsequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm,pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction,ventricular fibrillation, cardiogenic shock, or anaphylactoid events. Premedicatepatients with an antihistamine and acetaminophen prior to dosing. Institutemedical management (e.g., glucocorticoids, epinephrine, bronchodilators, oroxygen) for infusion reactions as needed. Depending on the severity of theinfusion reaction and the required interventions, consider resumption of theinfusion at a minimum 50% reduction in rate after symptoms have resolved.Closely monitor the following patients: those with preexisting cardiac orpulmonary conditions, those who experienced prior cardiopulmonary adversereactions, and those with high numbers of circulating malignant cells(≥25,000/mm3). [See Boxed Warning, Warnings and Precautions, AdverseReactions.] Tumor Lysis Syndrome (TLS) Rapid reduction in tumor volumefollowed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, orhyperphosphatemia, can occur within 12–24 hours after the first infusion. FatalTLS cases have occurred after administration of Rituxan. A high number ofcirculating malignant cells (≥25,000/mm3) or high tumor burden confers a greaterrisk of TLS after rituximab. Consider prophylaxis for TLS in patients at high risk.Correct electrolyte abnormalities, monitor renal function and fluid balance, andadminister supportive care, including dialysis as indicated. [See Boxed Warning.]Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fataloutcome, can occur in patients treated with Rituxan. These reactions includeparaneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis,vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of thesereactions has varied from 1–13 weeks following Rituxan exposure. DiscontinueRituxan in patients who experience a severe mucocutaneous reaction. The safetyof readministration of Rituxan to patients with severe mucocutaneous reactionshas not been determined. [See Boxed Warning, Adverse Reactions.] ProgressiveMultifocal Leukoencephalopathy (PML) JC virus infection resulting in PMLand death can occur in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologicmalignancies diagnosed with PML received Rituxan in combination withchemotherapy or as part of a hematopoietic stem cell transplant. The patients withautoimmune diseases had prior or concurrent immunosuppressive therapy. Mostcases of PML were diagnosed within 12 months of their last infusion of Rituxan.Consider the diagnosis of PML in any patient presenting with new-onsetneurologic manifestations. Discontinue Rituxan and consider discontinuation orreduction of any concomitant chemotherapy or immunosuppressive therapy inpatients who develop PML. [See Boxed Warning, Adverse Reactions.] Hepatitis BVirus (HBV) Reactivation Hepatitis B Virus (HBV) reactivation with fulminanthepatitis, hepatic failure, and death can occur in patients with hematologicmalignancies treated with Rituxan. The median time to the diagnosis of hepatitiswas approximately 4 months after the initiation of Rituxan and approximately onemonth after the last dose. Screen patients at high risk of HBV infection beforeinitiation of Rituxan. Closely monitor carriers of hepatitis B for clinical andlaboratory signs of active HBV infection for several months following Rituxantherapy. Discontinue Rituxan and any concomitant chemotherapy in patients whodevelop viral hepatitis, and institute appropriate treatment including antiviraltherapy. Insufficient data exist regarding the safety of resuming Rituxan in patientswho develop hepatitis subsequent to HBV reactivation. [See Adverse Reactions.]Other Viral Infections The following additional serious viral infections, eithernew, reactivated, or exacerbated, have been identified in clinical studies orpostmarketing reports. The majority of patients received Rituxan in combinationwith chemotherapy or as part of a hematopoietic stem cell transplant. These viralinfections included cytomegalovirus, herpes simplex virus, parvovirus B19,varicella zoster virus, West Nile virus, and hepatitis C. In some cases, the viralinfections occurred as late as one year following discontinuation of Rituxan andhave resulted in death. [See Adverse Reactions.] Cardiovascular Discontinueinfusions for serious or life-threatening cardiac arrhythmias. Perform cardiacmonitoring during and after all infusions of Rituxan for patients who developclinically significant arrhythmias or who have a history of arrhythmia or angina.[See Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occurafter Rituxan administration in patients with hematologic malignancies. Renaltoxicity has occurred in patients with high numbers of circulating malignant cells(≥25,000/mm3) or high tumor burden who experience tumor lysis syndrome andin patients with NHL administered concomitant cisplatin therapy during clinicaltrials. The combination of cisplatin and Rituxan is not an approved treatmentregimen. Use extreme caution if this non-approved combination is used in clinicaltrials and monitor closely for signs of renal failure. Consider discontinuation ofRituxan for patients with a rising serum creatinine or oliguria. Bowel Obstructionand Perforation Abdominal pain, bowel obstruction and perforation, in some

WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME(TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVEMULTIFOCAL LEUKOENCEPHALOPATHY (PML)Infusion Reactions: Rituxan administration can result in serious,including fatal infusion reactions. Deaths within 24 hours of Rituxaninfusion have occurred. Approximately 80% of fatal infusion reactionsoccurred in association with the first infusion. Carefully monitorpatients during infusions. Discontinue Rituxan infusion and providemedical treatment for Grade 3 or 4 infusion reactions [see Warningsand Precautions, Adverse Reactions]. Tumor Lysis Syndrome (TLS):Acute renal failure requiring dialysis with instances of fatal outcomecan occur in the setting of TLS following treatment of non-Hodgkin’slymphoma (NHL) patients with Rituxan [see Warnings and Precautions,Adverse Reactions]. Severe Mucocutaneous Reactions: Severe,including fatal, mucocutaneous reactions can occur in patientsreceiving Rituxan [see Warnings and Precautions, Adverse Reactions].Progressive Multifocal Leukoencephalopathy (PML): JC virus infectionresulting in PML and death can occur in patients receiving Rituxan [seeWarnings and Precautions, Adverse Reactions].

cases leading to death, can occur in patients receiving Rituxan in combinationwith chemotherapy. In postmarketing reports, the mean time to documentedgastrointestinal perforation was 6 (range 1–77) days in patients with NHL.Perform a thorough diagnostic evaluation and institute appropriate treatment forcomplaints of abdominal pain, especially early in the course of Rituxan therapy.[See Adverse Reactions.] Immunization The safety of immunization with live viralvaccines following Rituxan therapy has not been studied and vaccination with livevirus vaccines is not recommended. For NHL patients, the benefits of primary orbooster vaccinations should be weighted against the risks of delay in initiation ofRituxan therapy. Laboratory Monitoring Because Rituxan binds to all CD20-positive B lymphocytes (malignant and non-malignant), obtain complete bloodcounts (CBC) and platelet counts at regular intervals during Rituxan therapy andmore frequently in patients who develop cytopenias [see Adverse Reactions]. Theduration of cytopenias caused by Rituxan can extend months beyond thetreatment period. ADVERSE REACTIONS The most common adverse reactions ofRituxan (incidence ≥25%) observed in patients with NHL are infusion reactions,fever, chills, infection, asthenia, and lymphopenia. The most important seriousadverse reactions of Rituxan are infusion reactions, tumor lysis syndrome,mucocutaneous toxicities, hepatitis B reactivation with fulminant hepatitis, PML,other viral infections, cardiac arrhythmias, renal toxicity, and bowel obstructionand perforation. Clinical Trials Experience Non-Hodgkin’s LymphomaBecause clinical trials are conducted under widely varying conditions, adversereaction rates observed in the clinical trials of a drug cannot be directly comparedto rates in the clinical trials of another drug and may not reflect the rates observedin practice. The data described below reflect exposure to Rituxan in 1606patients, with exposures ranging from a single infusion up to 6–8 months. Rituxanwas studied in both single-agent and active-controlled trials (n = 356 and n =1250). These data were obtained in adults with low-grade, follicular, or DLBCLNHL. Most patients received Rituxan as an infusion of 375 mg/m2 per infusion,given as a single agent weekly for up to 8 doses, in combination withchemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses.Infusion Reactions In the majority of patients with NHL, infusion reactionsconsisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension,headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, orhypertension occurred during the first Rituxan infusion. Infusion reactions typicallyoccurred within 30 to 120 minutes of beginning the first infusion and resolvedwith slowing or interruption of the Rituxan infusion and with supportive care(diphenhydramine, acetaminophen, and intravenous saline). The incidence ofinfusion reactions was highest during the first infusion (77%) and decreased witheach subsequent infusion. [See Boxed Warning, Warnings and Precautions.]Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis,occurred in less than 5% of patients with NHL in the single-arm studies. Theoverall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%,and fungal 1%). [See Warnings and Precautions.] In randomized, controlledstudies where Rituxan was administered following chemotherapy for thetreatment of follicular or low-grade NHL, the rate of infection was higher amongpatients who received Rituxan. In diffuse large B-cell lymphoma patients, viralinfections occurred more frequently in those who received Rituxan. Cytopeniasand hypogammaglobulinemia In patients with NHL receiving rituximabmonotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% ofpatients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%),anemia (3%), and thrombocytopenia (2%). The median duration of lymphopeniawas 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116days). A single occurrence of transient aplastic anemia (pure red cell aplasia) andtwo occurrences of hemolytic anemia following Rituxan therapy occurred duringthe single-arm studies. In studies of monotherapy, Rituxan-induced B-celldepletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgGserum levels occurred in 14% of these patients. Single-Agent Rituxan Adversereactions in Table 1 occurred in 356 patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL treated in single-arm studies ofRituxan administered as a single agent. Most patients received Rituxan 375 mg/m2

weekly for 4 doses.Table 1Incidence of Adverse Events in ≥5% of Patients with Relapsed or Refractory, Low-Grade or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b

aAdverse reactions observed up to 12 months following Rituxan. bAdverse reactions graded for severity by NCI-CTC criteria.

In these single-arm Rituxan studies, bronchiolitis obliterans occurred during andup to 6 months after Rituxan infusion. Rituxan in Combination WithChemotherapy Adverse reactions information below is based on 1250 patientswho received Rituxan in combination with chemotherapy or followingchemotherapy. Rituxan in Combination With Chemotherapy for Low-GradeNHL In Study 4, patients in the R-CVP arm experienced a higher incidence ofinfusional toxicity and neutropenia compared to patients in the CVP arm. Thefollowing adverse reactions occurred more frequently (≥5%) in patients receivingR-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing(14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), neutropenia (8% vs.3%), and chest tightness (7% vs. 1%). In Study 5, the following adverse reactionswere reported more frequently (≥5%) in patients receiving Rituxan following CVPcompared to patients who received no further therapy: fatigue (39% vs. 14%),anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections(19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs.7%), rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain(11% vs. 4%). Neutropenia was the only Grade 3 or 4 adverse reaction thatoccurred more frequently (≥2%) in the Rituxan arm compared with those whoreceived no further therapy (4% vs. 1%). Rituxan in Combination With

All Grades (%) Grade 3 and 4 (%)

Any Adverse Events 99 57Body as a Whole 86 10

Fever 53 1Chills 33 3Infection 31 4Asthenia 26 1Headache 19 1Abdominal Pain 14 1Pain 12 1Back Pain 10 1Throat Irritation 9 0Flushing 5 0

Heme and Lymphatic System 67 48Lymphopenia 48 40Leukopenia 14 4Neutropenia 14 6Thrombocytopenia 12 2Anemia 8 3

Skin and Appendages 44 2Night Sweats 15 1Rash 15 1Pruritus 14 1Urticaria 8 1

All Grades (%) Grade 3 and 4 (%)

Respiratory System 38 4Increased Cough 13 1Rhinitis 12 1Bronchospasm 8 1Dyspnea 7 1Sinusitis 6 0

Metabolic and Nutritional Disorders 38 3

Angioedema 11 1Hyperglycemia 9 1Peripheral Edema 8 0LDH Increase 7 0

Digestive System 37 2Nausea 23 1Diarrhea 10 1Vomiting 10 1

Nervous System 32 1Dizziness 10 1Anxiety 5 1

Musculoskeletal System 26 3Myalgia 10 1Arthralgia 10 1

Cardiovascular System 25 3Hypotension 10 1Hypertension 6 1

Chemotherapy for DLBCL In Studies 6 and 7, the following adverse reactions,regardless of severity, were reported more frequently (≥5%) in patients age ≥60years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lungdisorder (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%).Detailed safety data collection in these studies was primarily limited to Grade 3and 4 adverse reactions and serious adverse reactions. In Study 7, a review ofcardiac toxicity determined that supraventricular arrhythmias or tachycardiaaccounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs.1.0% for CHOP). The following Grade 3 or 4 adverse reactions occurred morefrequently among patients in the R-CHOP arm compared with those in the CHOParm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%). Other Grade3 or 4 adverse reactions occurring more frequently among patients receiving R-CHOP were viral infection (Study 7), neutropenia (Studies 7 and 8), and anemia(Study 8). Immunogenicity As with all therapeutic proteins, there is a potentialfor immunogenicity. The observed incidence of antibody (including neutralizingantibody) positivity in an assay is highly dependent on several factors includingassay sensitivity and specificity, assay methodology, sample handling, timing ofsample collection, concomitant medications, and underlying disease. For thesereasons, comparison of the incidence of antibodies to Rituxan with the incidenceof antibodies to other products may be misleading. Using an ELISA assay, anti-human anti-chimeric antibody (HACA) was detected in 4 of 356 (1.1%) patientswith low-grade or follicular NHL receiving single-agent Rituxan. Three of the fourpatients had an objective clinical response. The clinical relevance of HACAformation in rituximab treated patients is unclear. Postmarketing ExperienceThe following adverse reactions have been identified during postapproval use ofRituxan in hematologic malignancies. Because these reactions are reportedvoluntarily from a population of uncertain size, it is not always possible to reliablyestimate their frequency or establish a causal relationship to drug exposure.Decisions to include these reactions in labeling are typically based on one or moreof the following factors: (1) seriousness of the reaction, (2) frequency of reporting,or (3) strength of causal connection to Rituxan. Hematologic: prolongedpancytopenia, marrow hypoplasia, and late-onset neutropenia, hyperviscositysyndrome in Waldenstrom’s macroglobulinemia. Cardiac: fatal cardiac failure.Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis,lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. Infection: viral infections, including progressive multifocalleukoencephalopathy (PML), increase in fatal infections in HIV-associatedlymphoma, and a reported increased incidence of Grade 3 and 4 infections inpatients with previously treated lymphoma without known HIV infection.Neoplasia: disease progression of Kaposi’s sarcoma. Skin: severe mucocutaneousreactions. Gastrointestinal: bowel obstruction and perforation. Pulmonary: fatalbronchiolitis obliterans and pneumonitis (including interstitial pneumonitis). DRUGINTERACTIONS Formal drug interaction studies have not been performed withRituxan. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There areno adequate and well-controlled studies of rituximab in pregnant women.Postmarketing data indicate that B-cell lymphocytopenia generally lasting lessthan six months can occur in infants exposed to rituximab in-utero. Rituximab wasdetected postnatally in the serum of infants exposed in-utero. Non-Hodgkin’slymphoma is a serious condition that requires treatment. Rituximab should beused during pregnancy only if the potential benefit to the mother justifies thepotential risk to the fetus. Reproduction studies in cynomolgus monkeys atmaternal exposures similar to human therapeutic exposures showed no evidenceof teratogenic effects. However, B-cell lymphoid tissue was reduced in theoffspring of treated dams. The B-cell counts returned to normal levels, andimmunologic function was restored within 6 months of birth. Nursing Mothers Itis not known whether Rituxan is secreted into human milk. However, Rituxan issecreted in the milk of lactating cynomolgus monkeys, and IgG is excreted inhuman milk. Published data suggest that antibodies in breast milk do not enterthe neonatal and infant circulations in substantial amounts. The unknown risks tothe infant from oral ingestion of Rituxan should be weighed against the knownbenefits of breastfeeding. Pediatric Use The safety and effectiveness of Rituxanin pediatric patients have not been established. Geriatric Use Diffuse Large B-Cell NHL Among patients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients received Rituxan in combination with chemotherapy.Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 orgreater. No overall differences in effectiveness were observed between thesepatients and younger patients. Cardiac adverse reactions, mostly supraventriculararrhythmias, occurred more frequently among elderly patients. Serious pulmonaryadverse reactions were also more common among the elderly, includingpneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin’sLymphoma Clinical studies of Rituxan in low-grade or follicular, CD20-positive,B-cell NHL did not include sufficient numbers of patients aged 65 and over todetermine whether they respond differently from younger subjects.OVERDOSAGE There has been no experience with overdosage in human clinicaltrials. Single doses of up to 500 mg/m2 have been given in dose-escalationclinical trials. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis,Impairment of Fertility No long term animal studies have been performed toestablish the carcinogenic or mutagenic potential of Rituxan or to determinepotential effects on fertility in males or females. PATIENT COUNSELINGINFORMATION Patients should be provided the Rituxan Medication Guide andprovided an opportunity to read prior to each treatment session. Because cautionshould be exercised in administering Rituxan to patients with active infections, it isimportant that the patient’s overall health be assessed at each visit and anyquestions resulting from the patient’s reading of the Medication Guide bediscussed. Rituxan is detectable in serum for up to six months followingcompletion of therapy. Individuals of childbearing potential should use effectivecontraception during treatment and for 12 months after Rituxan therapy.

Revised 9/2008 (4835505)Jointly Marketed by: Biogen Idec Inc. 5200 Research Place San Diego, CA 92122Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990

©2008 Biogen Idec Inc. and Genentech, Inc. 7140917 October 2008

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For previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens

When planning a treatment course for DLBCL

Take the essential path toward improved survival

47% INCREASEin 7-year OS in GELA* trial1,2

RITUXAN+CHOP isproven to prolongsurvival in DLBCL

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R-CHOP (n=202)CHOP† (n=197)p =0.0004

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R-CHOP (n=202)CHOP† (n=197)p =0.0004

• At 7 years, 8 cycles of RITUXAN+CHOP increased overall survival (OS) from 36% to 53% compared with CHOP alone1

• At 5 years, 8 cycles of RITUXAN+CHOP increased OS from 46% to 58% compared with CHOP alone5

BOXED WARNINGS and Additional Important Safety InformationThe most important serious adverse reactions of RITUXAN are fatal infusion reactions,tumor lysis syndrome (TLS), severe mucocutaneous reactions, progressive multifocalleukoencephalopathy (PML), hepatitis B reactivation with fulminant hepatitis, other viralinfections, cardiovascular events, renal toxicity, and bowel obstruction and perforation. Themost common adverse reactions of RITUXAN (incidence ≥25%) observed in patients withNHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia.5

RITUXAN in Combination with CHOP Chemotherapy for DLBCL: The following adversereactions, regardless of severity, were reported more frequently (≥5%) in patients age ≥60years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs 46%), lung disorder(31% vs 24%), cardiac disorder (29% vs 21%), and chills (13% vs 4%). In the GELA LNH98-5 study, a review of cardiac toxicity determined that supraventricular arrhythmias ortachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs1.0% for CHOP).5

The following Grade 3 or 4 adverse reactions occurred more frequently among patients inthe R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs 7%) andlung disorder (6% vs 3%). Other Grade 3 or 4 adverse reactions reported more frequentlyamong patients receiving R-CHOP were viral infection (GELA LNH 98-5 study), neutropenia(GELA LNH 98-5 and MInT studies), and anemia (MInT study).5

Please see brief summary of prescribing information on adjacent page.Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion.*GELA (Groupe d’Etude des Lymphomes de l’Adulte) LNH 98-5 trial: A Phase III trial of 399 previouslyuntreated elderly (age ≥60 years) DLBCL patients.3,4

†CHOP: Cyclophosphamide, doxorubicin, vincristine, and prednisone.

References: 1. Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOPand CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-riskpatients. J Clin Oncol. 2007;25(suppl 18S):443s. Abstract 8009. 2. Coiffier B, Feugier P, Mounier N, et al.Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients withdiffuse large B-cell lymphoma show good survival in poor-risk patients. Paper presented at: 43rd AmericanSociety of Clinical Oncology Annual Meeting; June 1-5, 2007; Chicago, Ill. Abstract 8009. 3. Coiffier B, Lepage E, Brière J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patientswith diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235-242. 4. Data on file, Genentech, Inc. 5. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2008.

PROVE N. POWE R FU L.

©2008 Genentech, Inc., and Biogen Idec Inc. All rights reserved. 3 Printed in USA on Recycled Paper 8974801 April 2008

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