Daniela Katz M.D.Sharett Institute of Oncology

Chemotherapy

Achilles heel

Pareto Principle

• Also known as the 80–20 rule:

80% of the effects come from 20% of the causes.

Example:

“80% of your sales come from 20% of your clients”

“80% of the traffic occurs during 20% of the time”

Objectives

Why is it difficult to develop an effective chemotherapy?

Drug

Host Parasite

No effect Cytotoxic

Bacteria, fungi, protozoa, helminths, viruses vs. cancer cell.

Theory

Paul Ehrlich 1854-1915Nobel Laureate 1908

CHEMOTHERAPY: The basis of anti-cancer chemotherapy and the problem

Qualitative

Quantitative

The goal is to selectively kill malignant cells and spare normal host cells. Selective toxicity is not possible, as malignant cells are derived from the host and the differences between normal and malignant cells are much more subtle. Therefore, successful treatment is with doses and strategies that allow recovery of normal proliferating cells.

• Most chemotherapy drugs are active in cells that are rapidly multiplying – Chemotherapy may not be very active in

indolent or slow growing tumors

• Because of cytotoxic action on rapidly dividing cells they are toxic to normal cells that are actively multiplying– Bone marrow, GI tract, hair follicles are all

rapidly multiplying

Common Toxicities• Thus common toxicity of chemo agents are -

1. Neutropenia, anemia, and thrombocytopenia (collectively called myelosuppression or bone marrow suppression)2. Mucositis, diarrhea (GI toxicity)3. Alopecia4. Sterility/Infertility (especially sterility in males)

• Common Toxicity Criteria Grading System (CTC)–Grade 0 – 4

COST

Gompertzian dynamics

Growth fraction (percentage of cells actively dividing)

S

M

G 1

G 2

G 0

A

B

Cnone cycling

cells

Anti-cancer chemotherapy most effect against cells in cell fraction A. Cells in fraction B can re-enter fraction A.

Cell number(tumor size)

Time

1012

109

The Cell Cycle

• G1 phase: cell prepares for DNA synthesis

• S phase: cell generates complete copy of genetic material

• G2 phase: cell prepares for mitosis

• M phase: replicated DNA is condensed and segregated into chromosomes

• G0 phase: resting state

3 x Problem associated with Anti-cancer chemotherapy

Cell No

Tum

ou

rS

ize

(cm

)

Pe rce n

ta ge o

fc

ell in c ycle (A

)

101210910 3 106

2

10

20

Limit of diagnostic procedures.

Exponential growth of a tumour

Cell number(tumor size)

Time

1012

109

Chemotherapy is present in 3 settings:

• Neoadjuvant chemo

• Adjuvant chemo

• Chemo for active disease

Goals of Cancer ChemotherapyCureProlong survivalPalliationRadiosensitive

Summary anti-cancer chemotherapy's

Cytotoxic drugs•Alkylating agentsCyclophosphamide, Busulfan, Carmustin, Chloramabucil, Ifosfamide, lomustine, Melphan, TreosulfanCisplatin, Carboplatin, Oxaliplatin

•Anti-metabolitesMethotrexate, Fluoruracil, Cytarabine, Cladribine, Fludarabine phosphate, Gemcitabine, Mercaptopurine

•Cytotoxic AntibioticsBleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitomycin

•Plant derivativesEtoposide, Vinblastine, Vincristine

HormoneTamoxifen, Anastrozole, Letrozole

MiscellaneousImatinib, Bortezomib, Bevacizumab, Trastuzumab, Taxol, Cristaspase, Arsenic

Chemotherapy Classes• Alkylating agents

– nitrogen mustards– thiotepa, busulfan– nitrosoureas, mitomycin– procarbazine,

dacarbazine• Taxanes

– paclitaxel, docetaxel– nab-paclitaxel

• Topoisomerase II inhibitors– etoposide

• Platinum Complexes– cisplatin, carboplatin– oxaliplatin

• Anthracyclines

– doxorubicin, daunorubicin

– idarubicin, mitoxantrone

• Antimetabolites

– methotrexate

– purine antagonists

– pyrimidine antagonists

• Tubulin interactive agents

– vincristine, vinblastine

• Miscellaneous agents

– bleomycin

– asparaginase

– hydroxyurea

Summary of cytotoxic drug action

PU R IN E SYN THES IS PYR IM ID IN E SYN THE SIS

R IB O NU C LEO TIDE S

PR O TEINS

M IR O TU BU LES EN ZYM ES

D N A

R NA( )transfer, m essenger, ribosom al

D EO XY RIBO N U CLEO TID ES

PENTO STATIN (ct2)

6-M ER CAPTO PUR INE(ct2)6-TH IOG U ANIN E (ct2)

M ETH O TREXATE (ct2 )

C YTARABIN E (ct2)

5-FLU O R OU R ACIL (ct2 )

BLEOM YC IN S (ct3)

D OXO R UBIC IN (ct3)ETO PO SID E (ct4)

D ACTIN OM YCIN (ct3)

V IN C A ALKALO ID S (ct4)TAXANES (ct4)

ALKYLATIN G AG EN TS (ct1)M ITO M YC IN (ct3)C ISPLATIN (ct1)

Inh ib its adenosinedeam inase

Inh ib it pu rine syn thesisInh ib it nucleo tidein te rconversion

Inh ib its pu rine synthesisInh ib its D TM P

Inh ib its D N A po lym eraseInh ib its R N A function

Inh ib its D TM P syn thes is

D am ages D N Aand p revent repa ir

C ross-link D N A

Inh ib its topoisom erase II

Inh ib its topoisom erase II

Inh ib its R N A synthesis

Inh ib its R N A synthesis

In terca la tes in D N A

Inh ib it func tion o f m icro tubes

Alkylating Agents

• Main effect is on DNA synthesis with most cytotoxicity to rapidly proliferating cells

Action of Alkylating drugs- DNA adducts, cell cycle non-specific

A

A

T

T

C

C

G

G

C

C

G

G

Intra-strand linkage

Cross-linkingAldehyde

dehydrogenase

In use in:

BreastSarcomaOvarianTestisCLL

Non-Hodgkin’s LY

PO, IV

Cyclophosphamide and Toxicity

• Myelosuppression– principle dose-limiting toxicity

– primarily leukopenia

• Syndrome of inappropriate antidiuretic hormone

• Alopecia

• Highly emetogenic if 1500 mg/m2

Ifosfamide Toxicity• Hemorrhagic cystitis

– excretion of acrolein into the urinary bladder– greater with bolus regimen– higher after ifosfamide that after equivalent doses of

cyclophosphamide– symptoms of dysuria and urinary frequency– MESNA- sulfhydryl compound binds acrolein– routinely recommended to protect against urothelial

toxicity- Prevention!!!

– treatment of hemorrhagic cystitis requires evacuation of clots and continuous bladder irrigation;

Ifosfamide Toxicity• hematologic toxicity

– leukopenia– the principal dose-limiting toxicity of ifosfamide

• white blood cell nadirs usually occur between days 8 to 13 of the treatment cycle

• recovery will usually be complete by day 17 or 18 of the treatment cycle

• neurotoxicity– chloroacetaldehyde metabolite penetrates the BBB

well after systemic administration– CNS toxicity occurring in 10–40% of the patients

receiving high doses of the drug– Somnolense, mental confusion, cerebellar ataxia,

complex visual hallucinations– methylene blue as an effective treatment for

ifosfamide-induced encephalopathy is controversial

Ifosfamide Toxicity• Fanconi syndrome

– impairment of proximal tubule function, including glucose, protein, phosphate, bicarbonate and amino acid transport

– generally irreversible, long-lasting and potentially progressive

– manifested as polyuria, metabolic acidosis, and renal phosphate wasting

• Nausea and vomiting• Alopecia• Cyclophospamide and ifosfamide have little cardiac toxicity at

standard doses– at high doses such as those used for bone marrow

ablation, can cause severe myocarditis, exudative pericarditis, myocardial depression, arrhythmias and congestive heart failure

The PlatinumsIntrastrend DNA adducts

Mg/m2

AUC

Nucleotide excision repair pathwayERCC1

Cisplatin Toxicity• Nephrotoxicity

– dose-limiting toxicity

– renal damage is usually reversible but rarely can be irreversible and require dialysis

– platinum concentrations are higher in the kidney than in the plasma or other tissues

– initiating event is proximal tubular lesion

– secondary events such as disturbances in distal tubular reabsorption, renal vascular resistance, renal blood flow, and glomerular filtration, and polyuria seen 2 to 3 days later

– hypomagnesemia develops in about 75% of patients, beginning 3 to 12 weeks after therapy and persisting for months to years

Cisplatin Nephrotoxicity

• Preventive Measures– aggressive saline hydration (enhance urinary excretion)– lower doses may require less hydration– infuse over 24 hours– avoid other nephrotoxic agents– magnesium supplementation– predisposing factors to developing nephrotoxicity

include age 60 years or older, higher doses, pretreatment GFR < 75 ml/min, cumulative dose, low albumin, single dose compared with daily x 5 administration schedules

Cisplatin Toxicity

• Hematologic toxicity– can affect all 3 blood lineages– minor neutropenia, thrombocytopenia, and ANEMIA– its mild hematologic toxicity has allowed its

combination with highly myelosuppressive chemotherapy

• Ototoxicity– audiograms show bilateral and symmetrical high

frequency hearing loss– usually irreversible– caution with other drugs (aminoglycosides)

Cisplatin Toxicity

• Neurotoxicity– dose-limiting toxicity– most common symptoms are peripheral neuropathy and

hearing loss– first signs are loss of vibration sensation, loss of ankle

jerks and painful paresthesias in hands and feet– proximal progression and deficits in proprioception, light

touch and pain– recovery is typically incomplete

– less common include Lhermitte’s sign (electric shock-like sensation transmitted down the spine upon neck flexion)

Cisplatin Toxicity

• Nausea and vomiting– acute or delayed

– highly emetogenic if use doses than 50 mg/m2

– moderately emetogenic if use doses 50 mg/m2

– severe if not adequately prevented with appropriate medications

– typical anti-emetic regimen• aprepitant 125 mg po day 1 then 80 mg po days 2 – 3

• dexamethasone 12 mg po day 1 then 8 mg po daily x 3 days

• palonosetron 0.25 mg IVP day 1

• metoclopramide 10 mg every 4 hours prn N/V

Carboplatin Toxicity • Moderately emetogenic • Renal impairment is rare

– because it is excreted primarily in the kidneys as an unchanged drug, it is not directly toxic to the renal tubules

• Neurotoxicity is rare• Myelosuppression

– especially THROMBOCYTOPENIA– dose-limiting toxicity

• Hypersensitivity reaction– incidence of hypersensitivity seems to be correlated with

increased number of cycles of carboplatin

Oxaliplatin Toxicity• Gastrointestinal

– Moderate emetogenicity– diarrhea

• Minimal hematologic toxicity– Thrombocytopenia is dose-related (doses > 135 mg/m2)– mild neutropenia– mild anemia

• No nephrotoxicity• Hypersensitivity reaction

– mild– slowing down infusion rate and giving an antihistamine

and/or steroid– desensitization protocol

• Peripheral neuropathy

Clinical characteristics of oxaliplatin neurotoxicity

Acute symptoms Chronic symptoms

• Common (90% of patients)• Transient, short lived• Dysesthesias and paresthesias• Manifesting as stiffness of the

hands or feet, inability to release grip, and sometimes affecting the legs or causing contractions of the jaw

• Distal extremeties, perioral, oral, and pharyngolaryngeal

• 10% to 15% moderate neuropathy after a cumulative dose of 780 to 850 mg/m2

• Does not seem to be schedule-dependent

• Dysesthesias and paresthesias persisting between cycles

• Progressively evolving to functional impairment: difficulties in activities requiring fine sensorimotor coordination, sensory ataxia

• Tends to improve/recover after treatment is stopped

• Spares motor neurons (like cisplatin)

Prevention: Stop and Go Strategy, Ca and Mg infusions (may compromise efficacy), Gloves avoid cold

Comparison of Platinum Toxicity

Table 5. Comparative adverse effect profiles of platinum drugs

Adverse effect cisplatin carboplatin oxaliplatin

Nephrotoxicity ++ + -

Gastrointestinal toxicity

+ + +

Peripheral neurotoxicity

+++ - ++

Ototoxicity + - -

Hematologic toxicity + ++ +

Hypersensitivity - + -

Anthracyclines

Cytotoxic antibiotics Doxorubicin, Dactinomycin, Etoposide (VA)

D ouble stranded D N A

D ouble stranded D N A break

N on-c leavab le com p lexTrans ien t c leavab lecom plex P ersis tan t c leavab le

com plex

Topo isom erase II

DR

UG

S trand passing, ro ta tionb reak resea ling

Administered i.v.Acute lymphocytic leukemiaAcute granulocytic leukemia

Cardiotoxicity

Red Devil

aLOPECIA

NauseaMyelosupression

Mucositis

palmar-plantar erythrodysesthesia, or hand-foot syndrome

Chemotherapy- induced mucositis

Plant alkaloids (vincristine & vinblastine, Taxol)

Steady state

Polym erization blocked by vincristine & vinblastine

Polym erization stabilized by Taxol

Tub lindim er

Assem bly

C ontinued d isassem bly

S table m icro tubu le

D rug

D isassem bly

Resistance due to multidrug resistance,altered tublin moleculesAdministered I.v.Childhood leukemia's, Hodgkin'sand non-Hodgkin's lymphoma, testicular,ovarian carcinomas and brain tumours

Vincristine & vinblastine

Resistancealtered tublin molecules

Administered i.v.Metastatic ovarian and breast cancer

Taxol

Antimetabolites

5-Fluorouracil

• Fluoropyrimidine analogue= 5-FU

N

N N

N

HO

HO HO

HO

O

O O

O

O

O O

O

O

O O

O

F

F

HN

HN HNCH 3

HN

Inhib ites Thymidilate synthasevia com plexing w ith Tetrahydrofolate

Thym idilate synthaseTetrahydrofolate

P

P P

P

5-F luorouracilF luorouracil-Deoxy Urid ine

+

Thym idinePhosphorylase

D eoxyuridy lic acid D eoxythym idylic acid

Anti-metabolites (5-Fluorouracil)

ResistanceDecreased levels of thymidine phosphorylaseor affinity for 5FU

Administered parentallyBreast, ovarian, prostate,pancreatic, hepatic carcinomas

Indications

• Breast

• Colorectal

• Head and Neck

• Hepatoma

Leucovorin=Folinic Acid Stabilizes TS-FdUMP complex (GI tract)

Contraindications

• Myocardial infraction previous 6m

Toxicity

• Mucositis (Dose limiting toxicity for infusional)• Diarrhea (Dose limiting toxicity for infusional)• Myelosupression (Dose limiting toxicity for bolus)• Hand and foot syndrome (more with infusional)• Hyperpigmentation of the infused vein• Metallic taste during infusion• Cardiac symptoms+ ECG changes• Neurotoxicity- somnolence, cerebellar ataxia…

Extreme toxicity DPD deficiency??

Methotrexate

Anti-metabolites (methotrexate)

FF (glu)n

(glu)n

(glu)n

(G lu) (glu)n(glu)nF H 2 F H 4

F H 4

DTMP DUMPThym idyla tesynthase

D ihydro fo la tereduc tase

D ihydro fo la tereduc taseMethotrexate

Methotrexate

O ne-ca rbon U n it

C ellB lood

Polyglutam ates are retained in the cell

DTMP=Deoxythymidylic Acid

DUM P=Deoxyuridylic Acid

Cancer cells have higher rates of g lutamation enzym es levels

ResistanceDecreased transport into cellsDecreased affinity of DHF reductaseIncrease levels of DHF reductase

Administered orally or i.v.Non-Hodgkin’s lymphomaBurkitt’s lymphomaChildhood acute lymphoblastic leukemia

Indications

• Breast

• Head and neck

• Osteosarcoma

• High dose MTX 1-12 grams/m2

Leucovorin rescues the toxic effects of MTX and also may impair antitumor effect.

Contraindications

• Abnormal renal function• Third space fluid (ascites, effusions)- MTX

half life is prolonged.

• How is MTX given:• Hydrate the patient• Bicarbonate for a PH >7• Monitor MTX levels (<50nM)

Toxicity

• Myelosupression DLT

• Mucositis DLT (3-7d after MTX therapy)

• Nephrotoxicity (intratubular precepitation of MTX+direct tubular effect)

• Transient elevation of LFTs with HD MTX (12-24h)

• Pneumonitis

• Radiation recall skin reaction

Combination therapy

Knowledge of the pharmacokinetics of each cytotoxic agent is less important than knowing the maximal dose and the duration of that drug can be administrated before adverse side effects become unacceptable

Individual drugs must be active against the tumour

Drugs must have different modes of action• Minimize drug resistance• Hit cancer cells in different parts of cell cycle

Drugs must have limited overlapping toxicity

Individuals should be optimally scheduled

EtoposideBleomycin

CisplatinCurative therapy testicular cancer (BEP)

Renal & hepatic FunctionBone Marrow reserveImmune statusPrevious Treatments

Likely natural History of TumorPatients Wishes to undergo treatmentPatients Physical & emotional ToleranceLong term gains & Risks

כמו לפני בודקים ?'מה

•. כמותרפי טיפול כל לפני דם ספירת בודקיםתסיות <• 100000דרישות8.5המוגלובין <•לבנה • PMN > 1500ספירה

, פינוי קראטינין בודקים מהטיפולים חלקקראטינין.

. לב אקו

Secondary Leukemias

• Leukemias secondary to chemotherapy agents have poor prognosis.

• Secondary to alkylating agents– Most often occur after 5 – 7 years

– Often have MDS preceding leukemia

– Frequently FAB class M1 or M2

– Alterations of chromosomes 5 and/or 7 in 60% – 90% cases

• Secondary to topo II inhibitors:– Diagnosed 2 -3 yrs after tx

– Most often FAB class M4 or M5

– Frequent translocation of chromosome 11 (11q23) t(11;19)(q23;p13)

Chemotherapy Toxicity

• Neurologic– CNS: cytarabine, methotrexate, ifosfamide

– Peripheral: paclitaxel, oxaliplatin, vincristine

• Gastrointestinal– Nausea and vomiting: cisplatin, doxorubicin, cyclophosphamide

– Mucositis: methotrexate, melphalan, etoposide, 5-FU

• Pulmonary– Methotrexate, bleomycin

• Cardiovascular– Anthracyclines

Chemotherapy Toxicity

• Hepatic– busulfan

• Metabolic– Ifosfamide, cisplatin

• Renal– Hemorrhagic cystitis: cyclophosphamide, ifosfamide

– Renal failure: cisplatin

• Dermatologic– Hand-foot syndrome: 5-FU, capecitabine, cytarabine

• Immune System– Immunosuppression: fludarabine, cyclophosphamide, steroids

– Hypersensitivity: paclitaxel, asparaginase, bleomycin

Miscellaneous Toxicity

• Etoposide– Hypotension, flushing (infusion-related)

• Irinotecan– Acute and delayed diarrhea (SN-38 metabolite)