1. Daniela Katz M.D. Sharett Institute of Oncology Chemotherapy

2. Achilles heel

3. 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”

4. Objectives

5. Why is it difficult to develop an effective chemotherapy? Drug HostParasite No effectCytotoxic Bacteria, fungi, protozoa, helminths, viruses vs. cancer cell. Theory Paul Ehrlich 1854-1915 Nobel Laureate 1908

6. 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.

7. 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

8. 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. Alopecia 4. Sterility/Infertility (especially sterility in males) Common Toxicity Criteria Grading System (CTC) –Grade 0 – 4 COST

9. Gompertzian dynamics Growth fraction (percentage of cells actively dividing) Anti-cancer chemotherapy most effect against cells in cell fraction A. Cells in fraction B can re-enter fraction A.

10. The Cell Cycle G 1 phase: cell prepares for DNA synthesis S phase: cell generates complete copy of genetic material G 2 phase: cell prepares for mitosis M phase: replicated DNA is condensed and segregated into chromosomes G 0 phase: resting state

11. 3 x Problem associated with Anti-cancer chemotherapy Limit of diagnostic procedures. Exponential growth of a tumour

12. Chemotherapy is present in 3 settings: Neoadjuvant chemo Adjuvant chemo Chemo for active disease Goals of Cancer Chemotherapy Cure Prolong survival Palliation Radiosensitive

13. Summary anti-cancer chemotherapy's Cytotoxic drugs Alkylating agents Cyclophosphamide, Busulfan, Carmustin, Chloramabucil, Ifosfamide, lomustine, Melphan, Treosulfan Cisplatin, Carboplatin, Oxaliplatin Anti-metabolites Methotrexate, Fluoruracil, Cytarabine, Cladribine, Fludarabine phosphate, Gemcitabine, Mercaptopurine Cytotoxic Antibiotics Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitomycin Plant derivatives Etoposide, Vinblastine, Vincristine Hormone Tamoxifen, Anastrozole, Letrozole Miscellaneous Imatinib, Bortezomib, Bevacizumab, Trastuzumab, Taxol, Cristaspase, Arsenic

14. 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

15. Summary of cytotoxic drug action

16. Alkylating Agents Main effect is on DNA synthesis with most cytotoxicity to rapidly proliferating cells

17. Action of Alkylating drugs- DNA adducts, cell cycle non-specific Aldehyde dehydrogenase

18. In use in: Breast Sarcoma Ovarian Testis CLL Non-Hodgkin’s LY PO, IV

19. Cyclophosphamide and Toxicity Myelosuppression –principle dose-limiting toxicity –primarily leukopenia Syndrome of inappropriate antidiuretic hormone Alopecia Highly emetogenic if  1500 mg/m 2

20. 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;

21. 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

22. 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

23. The Platinums Intrastrend DNA adducts Mg/m2 AUC

24. Nucleotide excision repair pathway ERCC1

25. 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

26. 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

27. 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)

28. 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)

29. Cisplatin Toxicity Nausea and vomiting –acute or delayed –highly emetogenic if use doses  than 50 mg/m 2 –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

30. 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

31. 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

32. Clinical characteristics of oxaliplatin neurotoxicity Acute symptomsChronic 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/m 2 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

33. Comparison of Platinum Toxicity Table 5. Comparative adverse effect profiles of platinum drugs Adverse effectcisplatincarboplatinoxaliplatin Nephrotoxicity+++- Gastrointestinal toxicity +++ Peripheral neurotoxicity +++-++ Ototoxicity+-- Hematologic toxicity++++ Hypersensitivity-+-

34. Anthracyclines

35. Cytotoxic antibiotics Doxorubicin, Dactinomycin, Etoposide (VA) Administered i.v. Acute lymphocytic leukemia Acute granulocytic leukemia

36. Cardiotoxicity Red Devil aLOPECIA Nausea Myelosupression Mucositis

37. palmar-plantar erythrodysesthesia, or hand-foot syndrome

38. Chemotherapy- induced mucositis

39. Plant alkaloids (vincristine & vinblastine, Taxol) Resistance due to multidrug resistance, altered tublin molecules Administered I.v. Childhood leukemia's, Hodgkin's and non-Hodgkin's lymphoma, testicular, ovarian carcinomas and brain tumours Vincristine & vinblastine Resistance altered tublin molecules Administered i.v. Metastatic ovarian and breast cancer Taxol

40. Antimetabolites

41. 5-Fluorouracil Fluoropyrimidine analogue= 5-FU

42. Anti-metabolites (5-Fluorouracil) Resistance Decreased levels of thymidine phosphorylase or affinity for 5FU Administered parentally Breast, ovarian, prostate, pancreatic, hepatic carcinomas

43. Indications Breast Colorectal Head and Neck Hepatoma Leucovorin=Folinic Acid Stabilizes TS-FdUMP complex (GI tract)

44. Contraindications Myocardial infraction previous 6m

45. 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??

46. Methotrexate

47. Anti-metabolites (methotrexate) Resistance Decreased transport into cells Decreased affinity of DHF reductase Increase levels of DHF reductase Administered orally or i.v. Non-Hodgkin’s lymphoma Burkitt’s lymphoma Childhood acute lymphoblastic leukemia

48. 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.

49. 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)

50. 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

51. 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 Etoposide Bleomycin Cisplatin Curative therapy testicular cancer (BEP) Renal & hepatic Function Bone Marrow reserve Immune status Previous Treatments Likely natural History of Tumor Patients Wishes to undergo treatment Patients Physical & emotional Tolerance Long term gains & Risks

52. מה בודקים לפני כמו'? בודקים ספירת דם לפני כל טיפול כמותרפי. דרישות תסיות >100000 המוגלובין >8.5 ספירה לבנה PMN > 1500 חלק מהטיפולים בודקים קראטינין, פינוי קראטינין. אקו לב.

53. 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)

54. 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

55. 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

56. Miscellaneous Toxicity Etoposide –Hypotension, flushing (infusion-related) Irinotecan –Acute and delayed diarrhea (SN-38 metabolite)