Principles of Chemotherapy and Chemotherapy Complications

1. Principles of Chemotherapy and Chemotherapy Complications Özlem Sönmez, MD Yeditepe University Hospital Section of Medical Oncology

2. Malignant cells

3. Malignant Transformation • Fundamental lesion: • Changes in DNA-> Alterations in proteins-> Cellular transformation • >1 genetic defect: almost certainly required • Accumulation of changesMalignant transformation

4. Malignant transformation 50.2 Rang

5. Biological basis of cancer chemotherapeutics • Anticancer drugs interfere cellular processes that are altered in malignancy. • Antineoplastic effects • Cell death • Cell growth inhibited • Cell differentiation

6. Cancer treatment usually involves one or more of surgery, radiotherapy and systemic therapy. • In early-stage disease, low-risk patients are often cured with surgery alone, but in many other cases a combination of treatments is required.

7. In metastatic disease, systemic therapy is the principal therapeutic modality, as delivery through the blood stream facilitates access to disseminated cancer sites. • Systemic therapies include hormonal therapy, targeted therapy, and chemotherapy.

8. Population kinetics • Tumor size: Size of proliferating pool of cells + # of cells dying spontaneously, • Growth rate (doubling time): rapid during early and exponential stages of growth • Growth fraction: The ratio of proliferating cells to cells in G0 • High % of proliferating cells & few cells in G0 high growth fraction • Mostly of cells in G0->Low groth fraction • When tm is small-> growth fraction is high • When tm gets larger ->growth fraction is low (restriction of space, nutrients, blood supply) • Larger the tumor mass, greater the % of nondividing, dying cells and longer it takes for average cell to divide (prolonged doubling time). • Tumors with greater growth fraction, benefit more from chemotherapy

9. Chemotherapy response • Solid tumors • Generally have a low growth fraction thus respond poorly to chemotherapy • In most cases need to be removed by surgery • Hematological tumors • Generally have a high growth fraction & generally respond well to chemotherapy

10. Population kinetics • 1x109 cells = 1 gr (1 cm) • 1 cell to 109 cells: 30 doubling times • Doubling time: 24 hours to years • 1012-1013 cells: Damage to vital organs, death

11. Gompertzian Growth

12. Chemotherapy kineticsLog kill hypothesis • Chemotherapy: kills fixed proportion of cells, not fixed number of cells. This is independent of tumor mass (2-5 log) • Repeated cycles of chemotherapy are neeeded for tumor eradication. • Dose administered within a certain period (mg/m2/week) determines success (not total dose).

13. Targets of Anticancer Drugs

14. Targets of Anticancer Drugs • All drugs have a target. • Traditional drug targets • DNA • Nucleotide bases • Enzymes of DNA synthesis • Degradation • Repair • Microtubules • GF receptors • Steroid hormone receptors

15. New targets • GFs (VEGF) • Mutated or overexpressed oncogene products • EGFR • Her-2/neu (c-erb-B2) • Bcr:abl • cKit • bRaf • Cell surface antigens • CD33, CD22, CD20, CD30, IL2-R • The machinery of protein synthesis (L-asparaginase) • Protein degradation (ubiquitin proteasomal degradation)

16. Targets • Drugs that affect these newer targets: “Targetted therapy” • Classic chemotherapeutics : Also have targets

17. Targets in Cancer Treatment

18. Classic chemotherapeutics

19. Drugs that alter nucleic acid synthesis and function • DNA synthesis • DNA replication • Transcription Inhibitors • DNA methylation • Topoisomerases • Microtubules • Protein Synthesis • Protein degradation

20. Classification of classic cytotoxic agents

21. Alkylating agents • Triazenes • Dacarbazine (DTIC) • Temozolamide • Hydrazines • Procarbazine • Platinum • Cisplatin • Carboplatin • Oxaliplatin • Nitrogen mustards • Mechloroethamine • Cyclophosphamide • Ifosfamide • Chlorambucil • Melphalan • Alkylsulfonates • Busulfan • Nitrosoureas • Carmustine (BCNU) • Lomustine (CCNU) • Streptozocin • Semustine

22. Alkylating agentsMechanism of action • Transfer alkyl groups to DNA • Alkylates nucleophilic groups on DNA bases, particularly at the N-7 position of guanine

23. Consequences of alkylation • Cross-linkage: Interstand and intrastrand cross-linkages • Mispairing of bases: Alkylation of N7 of guanine base pairing with thymidine, instead of cytosine  Gene miscoding AT base pairs replacing GC base pairs Defective proteins • DNA strand breaks N7 alkylation –> Cleavage of imidazole ring excision of guanine residue Inhibition of DNA replication and transcription

24. Cyclophosphamide Toxic to bladder Antitumor activity

25. Ifosfamide • Analogue of cyclophosphamide • Metabolic activation to forn 4-hydroxyifosfamide • More toxic to bladder Hemorrhagic cystitis

26. Side effectsIfosfamide-Cyclophosphamide • Side effect: • Hemorrhagic cystitis • Prevention: • Hydration • Mesna  Detoxification

27. Side effectsPlatinums (cisplatin, carboplatin, oxaliplatin) Cisplatin • Renal insufficiency • Prevention • Hydration: If adequate->5%, if inadequate-> 25-45% • Forced diuresis: Mannitol • Avoid nephrotoxic agents • Ototoxicity: Tinnitus, hearing loss • Constipation • Periferal sensorial neuropathy • Severe nausea and vomiting

28. Side effectsPlatinums (cisplatin, carboplatin, oxaliplatin) Oxaliplatin • Acute dysesthesia (hands, foot, peroral, throat) • During administration –upto 2 days • Can be induced or augmented by cold • Resolves in 2 weeks • Prevention: Prolong administration period (6 hours) • Periferal sensorial neuropathy • Cumulative toxicity • Usually reversible (within 1 year)

29. Nitrosoureas • Carmustine (BCNU) • Lomustine (CCNU) • Highly lipid soluble Cross BBB

30. Antimetabolites Purine (A, G) Analogs Pyrimidine (C, T,U) Analogs Folic Acid Analogs Methotrexate Mercaptoguanine Fluorouracil Thioguanine Fludarabine Cladribine Pentostatin Trimetrexate Pemetrexed Cytarabine Gemcitabine Capecitabine

31. Antimetabolites • They are structurally similar to endogenous compounds • Compete with natural metabolites blocking one or more of the metabolic pathways involved in DNA synthesis. • Mostly active in S phase • They act as antagonists of: • Folic acid (methotrexate) • Purines (Mercaptopurine and thioguanine) • Pyrimidine (fluorouracil, cytarabine)

32. Purines and pyrimidines Purines Pyrimidines C, T: DNA C, U: RNA

33. Antimetabolites: sites of drug action

34. Methotrexate (MTX) • Folic acid analog • Binds with high affinity to the active catalytic site of dihydrofolate reductase (DHFR) • Thus it interferes with the synthesis of tetrahydrofolate (THF) • THF serves as the key one-carbon carrier for enzymatic processes involved in de novo synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine. • Result:Interferes with the formation of DNA, RNA, and key cellular proteins

35. Methotrexate side effects • Bone marrow suppression • Mucositis • Folic acid deficiency • The toxic effects of MTX on normal cells is reduced by administering folinic acid (leucovorin) • This is called leucovorin rescue • Higher the dose of MTX: more the leucovorin you give

36. Side effects: Methotrexate • Side effects: • Mucositis • Folic acid deficiency • Prevention: • Hydration • Alkalinization of urine • Leukovorin rescue: 24 hours after treatment (calcium folinate)

37. Inhibit several enzymes involved in purine metabolism 6-Mercaptopurine (6-MP) & Thioguanine

38. 6-MP & Allopurinol • 6-MP: metabolized in the liver by xanthine oxidase and the inactive metabolites are excreted in the urine • Allopurinol (Ürikoliz) • Xanthine oxidase inhibitor • used to treat/prevent hyperuricemia • Do not use 6-MP and allopurinol in combination. • If Allopurinol have to be used with 6-MP, then the dose of 6-MP is reduced by more than 75%

39. Cytarabine (Ara-C) • Cytarabine arabinoside is a pyrimidine antimetabolite • Inhibits conversion of cytidine to deoxycytidine • The drug is activated by kinases to AraCTP • This acts as an inhibitor of DNA polymerase • Side effect: At high doses cause neurotoxicity (cerebellar dysfunction and peripheral neuritis) • Hand-foot syndrome

40. 5-FU is converted to 5-FdUMP, which competes with deoxyuridine monophosphate (dUMP) for the enzyme thymidylate synthetase 5-FU causes, “thymidineless death” of cells Imbalance DNA and RNA synthesis Side effects:Mucositis, diarrhea, hand and foot syndrome, hyperpigmentation Activity increased if given with folinic acid. 5-FU = 5-fluorouracil 5-FUR = 5-fluorouridine 5-FUMP = 5-fluorouridine monophosphate 5-FUDP = 5-fluorouridine diphosphate 5-FUTP = 5-fluorouridine triphosphate dUMP = deoxyuridine monophosphate dTMP = deoxythymidine monophosphate 5-FdUMP = 5-fluorodeoxyuridine monophosphate. 5-FU

41. Topoisomerase inhibitors • These drugs are most active in late S and early G2 phase • Epipodophyllotoxins: Inhibittopoisomerase II • Etoposide • Teniposide • Camptothecins: Inhibittopoisomerase I • Irinotecan • Topotecan

42. Topoisomerase inhibitors

43. Irinotekan (Campto) • Diarrhea :2 mechanisms • Early (first 24 hour) • Cause: Cholinergic response (concomitant symptoms: tearing, abdominal crampsterleme) • Treatment/prevention: Atropine • Late (>24 hour): life-threatening • Cause: Secretory, toxic effect to mucosa • Treatment: High dose loperamide

44. Mitotic spindle inhibitors • Primarily on the M phase of cancer cell cycle • Vinca alkaloids • Vinblastine • Vincristine • Vinorelbine • Taxanes • Paclitaxel • Docetaxel

45. Block the formation of mitotic spindle by preventing the assembly of tubulin dimers into microtubules Side effects Severe neurotoxicity Paresthesias (Periferal sensorial neuropathy) Loss of reflexes Foot drop Ataxia Cortical blindness Vinka alkaloids (Vinblastine, vincristine)

46. Prevent microtubule disassemblyinto tubulin monomers Side effects Peripheral neuropathy Allergic reactions Paclitaxel & Docetaxel

47. Anticancer Antibiotics • Anthracyclines • Doxorubicin (Adriamycin) • Daunorubicin • Idarubicin • Epirubicin • Bleomycin • Dactinomycin • Mitomycin-C

48. Intercalate between base pairs, inhibit topoisomerase II and also generate free radicals (damage DNA) Block RNA and DNA synthesis and cause strand scission Antracyclines

49. Antracyclines-Side effects • Cardiac toxicity • due to generation of free radicals • Acute form: arrthythmias, ECG changes, pericarditis, myocarditis • Chronic form: ***Dilated cardiomyopathy, heart failure • Prevention: Dexrazoxane • This is an inhibitor of iron mediated free radical generation • Adriamycin:If dose>300 mg/m2 • Radiation recall reaction

50. Maximum total dose during lifetime • Adriamycin (Doxorubisin) 450 mg/m2 • Epirubicine 900 mg/ m2 • Mitoxantrone 160 mg/m2 • Bleomycin 200 mg/m2