Principles of chemotherapy. Ann De Becker Klinische Hematologie UZ Brussel

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1 Principles of chemotherapy Ann De Becker Klinische Hematologie UZ Brussel

2 History Paul Ehrlich ( ) 1909 Arsphenamine for syphilis treatment Definition: Use of any drug to cure any disease Antineoplastic/cytotoxic treatment Origin in warfare Mustard gas in WW II: pancytopenia First trial reported in sept 1946: Nitrogen mustard therapy for Hodgkin s disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders Goodman & Gilman

3 Chemotherapy: goal Attacks tumour at cellular level Interference with cellular replication impact on one/several phases of cell cycle Chemotherapy use: Cure Palliate Adjuvant Neo-adjuvant

4 The cell cycle 5 phases: G0: resting phase (hours-days) G1: preparation for DNA synthesis (18-30h) S: generation of complete copy of genetic material (18-20h) G2: cell prepares for mitosis (2-10h) M: mitosis, cell splits in 2 (30-60 min)

$The cell cycle Growth fraction: # proliferating cells # G0$

5 The cell cycle Growth fraction: # proliferating cells # G0 cells Higher growth fraction = higher chemosensitivity

6 Cancer cell kinetics Log Kill Howard E Skipper: tumour models mouse L1210 leukemia model Skipper-Schabel-Wilcox model: a given dose of a given drug will kill the same percentage not the same number of cancer cells = Log Kill Model Log Kill Model assumes exponential growth of tumour e.g. leukemia

7 Log Kill Model

8 Cancer cell kinetics: other models Exponential cancer cell growth: Delbrück-Luria Bacterial growth/resistance Resistent clone within tumor Combination chemotherapy Goldie Coldman Multiple drug resistance within tumour Sequential administration of different chemotherapeutic drugs

9 Cancer cell kinetics: other models Gompertzian model: Tumour growth pattern not explained by dormancy+exponential cell growth Solid tumours Doubling time increases with tumour growth Homeostatic model: target size, when reached slower growth en less chemosensitive, when small rapid growth to reach target size and more chemosensitive

10 Drug development Screening / selection of molecules, substances candidate for drug development Preclinical development ( 5y) Clinical development ( 5y) Phase I: dose finding, pharmacokinetics, effect on biological target, antitumour activity Phase II: antitumour activity, effect on biological target, dose-response, toxicity Phase III: therapeutic benefit, risk/benefit ratio

11 Chemotherapy classes Alkylating agents: Direct DNA damage, non phase specific Nitrogen mustards: chlorambucil, cyclofosfamide, ifosfamide, melphalan Nitrosureas: carmustine (BCNU) Alkyl sulfonates: busulphan Triazines: dacarbazine Ethylenimines: thiotepa

12 Chemotherapy classes Antimetabolites: Substitute for normal building block S-phase cladribine cytarabine fludarabine gemcitabine hydroxyurea 5-FU 6-MP metotrexate (antifolate)

13 Chemotherapy classes Antitumoral antibiotics: Anthracyclines: topo II inhibitor, DNA intercalation Non phase specific daunorubicin, doxorubicin, epirubicin, idarubicin Other: bleomycin mitoxantrone

14 Chemotherapy classes Topoisomerase inhibitors: Topoisomerase I inhibitors: topotecan, irinotecan Topoisomerase II inhibitors: etoposide (VP16), teniposide Platinum derivatives: cisplatinum carboplatinum oxaliplatinum

15 Chemotherapy classes Mitotic inhibitors Metaphase arrest, chromosomal damage, microtubule disruption Taxanes: paclitaxel, docetaxel Vinca alkaloids: vinblastine, vincristine, vinorelbine Miscellaneous: L-asparaginase

16 Chemotherapy and cell cycle

17 Chemotherapy: administration Intravenous Per os Intrathecal Lumbar puncture Ommaya reservoir Intra-arterial Intraperitoneal Topical Subcutaneaous Intramuscular

18 Chemotherapy dosage Weight Body surface area (BSA)

19 Chemotherapy: general principles Remission-induction Consolidation Combination chemotherapy Different mode of action Different toxicity profile Different resistance mechanisms Maximize chance of lasting remission/cure

20 Chemotherapy: common toxicities Nausea, vomiting Infertility Myelosuppression Mucositis, diarrhea Alopecia Secondary tumours/leukemias Alkylating agents After 5-7 years, preceding MDS Topoisomerase II inhibitors After 2-3 years

21 Cytarabine Purine analogue cell cycle phase specific IV or IT administration Corner stone of AML treatment Activity in other hemato malignancies Penetration in CSF after IV infusion CSF levels 40-50% of plasma level High dose (2-3g/m²) can overcome cellular resistance by altering transport of drug into the cell

22 Cytarabine: toxicity Myelosuppression Stomatitis Conjunctivitis Hand-foot syndrome CNS: Cerebellar syndrome Onset 3-8 days after initiation of high dose Dysarthria, dysdiadochokinesia, dysmetria, ataxia

23 Cyclophosphamide Alkylating agent Formation of mustards following metabolic activation Cross linking of DNA strands (non Hodgkin s) Lymphoma High dose: Stem cell mobilisation Conditioning HCT IV/PO administration

24 Cyclophosphamide: toxicity Myelosuppression Hemorrhagic cystitis acrolein metabolite, onset 24h to several weeks high dose hydration! Mesna bladder irrigation Alopecia SIADH Cardiotoxicity (high dose)

25 Metotrexate Antifolate Cell cycle specific (S phase) IV or IT (12-15mg) or PO administration High dose IV penetrates in CSF CNS prophylaxis Lymphoma/leukemia Folinic acid rescue when high dose MTX Start 24h after MTX administration Until MTX levels < 0,05 µm/l IV dose = PO dose

26 Metotrexate: toxicity Myelosuppression Mucositis Renal cytotoxicity tubular cells alkalinize urine (ph>7) hydration! Hepatic Neurotoxicity (IT) arachnoiditis, paralysis, seizures, coma Pulmonary (rare) fever, dry cough, chest pain R/corticosteroids

27 Cisplatinum Platinum derivative/alkylating agent Cross linking DNA IV administration Lymphoma (DHAP) Toxicity: Myelosuppression Ototoxicity High frequency hearing loss Usually irreversible

28 Cisplatinum: toxicity Neurologic Peripheral neuropathy, autonomic neuropathy Incomplete recovery Renal Usually reversible Preventive measures: Infuse over 24h Hydration (NaCl 0,9%)! Follow urine output (furosemide) Avoid other nephrotoxic drugs

29 Specific toxicities Anthracyclines: Cardiotoxicity Bleomycin: Hypersensitivity Pulmonary toxicity Vinca alkaloids: Peripheral neuropathy Busulphan Hepatic (VOD) L asparaginase: Coagulation Hypersensitivity Pancreatitis

30 Response assessment Hematology Disease specific Laboratory evaluation (blood, marrow) Molecular analysis, cytogenetics Imaging: (PET-)CT / MRI

31 Response assessment Oncology Disease specific Integration of PET-CT

32 Chemotherapy resistance Response to initial treatment? Primary chemoresistance Acquired chemoresistance Multidrug resistance (MDR) Origin of resistant cells: Cancer stem cells Diverge from normal tissue stem cells Natural quiescent state Environment mediated drug resistance Acquisition of quiescence Genetic changes => permanent resistance Alter tumour microenvironment

33 Chemotherapy resistance mechanisms

34 Overcoming chemotherapy resistance Different class agent High dose therapy Combination chemotherapy MDR: P-glycoprotein overexpression Efflux pump (anthracyclines, taxanes, vincaalkaloids) Verapamil/CSA & other => no benefit in trials Nanomedicine: liposomes/nanoparticles New generation drugs evading P-gp mirna

35 Future perspectives: targeted therapy Tyrosine kinase inhibitors Bcr-abl: imatinib, dasatinib, nilotinib, bosutinib Flt3 inhibitors Bruton kinase inhibitors ibrutinib Monoclonal antibodies CD20 rituximab, ofatumumab, ibritumomab (+Yttrium 90) CD30 CD133 CD19 CD38 CS1 brentuximab (+vedotin) gemtuzumab (+ozogamycin) blinatumomab daratumumab elotuzumab

36 Future perspectives: targeted therapy IMiDs thalidomide, lenalidomide, pomalidomide Proteasome inhibitors bortezomib, carfilzomib Epigenetic modulators 5-azacytidine, deoxycytidine Panobinostat, vorinostat Vaccination: DC vaccination

37 Future perspectives: personalized therapy?

through the cell cycle. However, how we administer drugs also depends on the combinations that we give and the doses that we give.

through the cell cycle. However, how we administer drugs also depends on the combinations that we give and the doses that we give. Hello and welcome to this lecture. My name is Hillary Prescott. I am a Clinical Pharmacy Specialist at The University of Texas MD Anderson Cancer Center. My colleague, Jeff Bryan and I have prepared this