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Principles of cancer chemotherapy(1).pptx
- 1. Principles of cancerchemotherapy By Dr Olofin
- 2. Outline • Introduction – Definitions –Goals • The cell cycle • Classification of chemotherapeutic agents • Principles – Pre-chemotherapy assessment – Counselling – Optimization – Modalities – Administration – Management of side effect and follow up • Commonly used anticancer regimen • Chemoresistance • Future trends • Conclusion
- 3. Introduction Definitions – Cancer: Agroup of disease involving abnormal cell growth with the potential to invade or spread to other part of the body. – Chemotherapy: the term chemotherapy is describe as the use of chemicals or drugs to treat cancer. – Cytotoxic drug: lysis both normal and cancer cells
- 4. Goals of cancerchemotherapy • Curative: eradication » induction: Given with the intent of inducing complete remission (eliminate clinical evidence) when initiating a curative regimen » Consolidation: Repetition of the induction regimen in a patient who has achieved a complete remission. » Maintenance : Long-term, low-dose, single or combination chemotherapy in a patient who has achieved a complete remission. To prevent recurrence. • Palliative: » Provide comfort » Improve/prolong quality of life
- 5. The cell cycle •Understanding the cell cycle is necessary in cancer chemotherapy • It is a series of events that takes place in a proliferating cell (normal and malignant ) leading to its division and duplication • 5- phases
- 6. Phases of cellcycle 1. G₀ Phase (resting phase) • The cell has not started dividing. • They spend much of their lives in this phase. • When the cell get a signal to reproduce, they move into the G₁ Phase. • Limitation to successful eradication of many tumours by chemotherapy. 2. G₁ PHASE (Pre-synthetic phase) – The cell starts to produce proteins and enzymes necessary for DNA synthesis. – During this phase, RNA synthesis occurs. – This phase last about 18 to 30 hours.
- 7. 3. S-Phase (syntheticphase) – DNA synthesis – Cellular DNA is duplicated in preparation in preparation for cellular division. – Length of time S phase is approximately 18-30hrs. – A weak link, and large number of anticancer agent act. 4. G₂ Phase (pre-mitotic phase) – the cell checks the DNA – Gets ready to start splitting into 2 cells. – Here both protein, RNA, and the precursors to the mitotic spindle apparatus are produced. – This phase is very short 1-2hrs. 5. Mitotic phase – In this phase, which last only 30-60min, the cell actually split into 2 new cells.
- 8. • Significance: – Drugsworks mainly on cells that are active (not in the Go) – Some drugs specifically attack cells in a particular phase – Determine drug combination – How often drug is given base on timing. • Cell cycle time • Growth fraction • Tumour burden
- 9. • Cell cycletime/generation – The amount of time required for cell to move from one mitosis to another.(time to complete one cycle) – Shorter time results in higher kill when exposed to specific agents. • Growth fraction – The percentage of cells actively dividing at a given point in time. High growth fraction results in higher cell kill with exposure to specific agent. • Tumour burden – The size of the tumour as determine by the number of cells present. – The cancer with a small tumour burden are usually more responsive to therapy. – The higher tumour burden the greater the greater the probability of development of resistance.
- 10. Regulation/ check points •To repair DNA damage , • Regulation is lost in cancer cells. – INHIBITORS: • Cyclin dependent kinase inhibitors lead generation of P53, Rb which inhibits at G₁/S(restriction point), G₂/M and M phase. – PROMOTERS: • Cyclin dependent kinase + proteins → E2F, cyclin D1, A and B drives the cycle at S and G2 phase
- 11. Classification Base on – Thephases of cell cycle (Bruce and colleagues 1966) • Non-phase dependent • Phase dependent – Mechanism of action/biochemical activity • Cytotoxic • Immunotherapeutic agents • Targeted therapy • Steroids and Non-steroidal Hormones
- 12. Non-phase dependent • Toxicto both cycling cells and those in Go phase. • They kill cells by direct DNA damage • Kills exponentially with increasing dose. – Alkylating agents; E.g nitrogen mustard (cyclophosphamide, Procarbazine, Dacarbazine), Nitrosoureas ( Streptozocin), platinum (Cisplatin, carboplatin)
- 13. Phase-dependent • They killcells only in specific parts of cell cycle. – Mitotic phase: Vinca alkaloid ( vincristin, vinblastine) Taxanes (Pacletaxel, Doxetaxel) – S-Phase: Antimetabolites (hydroxyurea, methotraxate, Ara-C, 5-FU, 6-MP, 6- TG), Antibiotics (Actinomycin D, Doxorubicine, epirubicin – G1- Phase: Corticosteroid, Anti-tumour antibiotics – G2-Phase: Anti-tumour antibiotics
- 14. Base on mechanismof action/biochemical activity – Cytotoxic agents – Alkylating agent – Antimetabolite – Vinca alkaloids – Antimitotic antibiotic – Taxanes – Miscellaneous compounds • Antiproliferative enzymes; L-asperaginase • Cisplatine • Nitrosourea
- 15. CHEMOTHERAPUETIC AGENT MECHANISM OF ACTIONSIDE EFFECT ALKYLATING AGENT Cyclophosphamide, chlorambucil, thiothepa, melphalan etc Interferes with cross linkage of DNA Myelosupression, Hemorrhagic cystitis Skin rash, Flu-like syndrome ANTIMETABOLITES • Folic acid antagonist e.g methotraxate • Purine antagonist e.g 6- mercaptopurine, • Pyrimidine antagonist e.g 5-fluorouracil Interfere with nucleic acid synthesis because they are analogues of normal metabolites Mucositis, Nephropathy, Hepato-toxicity & Hand & foot syndrome VINCA ALKALOID- vincristin, vimblastin Cause mitotic arrest via spindle fiber inhibition Neuropathy, constipation, Mucositis & myelosuppresion ANTITUMOUR ANTIBIOTIC e.g adramycin, daunorubicin, actinomycin D, bleomycin Bind to DNA to block RNA production cardio toxicity, pulmonary toxicity & myelosuppresion TAXANES e.g paclitaxel, docetaxel Bind to tubulin. Stop disassembly of mitotic spindle neuropathy skin rash & myelosuppresion MISCELLANEOUS L-Asparaginase, Nitrosourea Cis- platinium
- 16. MECHANISM OF ACTIONOF CYTOTOXICS
- 17. IMMUNO-THERAPUETIC AGENTS MECHANISMOF ACTION CLINICAL USE Levamisole (antihelmenthic) immunomodulator Adjuvant in colonic cancer in combination with 5-FU Interleukin-2(IL-2) Enhances NK-cells and tumour specific T-cells MelanomaRenal cell ca Neuroblastoma NHL Interferon Enhance NK-cells Re-expression of HLA gene Kaposi’s sarcoma Multiple myeloma Leukemia BCG Stimulate immune response CIS of the bladder TARGET THERAPY MECHANISM OF ACTION CILNICAL USES SMALL MOLECULES Gefitinib, Erlotinib Inhibits EGFR tyrosine kinase thereby inhibiting growth of cancer cells Non-small cell cancer of the lungs MONOCLONAL ANTIBODIES Trastuzumab(Herceptin), Rituximab(mabthera), Bevacizumab, cetuximab Selectively kill tumour cells expressing certain receptors Trastuzumab is use Her-2 positive breast cancer
- 18. HORMONE CLINCAL USES ANTI-ANDROGENS Flutamide oestrogen Usewith gosereline in the treatment of metastatic prostate cancer ANTI-ESTROGEN Tamoxifen Pure anti-oestrogen (fasodex Breast cancer SELECTIVE AROMATASE INHIBITORS Anastrozole 2nd line in ER/PR +ve breast ca AMINOGLUTETHIMIDE Breast and adrenal ca PROGETINS Medroxyprogesterone acetate Breast and endometrial LHRH analogue Goserelin Prostate and breast ca CORTICOSTEROIDS Dexamethasone prenisolone Breast ca as acombination, treatment of hypercalcemia, raise ICP from brain metastesis
- 19. Principles 1. Pre-chemotherapy assessment 2.Counselling 3. Optimization 4. Modalities 5. Administration 6. Management of side effect and follow up
- 20. 1. Pre-chemotherapy assessment •Aim – Establish diagnosis – Fitness of patient • Methods – Clinical evaluation – Laboratory investigations • Clinical evaluation – History • Detail history • Systemic involvement • Co-morbidities • Performance status
- 21. Performance status: • Anattempt to quantify the general well being and daily activity of a cancer patient. – whether they can receive chemotherapy – whether dose adjustment is necessary – a measure for the required intensity of palliative care. – measure of quality of life – Utilizes two main scales: Karnofsky score and Eastern Cooperative Oncology Group (ECOG) system
- 22. ECOG KARNOFSKY 0: fullyactive, able to carry on all predisease performance without restriction. 100% - Normal; no complaints; no evidence of disease. 90% - Able to carry on normal activity; minor signs or symptoms of disease 1 – Symptomatic but completely ambulatory (Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. For example, light housework, office work) 80 %- Normal activity with effort; some signs or symptoms of disease. 70% - Cares for self; unable to carry on normal activity or to do active work 2 – Symptomatic, <50% in bed during the day Ambulatory and capable of all self care but unable to carry out any work activities. Up and about more than 50% of waking 60% - Requires occasional assistance, but is able to care for most of his personal needs. 50 %- Requires considerable assistance and frequent medical care. 3 – Symptomatic, >50% in bed, but not bedbound (Capable of only limited self-care, confined to bed or chair 50% or more of waking hours) 40% - Disabled; requires special care and assistance. 30% - Severely disabled; hospital admission is indicated although death not imminent. 4 – Bedbound (Completely disabled. Cannot carry on any self- care. Totally confined to bed or chair) 20% - Very sick; hospital admission necessary; active supportive treatment necessary. 10% - Moribund; fatal processes progressing rapidly. 5 – Death 0 - Dead
- 23. • Physical examination –The extent of primary and metastatic disease via the general and thorough systemic examination – Body surface area •√ 𝑤𝑒𝑖𝑔ℎ𝑡(𝑘𝑔) ×ℎ𝑒𝑖𝑔ℎ𝑡 (𝑐𝑚)/3600
- 24. • Laboratory test –Diagnostic: histology – Extent: » imaging ;CXRay, CT, MRI,PET,SPET » Uss » LFT – Baseline: » FBC • PCV- 30% • WBC<3 ×10⁹/L • PLT <75, 75-150, >150 ×10⁹/L » U/E/Cr » Stool microscopy- Strogiloides Stercoralis – Others; depend on the type of cancer e.g tumour markers
- 25. 2. Counselling • Adequatecounseling – Disease explained in simple terms that can be understood – Extent – Plan of treatment – Side effect expected – Fair idea of prognosis • Opportunity given to ask adequate questions and get accurate answers • A professional counsellor/ psychologist should be involved
- 26. • The aimof the therapy most clearly be stated to patient and relative – Curative – Palliative • Modalities of treatment • Informed consent obtained
- 27. 3. Modalities • Modalityis selected base on the type and stage of the cancer. • Neoadjuvant • Adjuvant • Multimodality – Surgery – Chemo-radiation
- 28. 4. Optimization – Anaemia –Dehydration – De-worming – Malnutrition – Control of infection – Dialysis -Uremia
- 29. 5. Administration • Choiceof agents – Type of cancer – The stage – Age – Clinical state of patient – Co-morbidities – Treatment in the past – Drug interactions
- 30. • The ORDERis written and signed – Name, diagnosis, drug combination, number of cycles and duration • DOSE – Calculate base on body surface area – Dose prescription • Standard dose: anticipate mild side effect, minimal supportive care • High dose: above standard, anticipated side effect, requires supportive care; blood transfusion • Ablative dose: ablation of tumour and stem cells, in conjunction with stem cell transplantation • Adjusted dose: reduced dose in renal impairment.
- 31. • Routes ofadministration – Oral – Intravenous • Bolus • Infusion – Arterial infusion – Extracorporeal limb perfusion – Intracavitory – Intrathecal – Subcutaneous – Intramuscular – Topical
- 32. • Pre-chemotherapy medications –IV fluids (allopurinol, alkylanizaton of urine) – prevent risk of tumour lysis syndrome. – Antiemetic: Ondansetron 0.15mg/kg given 30min before commencement. – Antidotes; leucovorin antidote for antifolate metothraxate. (Co-administered, after administration)
- 33. • MODES/METHODS – Singleagent continuous therapy • Little value in modern cancer management • Low response rates. • Complete remissions were infrequent. • Kill small fractions of tumour cell • Potentiates the development of drug resistance – Cyclical chemotherapy • Drugs is given in cyclical fashion • To prevent drug resistance • This gives normal cells time to recover from the drug’s side effects.
- 34. Combination chemotherapy • Superiorto single drug chemotherapy • Considerations: • Drug should be active as a single agent • Avoid drugs with similar toxicity • To reduce toxicity • Use drugs with different mech. of actions • Use maximum therapeutic doses
- 35. Monitoring – Premedication vitalsigns take, then regular monitoring – Mainly cardiovascular- cardiotoxicity • Tarchcardia • Arrhythmias • S3 gallop • Chest pain, tightness – acute coronary sydrome • Esp anthracyclins, trastuzumab, cyclophophamide, pacletaxel – Nausea, vomiting – Breathing pattern – Antidotes and emergency drugs
- 36. Safety – Chemotherapeutic agentare hazardous • Mutagenic • Teratogenic • Carcinogenic • Skin irritation – Gloved, goggle and gowns when administering. In a good ventilation to prevent inhalation of droplets when preparing. – Care in handling patient urine and feaces
- 37. 5. Management ofside effects: • Side effects results from; lyses of normal cells, depends on the type of drug, dose, route and individual response. • Rapidly dividing cells are more affected; blood cells, hair follicle, digestive tract and reproductive tracts.
- 38. • Local – Flarereaction/thrombophebitis • Irritation along the tracts. Triggering inflammation along the tract and surrounding skin. – Vesiculation • From extravasation into surrounding subcutaneous tissue leading to vesicles which subsequently ulcerates. • Chemical burns – Treatment ; (easily prevented- good vein, ensure no leakage before chemo, set fresh not pre-existing line, monitor line, start with vesicant.) • Stop immediately • Antihistamine • Hydrocortisone • Analgesics • Care of ulcer when developed
- 39. • Systemic – Haemopoietic;Myelosuppresion • Treat emergencies- aneamia, throbocytopenia, treat infection – Gastrointestinal; nausea, vomiting, anorexia, constipation, diarrhea • 5-HT antagonist- ondasetron – Hypergycalcaemia; • Bisphosphonate • Corticosteroid
- 40. •Urinary- hemorrhagic cystitis •Neurologic –peripheral neuropathy • Cardiovascular ; Cardiomyopathy • Respiratory ; pulmonary fibrosis • Reproductive; infertility, menorrhagia.
- 41. Follow-up • Complication – History –Physical examination – Laboratory investigation- repeat baseline and histology, tumour marker – Treat complication as they arise • Response • Resistance
- 42. Response WHO • Objective response– Change in longest diameter of the target lesion • Complete: Disappearance of all known disease, confirmed at ≥ 4 weeks. • Partial: ≥ 50% decrease from baseline, confirmed at ≥ 4weeks • Progressive: ≥ 25% increase in one or more lesions or appearance of new lesions • Stable: no change
- 43. Chemo-resistance • Reduction inthe effectiveness or failure of response could be primary or secondary • Depend on grade of tumour, type of drug and dose use. • Mechanisms – Overexpression of Adenosine triphosphate binding cassette – Inactivation of apoptosis – Inactivation of nuclear factor- kB transcription factor – Cancer stem cell
- 44. Commonly used anticancerregimen • Breast cancer – CMF – CAF/VAC-P – Taxane based eg » paclitaxel and xeloda » Paclitaxel, cyclophosphamide and doxorubicine • Gastric – ECF • Wilm’s – Methotrexate or dactinomycin, douxorubicin and vincristin
- 45. Future trends • Tumourvaccine- stimulate the body to produce CD4 cells which suppresses tumour cells e.g sipuleucel-T, prostate G-vax still under investigations • Gene therapy
- 46. Conclusion • Cancer chemotherapyis an important component in cancer management singly or in multi-modal therapy. • They are toxic to normal tissues hence require knowledge of drugs, early recognition, and management of side effect. • Adequate counseling is required for compliance to treatment.
- 47. References • E.A Badoeet al, “Principles and Practice of surgery including pathology in the tropics” 4th edition, Assembly of God Literature Center ltd, 2009 • M.A.R Al-Fallouji; “Postgraduate Surgery the candidate guide”. 2nd Edition. Rced Educational and Professional Pub. Ltd 1998 • Sriram Bhat S “SRB manual of surgery” 4th edition Jaypee Brothers Medical Publishers (P) Ltd • Guidelines for the Safe Prescribing, Dispensing and Administration of Cancer Chemotherapy “Clinical Oncological society of Australia” Nov. 2008 • Joseph O. Jacobson et al,” American Society of Clinical Oncology/Oncology Nursing Society Chemotherapy Administration Safety Standards” journal of clinical oncology. volume 27 number 32 November 10 2009. • www.slideshare.net • www.wikepedia .org
- 48.
Editor's Notes
- #14 Cytosine Arabinose, 6- thioguanin
- #28 Ajuvant : use of chemotherapy following an initial intervention such as surgery. Aim is to sterilize or mop up any circulating cells Chemoradiation: Aim is to potentiate the cell killing by the radiation A radio sensitizing drug is used cisplatadiationin /5FU , started on the 1st day of radiation
- #32 Arrerlnl infi<sio,i Malignant melanoma recurrence: phenylalanine mustard. Hcad and neck lumours: through the external camtid artery with methotrexate followed hy antidote folinic acid for rapid neutralisition. Liver secondaries: through the hepatic artery doring laparotomy with 5-tluorouracil. Intrathecal Fur example, subarachnoid ~nsthotrcxate injection in acute lymphatic leukaemia