Principles of cancer chemotherapy.pptx

For surgical residents presentation

1. Principles of cancer chemotherapy By Dr O lofin

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 : A group 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 cancer chemotherapy 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 cell cycle G ₀ 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. 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 ( synthetic phase) – 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: – Drugs works 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 cycle time/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 – The phases 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 • Toxic to 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 kill cells 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 mechanism of 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 ACTION SIDE 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 ACTION OF CYTOTOXICS

17. IMMUNO-THERAPUETIC AGENTS MECHANISM OF 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 Use with 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 Pre-chemotherapy assessment Counselling Optimization Modalities Administration 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: • An attempt 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: fully active, 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/ C r » Stool microscopy- Strogiloides Stercoralis – Others; depend on the type of cancer e.g tumour markers

25. 2. Counselling • Adequate counseling – 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 aim of the therapy most clearly be stated to patient and relative – Curative – Palliative • Modalities of treatment • Informed consent obtained

27. 3. Modalities • Modality is 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 • Choice of agents – Type of cancer – The stage – Age – Clinical state of patient – Co-morbidities – Treatment in the past – Drug interactions

30. • The ORDER is 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 of administration – 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 – Single agent 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 Superior to 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 vital signs 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 agent are 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 of side 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 – Flare reaction/ 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 ulcerate s. • 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 in the 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 anticancer regimen • 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 • Tumour vaccine- 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 chemotherapy is 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 Badoe et 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. Thank you