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principles of chemotherapy


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principles of chemotherapy

  1. 1. • German chemist Paul Ehrlich- Coined the term ‘‘chemotherapy’’ • Originally chemotherapy referred to treatment of disease with drugs or chemical • but by mid 1950’s the term was only being used primarily in reference to drugs which were used to treat cancer.
  2. 2. • Diseases of cells that shows uncontrolled proliferation , anaplsia, invasivness and ability to metastasis . • Due to Chromosomal abnormality and expression of oncogens . • Second most common cause of death after cardiovascular disorders in world.
  3. 3. • Surgery • Radiotherapy • Chemotherapy, Immunotherapy, Gene therapy Choice of therapy depends upon the • Location of tumour • Stage of tumour • General state of the patient. • For solid cancers • 1/3 of patients can be cured, • Effective when tumor has not metastasized
  4. 4. • 1943 - During World War II , soldiers were exposed to nitrogen mustard gas and shows marked depletion in marrow and lymphoid cells. • Based on this finding, Alfred Gilman and Louis Goodman from Yale university used Nitrogen Mustard to induced remission of Lymphoma in mice.
  5. 5. 1948 - Sidney Farber showed that aminopterin, a folic acid analogue, developed by Y. Subbarao can induced remission in acute lymphoblastic leukemia. Latter more safer amethopterin ( Methotrexate ) was developed.
  6. 6. 1950- Actinomycin D was developed as antibiotics, but found to be very toxic but have significant antitumour activity 1951 - Hitchings and Elion isolated 6-thioquanine and 6- mercaptopurine that inhibited purine metabolism, which are widely used for various cancer and as immunosuppressant.
  7. 7. • 1970’s - “Golden Age” of medical oncology. Development of effective combination chemotherapy regimens. • New classes of drug developed - anthracyclines, platinum compounds . • Cures achieved in some forms of cancer (lymphomas, leukemias, testis cancer). • Significant responses in some common types of cancer (breast, stomach, small cell lung cancer) • Effective use of chemotherapy to prevent recurrence in high risk breast cancer patients.
  8. 8. • Scientist continue to look for “the magic bullet” to eliminate cancer. • Nowdays research is being focused on specific agents that interfere with cell division, as well as monoclonal antibodies, biologic modifiers, gene therapies, etc.
  9. 9. • Wilm’s tumor, ALL, Testicular cancer, Burkitt’s lymphoma, NHL To Cure • Prolong remission • Decreases rate of relapseTo Control • Relive symptoms and improved quality of lifePalliation
  10. 10. 1. Primary Chemotherapy • Chemotherapy is main modality of treatment • Can be single drug or combination chemotherapy • e.g. Hematological malignancy- • ABVD regimen for hodgkins lymphoma. 2. Adjuvant Chemotherapy • Combined with radiation or surgery. • For advanced cancer • e.g. Ca breast After surgery to remove microscopic foci.
  11. 11. 3. Neoadjuvant chemotherapy • Chemotherapy is given before surgery. • Shrink a large cancerous tumour to make surgery easy. • e.g. laryngeal carcinoma before surgery. 4. Concurrent chemotherapy • Simultaneously with • Radiation. • mainly act as radiation sensitizer, encoura ges the cancer cells to take radiotherapy. • e.g.Head and neck CA, rectal CA, lung CA
  12. 12. High Intermediate Low Lymphoma Breast Head and neck Leukemia Colon Prostate Small Cell Lung cancer Non-small cell lung cancer Gastric Testicular cancer Pancreatic
  13. 13. • Cell life cycle and drug • Log kill hypothesis • Growth fraction • Tumour burden
  14. 14. cell cycle and drugs G1 – L- Asparginase S – Methotrexate 6-Mercaptopurine 5-Fluorouracil Mitomycin C Hydroxyurea Doxorubicin G2 – Bleomycin Etoposide, Topotecan Daunorubicin M – Vincristine Vinblastine Paclitaxel, Docetaxel
  15. 15. • Cell kill by first order kinetics. • A constant fraction of cells are killed by a given drug dose, not constant number. • A constant percentage of the total number of cancer cells present in tumor will be killed with each course of chemotherapy. • Hence repeated doses of chemotherapy must be used for total cells kill.
  16. 16. 1 log regrowth 3 log cell kill Tumor regrowth after premature Cessation of Therapy.
  17. 17. Growth fraction is the percentage of actively dividing cells at any given point in time. 1. High growth fraction tumour : more sensitive to cycle- specific drugs. e.g. 1. leukemia and lymphoma 2. Normal with tissues high growth fraction like bone marrow, hair follicles, and intestinal 2. Low growth fraction tumour : Solid tumour e.g. carcinomas of the colon, lung cancer) are less responsive to cycle-specific drugs.
  18. 18. • The tumor burden is the size of the tumor as determined by the number of cells present. • Small tumor burden → more responsive • Higher the tumor burden → probability of drug resistance. • Cancer cells usually follows Gompertzian growth pattern.
  19. 19. It is model of cancer cell growth. “Cell rapidly divide early in life, then plateaus.” Significance : 1. Most anticancer drugs are ineffective in advanced cancers which have very low growth fraction. 2. Debulking procedures makes tumour again responsive to drugs by inducing remaining cells to divide.
  20. 20. Alkylating Agents e.g. Nitrogen mustards , Nitrourea Antimetabolites e.g. Folic acid analogue, Pyrimidine and Purine analogue Natural Agents e.g. Vinca alkaloid, Taxens, Tecans. Antibiotics and enzymes e.g. Dactinomycin, Daunorubicin , L- Asparaginase Hormones and antagonists e.g. Progestins , Estrogen, GnRH, Anti- estrogens Miscellaneous agents e.g. Hydroxyurea , Immunomodulators , Tyrosine kinase inhibitor, Biological Response Modifiers ,monoclonal antibody
  21. 21. Purine Synthesis Pyrimidine Synthesis Ribonucleotides Deoxyribonucleotides DNA RNA Proteins Enzymes Microtubules 6-Mercaptopurine 6-Thioguanine Methotrexate → DHFR 5-Fluorouracil Cytarabine Gemcitabine Hydroxyurea Etoposide Topoisomerase II Inhibitor- DNA break Antibiotics L-Asparaginase Vinca Alkaloids → prevent polymerization Taxens →enhance polymerization Antimetabolites Alkylating agents Alkylation→ Alter structure & function of DNA by cross linking and/or fragmenting DNA
  22. 22. CLASS DRUGS MAJOR USES Nitrogen Mustards Meclorethamine HL, NHL Melphalan Multiple myeloma; breast, ovarian cancer Chlorambucil ALL, CLL , HL, NHL, Multiple myeloma; Neuroblastoma; Breast, Ovary, Lung cancer; Wilms’ tumor; cervix, testis cancer; Cyclophosphamide Ifosfamide Etylenimine ThioTEPA Bladder, breast, ovarian cancer Alkyl sulfonte- Busulfan CML Nitrosoureas Carmustine Primary brain tumor; Melanoma, HL,NHL, Streptozocin Pancreatic insulinoma; Malignant carcinoid Triazine Dacarbazine Malignant melanoma;
  23. 23. CLASS DRUGS MAJOR USES Folic acid analogue Methotrexate ALL; choriocarcinoma breast, head, Lung cancer; osteogenic sarcoma; bladder ca Pemetrexed Mesothelioma, lung cancer Pyrimidine analogue Fluorouracil Capecitabine Breast, colon, esophageal, stomach cancer. Cytarabine AML, ALL, NHL Gemcitabine Pancreatic, ovarian, lung ca. Purine analogue and related inhibitors Mercaptopurine AML, ALL Pentostatin Hairy cell leukaemia; CLL, small cell NHL. Fludarabine CLL
  24. 24. CLASS DRUGS MAJOR USES Vinca alkaloids Vinblastine HL, NHL, Testis cancer Vinorelbine Non small cell lung cancer Vincristine ALL, Neuroblastoma; Wilms’ tumor; Taxanes Paclitaxel, Docetaxel Metastatic ovarian, breast ca. Epipodo- phyllotoxins Etoposide Testicular tumour, lung cancer ,HL, NHL Camptothecins Topotecan, Irinotecan Ovarian cancer; small-cell lung cancer; colon ca.
  25. 25. CLASS DRUGS MAJOR USES Antibiotics Dactinomycin (actinomycin D) Choriocarcinoma; Wilms’ tumor; Rhabdomyosarcoma Daunorubicin AML, ALL. Doxorubicin Soft-tissue, osteogenic, and other sarcoma; HL, NHL , AML, ALL. Breast, Genitourinary, Thyroid, lung, stomach cancer; Neuroblastoma Mitoxantrone AML, breast and prostate cancer Bleomycin Testis, cervical cancer; HL, NHL Mitomycin Stomach, anal, and lung cancer Enzymes L-Asparaginase ALL
  26. 26. CLASS DRUGS MAJOR USES Glucocorticoides Prednisone ALL, CLL, HL, breast cancer, multiple myeloma Progestins Hydroxyprogesterone caproate, Medoxyprogesterone acetate, Megestrol acetate Endometrial, breast cancer Estrogens Diethylstilbestrol, Ethinyl estradiol Breast, prostate cancer Anti-estrogens Tamoxifen, Toremifene, Breast cancer Aromatase inhibitors Anastrozole, Letrozole, Breast cancer Androgens Testosterone propionate Breast cancer Antiandrogen Flutamide , casodex Prostate cancer GnRH analogue Leuprolide Prostate cancer
  27. 27. CLASS DRUGS MAJOR USES Substituted urea Hydroxyurea CML ; Polycythemia vera; Essential thrombocytosis Differentiating agents Tretinoin, Arsenic trioxide Acute Promyelocytic Leukemia Protein tyrosine kinase inhibitor Imatinib CML, GIST Gefitinib Non-small-cell lung cancer Sorafenib Hepatocellular cancer, Renal cancer Proteasome inhibitor Bortezomib Multiple myeloma Immunomodulators Thalidomide Multiple myeloma Lenalidomide Myelodysplasia , multiple myeloma mTOR Inhibitors Temsirolimus, Everolimus Renal cancer
  28. 28. CLASS DRUGS MAJOR USES Biological Response Modifiers Interferon-α, Interleukin 2 Hairy cell leukemia; Kaposi’s sarcoma; Melanoma; carcinoid; Renal cell; Ovary; Bladder; Mycosis fungoides; Multiple myeloma; NHL, CML CD20 Rituximab B-cell lymphoma and CLL CD52 Alemtuzumab B-cell CLL and T-cell lymphoma CD33 Gemtuzumab Acute Myelocytic Leukemia HER2/neu Trastuzumab Breast cancer EGFR Cetuximab colorectal, pancreatic, breast ca. VEGF Bevacizumab colorectal cancer
  29. 29. Dosage of chemotherapy are difficult: If the dose is too low, it will be ineffective , whereas excessive causes toxicity . In most cases, the dose is adjusted for the patient's body surface area (BSA), a measure that correlates with blood volume. The BSA is usually calculated with a mathematical formula using a patient's weight and height, rather than by direct measurement. W is weight in kg, and H is height in cm.
  30. 30. • Standard doses –doses in which anticipate side effect are mild and no supportive therapy required • High dose therapy – Increases in dosing amount, severe side effects are present. Supportive therapy is essential. Large amounts of free drug in the serum not only increase efficacy of the drug but also facilitate penetration into the tumour cells. Example : In AML , High-dose cytarabine (2000 to 3000 mg /m2 of BSA) have higher rates of relapse-free survival than standard dose of 100 to 400 mg /m2.
  31. 31. Dose intensification (DI) – higher than standard dose given in short interval Achieved by 1. Increasing the dose of the chemotherapy per cycle (dose escalation) 2. Decreasing the time between the treatments (dose density) Steep dose-response curve, meaning that relatively small increases in the chemotherapy dose will have a substantial effect on the number of tumor cells killed.
  32. 32. Combination therapy involves the use of two or more drugs proven effective against a tumor type. Major advances in cancer treatment in the past 20 years. RATIONALE OF COMBINATION CHEMOTHERAPY • Prevention of resistant clones. • Cytotoxicity to resting and dividing cells. • Biochemical enhancement or effect – Synergistic effect
  33. 33. Combination therapy is superior to single-drug therapy in terms of • Higher tumor response rates • Increased duration of remissions. • Minimal chances of resistance.
  34. 34.  Active as single agents  Different mechanism of action  Different dose limiting toxicity  Used at optimal dose and schedule  Given at consistent interval  Different resistance mechanism  Drugs with known synergistic biochemical interaction  Cell kinetics scheduling: on basis of cell cycle specificity / non specificity of drugs and phase of cycle at which drug exert toxicity.
  35. 35. vinblastin
  36. 36. REGIMEN CANCER DRUGS ABVD Hodgkin's Doxorubicin, Bleomycin, Vinblastine, Dacarbazine CHOP-R NHL Cyclophosphamide, Hydroxydaunorubicine, Vincristine, Prednisolone, Rituximab VAMP AML Vincristine, Amethopterine, 6 MP, Prednisolone FOLIFIRI COLON CANCER 5 FU, Leucovorin, Irinotecan,
  37. 37. 1. Complete response – disappearance of disease on imaging test. 2. Partial response – size decrease of 50% or more from original tumor. No new lesions. 3. Stable disease – less than 50% response without actual progression of disease. 4. Disease progression – 25% increase in the size of the original tumor. Or new lesions developed.
  38. 38.  Infection  Previous chemotherapy given < 2 weeks  Leukopenia and thrombocytopenia  Severely debilitated patients  Pregnancy (1st trimester)  Major surgery < 2 weeks  Poor patient follow-up  Psychological problems
  39. 39. Not all patients can tolerate drugs, and not all drug regimens are appropriate for a given patient. Choice of drug depends on following factor • Tumour type • General performance status of patient • Renal and hepatic function • Bone marrow reserve • Concurrent medical problems • Patient's willingness • Patient's physical and emotional tolerance for side effects
  40. 40. 2 major challenges to Chemotherapy 1. Toxic side effects 2. Drug resistance
  41. 41. Resistance constitutes a lack of response to drug-induced tumour growth inhibition 1. Primary resistance: No response from very first exposure. e.g. malignant melanoma, renal tumours. 2. Acquired resistance : During continuation of therapy . Due to adaption of tumour cells or due to mutation in one or more gene.
  42. 42. 1. ↑ drug efflux via P-glycoprotein transporters e.g. doxorubicin, paclitaxel, vincristine, etoposide 2. Overexpression of the multidrug resistance protein 1(MRCP1) → ↑resistance to natural drugs e.g. vinca alkaloid, anthracyclins . 3. ↓ inward transport e.g. methotrexate 4. Insufficient activation of the drug (e.g. mercaptopurine , fluorouracil and cytarabine. 5. Increase in inactivation (e.g. cytarabine and mercaptopurine ) 6. Increased concentration of target enzyme (methotrexate) 7. Rapid repair of drug-induced lesions (alkylating agents). 8. Altered activity of target proteins, for example modified topoisomerase II (doxorubicin).
  43. 43. • Use of combination drug therapy using different classes of drugs with different mechanism of action. • With narrowest cycle intervals, necessary for bone marrow recovery. • Drugs that reverse multidrug resistance include verapamil, quinidine, and cyclosporine .
  44. 44. • Rapidly multiplying cells • Nausea & Vomiting • Bone marrow depression • Alopecia • Gonads: Oligospermia, impotence, ↓ ovulation • Foetus: Abortion, foetal death, teratogenicity • Carcinogenicity • Hyperuricemia • Hazards to staff
  45. 45. Cause by almost all anticancer drugs except Bleomycin, Vincristin and Asparginase. Most serious toxicity and often limit dose of chemotherapy • Granulocytopenia • Agranulocytosis • Thrombocytopenia • Aplastic anemia • Lymphocytopenia • immunosppression Drug causing severe myelosuppression Carmustin Cytarabine Daunorubicine Paclitaxel Alkylating agents Antimetabolites Complications : • Opportunistic infections • Bleeding
  46. 46. Gastrointestinal toxicity Drugs Nausea and vomiting Carmustin,cisplatin,cyclophosphamide,dacarb azine,cytarabine,lomustine,thiotepa Stomatitis Capecitabine,5 FU,methotrexate,mercaptopurine Diarrhea Irinotecan, 5FU Constipation Vincristine Anorexia, taste change,etc Dermatological toxicity Drugs Alopecia Cyclophosphamide, Ifosfamide Vincristin ,Methotrexate , Paclitaxel, Local necrosis- extravasation Dactinomycin, Doxorubicin, vinca alkaloid Hyperpigmentation of skin
  47. 47. Toxicity Drugs Neuropathy Oxaliplatin,Paclitaxel, Cytarabine,5FU, Renal toxicity Cisplatin, Ifosfamide, Methotrexate Hemorrhagic cystitis Cyclophosphamide, Ifosphamide Hepatotoxicity Asparginase, Cytarabine, Mercaptopurine,Thioguanine, Methotrexate Cardio toxicity Daunorubicin, Doxorubicin,Epirubicine, Mitoxantrone,Transtuzumab, Bevacizumab Pulmonary toxicity Bleomycin, Melphalan, Chlorambucil, Busulphan, Infertility Alkylating agents Hypersensitivity reaction Asparginase, Platinum compound, etoposide
  48. 48. Drugs Use Filgrastim (G-CSF) 1. Prevent neutropenia, 2. Increases neutrophil count, 3. prevent infection.Sargramostim (GM-CSF) Amifostine 1. Cisplatin induced nephrotoxicity, 2. Prevent radiation induced xerostomia Oprelvekin (IL-11) 1. Prevent thrombocytopenia Thrombopoietin
  49. 49. Drugs Use Folinic acid Methotrexate toxicity Mesna Cyclophosphamide induced cystitis Dexrazoxane Doxurubicine /Daunorubicine cardiotoxicity Ondansetron, Dexamethaone, Lorazepam Vomiting Allopurinol, Alkalization of urine Hyperuricaemia Hydration , Bisphosphonates Hypercalcaemia
  50. 50.  The practice of cancer medicine has changed dramatically over the years from palliative → curative. e.g. Wilms tumour, Ewing sarcoma, Choriocarcinoma, Hodgkins disease, testicular cancer can be cured with chemotherapy.  Adjuvant chemotherapy and hormonal therapy can extend life and prevent disease recurrence following surgical resection of localized breast, colorectal, and lung cancers.
  51. 51.  Increasingly used in autoimmune diseases like rheumatoid arthritis (methotrexate and cyclophosphamide), Crohn's disease (6-mercaptopurine), organ transplantation (methotrexate and azathioprine) etc.  As part of multimodal treatment of locally advanced head and neck, breast, lung, and esophageal cancers, thereby allowing for more limited surgery and even cure in these formerly incurable cases  Toxicities of Cytotoxic drugs have become more manageable with the development of better supportive therapy like G-CSF, IL-11 to restore bone marrow function
  52. 52.  Newer target molecules or monoclonal antibody are not likely to replace cytotoxics in the future. Rather, both will be used in combination.  e.g. For instance, monoclonal antibodies or small targeted molecules, used as single agents against solid tumors, produce low response rates and modest benefits; however, in combination with cytotoxics they are dramatically effective .
  53. 53. Bevacizumab plus irinotecan, fluorouracil, and leucovorin (IFL) for metastatic colorectal cancer. The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo,
  54. 54. Molecular tests are increasingly employed to identify patients likely to benefit from treatment and those at highest risk of toxicity Pre-treatment testing has become standard practice for following tumours 1. Estrogen receptor –breast cancer- transtuzumab 2. B cell non Hogdkins lymphoma- Rituximab (CD20)- 3. EGFR- for colorectal cancer- to use Cetuximab
  55. 55. • The future may see the development of agents which could induce differentiation in tumour cells, rendering them non- neoplastic. • By inhibiting an abnormal oncogene product but not the normal equivalent. • By using antisense oligonucleotides to inhibit translation of an abnormal oncogene messenger RNA. • By introducing MDR-1 gene into bone marrow cells and rendering them less susceptible to myelosuppressant drugs.