Downloaded 1,541 times
Uploaded byDR NILESH KATOLE
principles of chemotherapy
- German chemist Paul Ehrlich coined the term "chemotherapy" to refer to treatment of disease with chemical drugs. By the 1950s, the term was primarily used to refer to drugs used to treat cancer. - Chemotherapy involves using drugs to treat cancer and typically involves drugs that interfere with cell division, such as methotrexate or fluorouracil. - The choice of chemotherapy depends on factors like the location and stage of the tumor and the patient's health. While it can cure some cancers, it is most effective against cancer before metastasis.
More Related Content
Similar to principles of chemotherapy
principles of chemotherapy
- 2. • German chemistPaul 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.
- 3. • Diseases ofcells 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.
- 4. • 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
- 5. • 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.
- 6. 1948 - SidneyFarber 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.
- 7. 1950- Actinomycin Dwas 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.
- 8. • 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.
- 9. • Scientist continueto 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.
- 10. • 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
- 11. 1. Primary Chemotherapy • Chemotherapyis 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.
- 12. 3. Neoadjuvant chemotherapy • Chemotherapyis 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
- 13. High Intermediate Low LymphomaBreast Head and neck Leukemia Colon Prostate Small Cell Lung cancer Non-small cell lung cancer Gastric Testicular cancer Pancreatic
- 14. • Cell lifecycle and drug • Log kill hypothesis • Growth fraction • Tumour burden
- 15. cell cycle anddrugs G1 – L- Asparginase S – Methotrexate 6-Mercaptopurine 5-Fluorouracil Mitomycin C Hydroxyurea Doxorubicin G2 – Bleomycin Etoposide, Topotecan Daunorubicin M – Vincristine Vinblastine Paclitaxel, Docetaxel
- 17. • Cell killby 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.
- 18. 1 log regrowth 3log cell kill Tumor regrowth after premature Cessation of Therapy.
- 19. Growth fraction isthe 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.
- 20. • The tumorburden 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.
- 22. It is modelof 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.
- 23. 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
- 24. Purine Synthesis PyrimidineSynthesis 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
- 25. CLASS DRUGS MAJORUSES 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;
- 26. CLASS DRUGS MAJORUSES 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
- 27. CLASS DRUGS MAJORUSES 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.
- 28. CLASS DRUGS MAJORUSES 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
- 29. CLASS DRUGS MAJORUSES 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
- 30. CLASS DRUGS MAJORUSES 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
- 31. CLASS DRUGS MAJORUSES 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
- 32. Dosage of chemotherapyare 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.
- 33. • 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.
- 34. 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.
- 35. Combination therapy involvesthe 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
- 36. Combination therapy issuperior to single-drug therapy in terms of • Higher tumor response rates • Increased duration of remissions. • Minimal chances of resistance.
- 37. Active assingle 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.
- 38.
- 39. REGIMEN CANCER DRUGS ABVDHodgkin'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,
- 40. 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.
- 41. Infection Previouschemotherapy given < 2 weeks Leukopenia and thrombocytopenia Severely debilitated patients Pregnancy (1st trimester) Major surgery < 2 weeks Poor patient follow-up Psychological problems
- 42. Not all patientscan 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
- 43. 2 major challenges toChemotherapy 1. Toxic side effects 2. Drug resistance
- 44. Resistance constitutes alack 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.
- 45. 1. ↑ drugefflux 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).
- 46. • Use ofcombination 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 .
- 47. • Rapidly multiplyingcells • Nausea & Vomiting • Bone marrow depression • Alopecia • Gonads: Oligospermia, impotence, ↓ ovulation • Foetus: Abortion, foetal death, teratogenicity • Carcinogenicity • Hyperuricemia • Hazards to staff
- 48. Cause by almostall 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
- 49. Gastrointestinal toxicity Drugs Nauseaand 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
- 50. 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
- 51. 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
- 52. Drugs Use Folinic acidMethotrexate toxicity Mesna Cyclophosphamide induced cystitis Dexrazoxane Doxurubicine /Daunorubicine cardiotoxicity Ondansetron, Dexamethaone, Lorazepam Vomiting Allopurinol, Alkalization of urine Hyperuricaemia Hydration , Bisphosphonates Hypercalcaemia
- 53. The practiceof 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.
- 54. Increasingly usedin 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
- 55. Newer targetmolecules 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 .
- 56. 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,
- 57. Molecular tests areincreasingly 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
- 58. • The futuremay 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.
Editor's Notes
- #4 Cancer is a disease in which there is uncontrolled multiplication and spread within the body of abnormal forms of bodys own cells. It is one of the major causes of death in developed nations atleast 1 in 5 of the population of europe and north america can expect to die of cancer. Cancers are more common in aged people as life expectancy is increasing the incidence of cancers is also increasing, with the present methods of treatment one third of the patients are cured with local modalities of treatment (surgery or irradiation therapy) which are quite effective when the tumor has not metastatized. In metastasis systemic chemotherpy is required along with surgery or irradiation at present 50 % of the patients of cancer can be treated with chemotherapy contributing to cure in 10 -15% of the patients. The terms cancer,malignant neoplasm and malignant tumor are synonymous
- #5 Chemotherapy is essentially required with surgery or irradiation when metastasis has occurred
- #48 Majority of cytotoxic drugs have more profound effects on rapidly multiplying cells