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Principles of chemotherapy
- 1. PRINCIPLES OF CHEMOTHERAPY Dr Sheetal R Kashid
- 2. Flow of the seminar • History • Biological basis of chemotherapy • Classification of chemotherapy drugs • Tumor growth models • Science of chemotherapy • Chemotherapy with other modalities • Toxicity of chemotherapy • Routes of administration
- 3. History • Arsenic compounds described in traditional Chinese medicine • 1865- Arsenic as a component of Fowler`s solution in treatment of chronic myeloid leukemia (CML) & Hodgkin’s Lymphoma. • Concept of Magic bullet- Paul Ehrlich • 1909- invented arsphenamine (salvarsan) for treatment of syphilis. • 1943- Accidental discovery of Alkylating agents (Nitrogen mustard gas) - first class of modern cancer chemotherapeutic drugs in World war II for treatment of advanced lymphomas
- 4. History • 1948- Sidney Farber showed folic acid antagonist aminopterin & Amethopterin (Methotrexate) analogue can induce remission in acute lymphoblastic leukemia. • 1960- Concept of cure • 2000- concept of genome sequencing & molecular profiling • 2001- Concept of Targeted therapy
- 5. BOLOGICAL BASIS OF CHEMOTHERPAY • Cell Proliferation: 1. Normal cells 2. Cancer cells • Most Chemotherapeutic agents appear to exert their effect primarily on Cell Proliferation. • Mechanism of action of chemotherapeutic drugs: mainly Apoptosis • Fast growth rate is responsible for the sensitivity of cancer cells to chemotherapy Proliferation Cell death
- 7. Potential Targets General Targets • Protein synthesis: -Transcriptional machinery -Ribosomes • Energy (metabolism): -Mitochondrial enzymes • Mitosis: - DNA - DNA replication machinery - Mitotic Spindle Specific targets • Regulatory switches That control whether a cell undergoes mitosis, remains quiescent, or undergoes apoptosis • p53 , cyclin-D, ubiquitine, telomerase.
- 8. Classification Cell Cycle Phase Specific • Agents with major activity in a particular phase of cell cycle • Schedule dependent Cell cycle Phase Nonspecific • Agents with significant activity in multiple phases • Dose dependent
- 9. Cell Cycle S Phase dependent Antimetabolites • Methotrexate • Flurouracil • Doxorubicin • Capecitabine • Cytarabine • Fludarabine • Floxuridine • Gemcitabine • Hydroxyurea • Mercaptopurine • Prednisone • Procarbazine • Thioguanine M Phase dependent Vinca alkaloids Vinblastine Vincristine Vinorelbine Podophyllotoxins Etoposide Teniposide Taxanes Docetaxel Paclitaxel G2 phase dependent Bleomycin Irinotecan Mitoxantrone Topotecan G1 phase-dependent Asparaginase Corticosteroids Carboplatin Cisplatin Cyclophosphamide Busulfan Carmustine Lomustine Mechlorethamine Melphalan Thiotepa Oxaliplatin Cell Cycle Phase Nonspecific
- 10. Classification Cell cycle specific agents Cell cycle non-specific agents ANTIMETABOLITES Taxanes ALKYLATING AGENTS Antitumor antibiotics Capecitabine Albumin-bound paclitaxel Busulfan Dactinomycin Cladribine Docetaxel Carmustine Mitomycin Fludarabine Paclitaxel Cyclophosphamide Camptothecins 5-Flurouracil (5-FU) Vinca alkaloids Lomustine Irinotecan Gemcitabine Vinblastine Mechlorethamine Topotecan 6-Mercaptopurine(6-MP) Vincristine Melphalan Anthracyclines Methotrexate (MTX) Vinorelbine Thiotepa Daunorubicin 6-Thioguanine (6-TG) Epipodophyllotoxins Platinum Analogs Doxorubicin Antitumor antibiotic Etoposide Carboplatin Epirubicin Bleomycin Teniposide Cisplatin Idarubicin Oxaliplatin Mitoxantrone
- 11. General Targets Precursors Precursors Purine Synthesis Pyrimidine Synthesis Ribonucleotides Deoxyribonucleotides mRNA DNA Proteins Enzymes Microtubules MERCAPTOPURINE METHOTREXATE 5-FU HYDROXYUREA CYTARABINE PROCARBAZINE ALKYLATING AGENTS CYTOTOXIC ANTIBIOTICS VINCAALKALOIDS
- 12. Tumor sensitivity to chemotherapy High Intermediate Low Lymphoma Breast cancer Head and neck cancer Leukemia Colon cancer Prostate cancer Small Cell Lung cancer Non-small cell lung cancer Gastric cancer Testicular cancer Pancreatic cancer
- 13. Factors affecting tumor growth Growth Fraction • Mendelsohn - 1960 • Ratio of the replicating cells to the resting cells of tumor. • If the growth fraction approaches 1 and the cell death rate is low, the tumor- doubling time approximates the cell cycle time • If growth fraction is constant , doubling time is constant. Cell Cycle Time • Time required for tumor to double in size TUMOR DOUBLING TIME (days) Burkitts Lymphoma 1 Choriocarcinoma 1.5 Hodgkin`s Lymphoma 3-4 Testicular embryonal carcinoma 5-6 Colon 80 Lung 90
- 14. Cellular Kinetics Pharmacotherapy Principles and Practice, 5e
- 15. Skippers Law • The first of Skipper’s laws is that the doubling time of proliferating cancer cells is a constant. • A plot of the tumor size over time on a semi-log graph forms straight line. • Skipper’s second law states that chemotherapeutic agents follow first order kinetics; a fixed fraction of the tumor cells are killed regardless of the tumor size. Perry`s The Chemotherapy Source Book
- 16. Skipper-Schabel-Wilcox Model • If a tumor grows exponentially and is homogenous in drug sensitivity, the fraction of cells killed by a specific chemotherapy regimen is always the same regardless of the initial size of malignant population. • This model lead to development of the log kill hypothesis.
- 17. Log Kill Hypothesis • The log kill model states that if a drug treatment reduces 106 cells to 105 the same therapy would reduce 104 cells to 103 . • Examples of one log kill are 106 to 105 meaning a 90% decrease in cell number. • For many drugs, the log kill increases with increasing dose, so that higher drug dosages are needed to eradicate larger tumors. • If two or more drugs are used, the log kills are multiplicative. • If enough drugs at adequate doses are applied against a tumor of sufficiently small size, less than one cell should be left, which is the definition of cure.
- 18. Log Kill Hypothesis • Drug A kills 90% of the cells = one log kill • Drug B kills 90% of the cells = one log kill • Drug A + Drug B = 99% of the cells = Two log kill • Drug C kills 90% of the cells = one log kill • Dug A + Drug B + Drug C = 99.9% = Three-log kill
- 19. Limitations of Skipper`s Laws • Applicable only for proliferating or stem cell compartment within the tumor. • Applied to an occasional human malignancy that is readily curable in early stage disease • Model failed to explain growth fraction of micromets in adjuvant settings • Heterogenity of drug sensitivity is not explained
- 20. Gompertzian model • Growth fraction falls exponentially over time • Growth rate of a tumor peaks before it is clinically detectable • Slowly, exponential phase, and slows again • Plateau is due to similarities in rate of cell production and cell loss. • Predicts patterns of growth of micrometastases. • The maximum growth rate - tumor is about 37% of its max. size
- 21. Gompertzian model •Initial tumor growth is first order, with later growth being much slower
- 22. Gompertzian model • Limitations: 1. Growth of a mass is more complex than the cell proliferation. • Not all tumors grow exponentially • The doubling time increases steadily as the tumor grows larger, which means that the tumor grows progressively more slowly. • As the tumor grows larger, decreased cell production than increased cell loss. • old concept- A solid tumor outgrows its supply of nutrients, so cannot sustain its exponential growth. • But Neovascularisation is an important hallmark of cancer 2. No commonly accepted theory that provides the biologic basis for Gompertzian growth 3. Unrealistically long estimates of length of time from carcinogenesis to clinical disease
- 23. Gompertzian model • Limitations: 1. Growth of a mass is more complex than the cell proliferation. • Not all tumors grow exponentially • The doubling time increases steadily as the tumor grows larger, which means that the tumor grows progressively more slowly. • As the tumor grows larger, decreased cell production than increased cell loss. • old concept- A solid tumor outgrows its supply of nutrients, so cannot sustain its exponential growth. • But Neovascularisation is an important hallmark of cancer 2. Unrealistically long estimates of length of time from carcinogenesis to clinical disease 3. No commonly accepted theory that provides the biologic basis for Gompertzian growth.
- 24. • If tumors always grow from a collection of cells outward like an expanding sphere, there must be some period of dormancy followed by re-growth. • Some cancers like skin metastases, first grow as reaching tendrils, later expanding to fill space between the thin arms. Fractal Dimension
- 25. • Non biologic geometry Volume V ∞ L3 • In fractal geometry, no. of cells in a mass increases as a function of the length (L) raised to a constant fractal dimension D between two and three . (e.g. V ∞ L2.5) • Length ∞ Density • A benign mass with a smaller fractal dimension D would have a smaller packing ratio (i.e., few cells per unit volume) than a malignant mass with a larger fractal dimension. • Dynamic entity , it changes under hormones ,genetic mutations. • Tumors with larger values of D tend to maintain their high growth fractions longer as they grow larger. Fractal Dimension
- 26. Fractal Dimension • It can be shown mathematically that masses growing in a manner that preserves the power relationship between cell number and volume follow a Gompertzian curve. • Values of D that are close to 3 give more aggressive growth, with little deviation from exponentiality — The doubling time stays close to constant. • Values of D that are close to 2 produce Gompertzian curves with rapidly lengthening doubling times. • Concept of fractal is also suggested to give relationship between cancer cell & its stromal environment • Fractal geometry may provide some interesting clues regarding preneoplasia, malignant transformation, and Gompertzian growth kinetics
- 27. Norton-Simon Hypothesis • Tumor cells are killed in response to a chemotherapeutic agent at a rate directly proportional to the tumor growth rate at the start of treatment. • Smaller tumors with greater growth fraction respond & are more sensitive to chemotherapy with a higher log-kill compared to large tumors. • Rate of tumor volume regression is proportional to growth rate.
- 28. Norton-Simon Hypothesis Best Treatment • Early treatment • Each agent at highest possible dose • Dose dense chemotherapy • Over shortest period of time • In an ideal system, chemotherapy kills a constant proportion of remaining cancer cells with each dose. • Between doses, cell re-growth occurs. When therapy is successful, cell killing is greater than cell re-growth •Tumors given less time to regrow between treatments are more likely to be destroyed
- 29. Delbruck- Luria Model • Different culture dishes of same bacterial strain developed resistance to bacteriophage infection at different random times before exposure to viruses. • Resistance - acquired spontaneously at random times in pretreatment growth of cancer. • High mitotic activity increases probability of finding genetic alteration. • So even at diagnosis, cancer cells are a heterogenous population with varied drug sensitivity • This disproves homogeneity of drug sensitivity as proposed by skipper and colleagues. • Best way – Multiagent chemotherapy.
- 30. Goldie-Coldman Hypothesis • Mathematically models genetic resistance of cancer cells to chemotherapeutic drugs • Based on Luria and Delbruck's studies. • Resistance is independent of the chemotherapeutic agent and dependent on the number of cell divisions that occur after treatment begins. • The larger the tumor size or the longer delay in initiating chemotherapy, the more resistant cells. • Chemotherapy resistance mutations occur in cell populations of 103 to 106 cancer cells, substantially lower than limit of clinical detection.
- 31. It predicts : 1. To overcome spontaneous drug resistance most effectively, multiple active agents should be given over the shortest time as early in the growth of the cancer as possible. 2. Multiple agents given simultaneously will be superior to sequential single agents at higher doses. 3. Regimen of alternating cycles of two different non–cross-resistant chemotherapy medicines yields a better chance of tumor eradication. 4. Resistance once acquired , remains through out the cell line. Goldie-Coldman Hypothesis
- 32. Drawbacks: 1. Not all failures are due to permanent drug resistance. e.g. Lymphoma recurrence respond to the same chemotherapy. 2. Cell mass > 107 does not signify incurability. e.g. Gestational choriocarcinoma and Burkitt’s lymphomas measuring >1cc are curable with single agent chemotherapy. Goldie-Coldman model
- 33. Drug resistance Combination drug regimens prevent the development of resistance Vinca Alkaloids Anthracyclines Paclitaxel, Methotrexate Imatinib Alkylating agents Antimetabolites
- 34. Intent of chemotherapy CURATIVE PALLIATIVE •Leukemia •Lymphoma •Ca Breast •Ca Lung
- 35. CHEMOTHERAPY TREATMENT MODALITIES SINGLE MODALITY MULTIMODALITY CONCURRENT ADJUVANT MAINTENANCE LOCAL TREATMENT INDUCTION/NACT
- 36. CHEMOTHERAPY TREATMENT MODALITIES 1. Primary induction chemotherapy for advanced disease or for cancers for which there are no other effective treatment approaches. E.g. ALL 2. Neoadjuvant chemotherapy for patients who present with localised disease, for whom local forms of therapy, such as surgery & / or radiation, are inadequate by themselves. E.g. Osteogenic sarcoma 3. Concurrent chemotherapy used in conjunction with radiation therapy to sterilize micrometastases within the radiation field or to increase the response of tumor cells to radiation. E.g. Ca cervix, HNSCC. 4. Adjuvant chemotherapy for patients at known high risk of recurrence after initial local therapy (surgery & radiation) has removed all evidence of disease. E.g. Ca breast 5. Maintenance chemotherapy to prevent or delay the recurrence if the cancer is in complete remission after initial treatment. Or to slow the growth of advanced cancer after initial treatment if the cancer is in incomplete remission. E.g. Multiple myeloma Physician`s Cancer chemotherapy drug manual 2018- Edward Chu
- 37. PRINCIPLES GOVERNING USE OF CHEMOTHERAPY SINGLE AGENT • First used individually • Initial Regimens – Kinetics of bone marrow recovery. • Although it lead to responses, occasionally complete response – progression remained inevitable DRUG CANCER METHOTREXATE CHORIOCARCINOMA CYCLOPHOSPHAMIDE BURKITT`S LYMPHOMA CISPLATIN HNSCC CARBOPLATIN TESTICULAR CANCER TEMOZOLAMIDE GLIOBLASTOMA
- 38. COMBINATION CHEMOTHERAPY Developed empirically & rationally using the principles of cancer cell growth kinetics and mechanisms of cancer cell resistance to chemotherapy. Rationale : • Provides maximal cell kill within the range of toxicity tolerated by the host for each drug as long as dosing is not compromised. • Provides broader range of interaction between drugs and tumour cells with different genetic abnormalities in a heterogeneous tumour population. • It may prevent and/or slow the subsequent development of cellular drug resistance.
- 39. COMBINATION CHEMOTHERAPY Principles - All drugs must have • Single agent activity • Non-overlapping toxicity • Different Mechanisms of action and resistance • Optimum dose and schedule to optimize dose intensity/ dose density. • Drugs should be individually titrated in individual patients to end-organ toxicity to optimize adherence to schedule. AIM - To increase efficacy of regimen ACTIVITY TOXICITY
- 40. EXAMPLES OF COMBINATION CHEMOTHERAPY REGIMEN CANCER DRUGS MOPP Hodgkin`s Lymphoma Nitrogen mustard, Vincristine, Procarbazine, Prednisone ABVD Hodgkin's Lymphoma Doxorubicin, Bleomycin, Vinblastine, Dacarbazine CHOP-R NHL Cyclophosphamide, Hydroxydaunorubicine, Vincristine, Prednisone, Rituximab VAMP AML Vincristine, Amethopterine, 6 MP, Prednisone CMF Ca Breast Cyclophosphamide, Methotrexate, 5-FU FOLIFIRI Ca Colon Leucovorin, 5 FU, Irinotecan,
- 41. OPTIMAL DURATION OF CHEMOTHERAPY • For patients without disease progression optimal duration of chemotherapy has not been well defined. • More potent drug regimens, potential risk of cumulative adverse events must be considered. • E.g. cardiotoxicity secondary to the anthracyclines • No evidence of clinical benefit in continuing therapy indefinitely until disease progression. • Infact stopping and rechallenging with the same chemotherapy provides a reasonable treatment option for palliative settings.
- 42. METHODS TO INCREASE EFFICACY Dose intensity Dose density Sequential Scheduling
- 43. Dose Intensity Total dose of an agent administered during a fixed time. • DI = Dose in mg / BSA Time (wks) • Rationale : Cells that are resistant to a particular dose level of a drug may be sensitive to a higher dose level by increasing intracellular accumulation of drug. • Growth factor support may be required in case dose intense regimens are used. • Positive relationship between dose intensity and response rate seen in treatment of several solid tumors & haematolymphoid malignancies.
- 44. Dose Density • Increasing the dose per unit time (in mg/m2/week) by shortening the interval between subsequent doses. Standard Dose Therapy Escalated Dose Therapy Dose dense Therapy
- 45. Sequential Scheduling • Either single or combination chemotherapy can be given in sequence Sequntial Scheduling Alternating Scheduling Sequntial + Dose dense Scheduling
- 46. Dose Calculation Based on BSA • Initially to define a safe starting dose for phase I trials of new anticancer agents, later became FDA requirement • Though inaccurate, is reproducible & easy to calculate • Better –use lean body mass, or ideally serum levels • In children BSA converted to mg/kg Area under curve (AUC) o For carboplatin o Calvert’s formula - total dose = target AUC x (GFR+ 25) o GFR ~ creatinine clearance = wt x (140-age) 72 x S. creat √ height(cm) X weight (kg) 3600 BSA (m2) =
- 47. METRONOMIC CHEMOTHERAPY • Administering agents (cytotoxic, non-cytotoxic or targeted drugs) continuously at lower doses or continuously at tolerable doses, without drug-free breaks over extended periods. Mechanism: • Primarily anti-angiogenic, either by direct killing or inhibiting endothelial cells in the tumor vasculature, killing bone-marrow-derived endothelial progenitor cells. • Stimulating the immune system, • Directly affecting tumor cells through a drug-driven effect. • Specifically inhibiting a target with target specific drugs. • Induction of senescence in cancer cells. Reduced toxicity. April 2000
- 48. • Chemotherapy used in conjunction with radiation therapy Rationale : • Presence of micrometastatic disease outside the treatment field • Inability to deliver an adequate dose to the target region because of risk of toxicity • Resistance to radiation damage. • Enhance tumor sensitivity by delivering each agent when enhanced sensitivity to the other has been induced by the first agent CONCURRENT CHEMORADIATION
- 49. • The successful reduction of tumor mass by chemotherapy may improve 1. Tumor's blood supply 2. Re oxygenation 3. Increase radiation induced cell kill • It may also alter the cell kinetics of the tumor in a favorable manner. • Permitting radiation to be more effective in a particular phase of cell cycle. • Conversely, radiation therapy may decrease the tumor mass, leading to improved blood supply and better drug delivery CONCURRENT CHEMORADIATION
- 50. Strategies to improve therapeutic index • Steel and Peckham in 1979 defined general strategies to improve therapeutic index: 1. Independent toxicity 2. Normal tissues protection 3. Spatial cooperation 4. Enhancement of tumor response
- 52. Drugs with radiation sensitizer properties • Cisplatin • Carboplatin • Paclitaxel • 5FU • Irinotecan • Topotecan
- 53. Chemotherapy and Immunotherapy (Biochemotherapy) • To combine cytotoxic chemotherapeutic drugs with biologic response modifiers such as interferons and interleukin-2 (IL-2). • Subject tumor cells to an activated tumor response– stimulated by IL-2 and/or the growth inhibitory action of Interferon and cytotoxic chemotherapies. • Metastatic melanoma, Metastatic RCC. • Commonly used regimen consists of cisplatin, vinblastine, and dacarbazine given with high doses of IL-2 and interferon. •Considerable toxicity and Inconsistent results.
- 54. Chemo-immunotherapy DRUG ANTIBODY DISEASE Rituximab Anti CD20 B cell NHLs Brentuximab Anti CD 30 ALCL, Hodgkin’s lymphoma Gemtuzumab ozogamicin Anti CD 33 AML Trastuzumab Anti Her2/neu Ca Breast, Ca Stomach Bevacizumab VEGF-A Ca Colon, Lung, GBM, RCC MONOCLONAL ANTIBODIES
- 55. TARGETED THERAPY Paradigm shift in the treatment of cancer today. Conventional cytotoxic drugs -Interact with DNA to prevent cell proliferation -not specific to cancer cells Targeted therapies -Targets cancer dependent pathways -Specific to cancer cells
- 56. • Targets pathways specifically or differentially activated in cancer cells • Pathways related to - Growth regulation, survival (including apoptosis) & angiogenesis. • Targeted agents produce partial or complete responses which are rarely curative. • Associated with the development of resistance in cancers exposed to them when used alone. • Hence use in combination with chemotherapy. Chemotherapy and Targeted agents
- 57. Chemotherapy and Targeted agents Drug Cancer All Trans-retinoic acid (ATRA) Acute Promyelocytic Leukemia Imatinib, Dasatinib, Nilotinib Chronic myeloid leukaemia Imatinib Gastrointestinal stromal tumor Bevacizumab Colorectal Cancer Erlotinib & Gemcitabine Pancreatic cancer
- 59. FDA-Approved TKIs Generic Name Cancer Imatinib CML, GIST, others Dasatinib CML, ALL Nilotinib CML Gefitinib Lung Erlotinib Lung, Pancreas Lapatinib Breast Sorafenib Kidney, Liver Sunitinib Kidney
- 60. Toxicity • Most cancer chemotherapeutic agents also have toxic effects on normal cells, particularly those cells with a rapid rate of turnover. • Therapeutic index of a particular drug / regimen is important • Alopecia • Nausea and vomiting • Mucositis • Skin changes • Anxiety, sleep disturbance • Altered bowel habits • Bone marrow suppression • Hypersensitivity • Neurotoxicity • Nephrotoxicity • Ototoxicity • Cardiotoxicity
- 61. • Oral route • Subcutaneous • Intramuscular • Intravenous • Intra-arterial • Intra-peritoneal • Intrapleural • Intravesical • Intrathecal • Topical Routes Of Administration
- 62. Routes Of Administration Oral Route Gefitinib Imatinib Cyclophosphamide Etoposide Busulfan Capecitabine Chlorambucil Lomustine Temozolomide Tamoxifen Melphalan 6- Mercaptopurine Methotraxate Mitotane Procarbazine Hydroxyurea IntramuscularAndSubcutaneous Asparaginase Interferon -2a & -2b Cytarabin - SC Methotrexate - IM
- 63. Routes Of Administration Intravenous Methotrexate Adriamycin Cisplatin Intra-arterial Floxuridine Cisplatin 5- Fluorouracil
- 64. Hyperthermic intraperitoneal chemotherapy (HIPEC) Melphalan Ifosphamide Cyclophosphamide Mitomycin c Cisplatin Oxaliplatin Doxorubicin Carboplatin 5-fluorouracil Gemcitabine Paclitaxel Routes Of Administration Use: 1. Ovarian cancer 2. Mesothelioma 3. Intraperitoneal GI Malignancies
- 65. Routes Of Administration Intra- Pleural Bleomycin 5- Flurouracil Nitrogen Mustard Intra-Vesical BCG vaccine Thiotepa Mitomycin C
- 66. Routes Of Administration Intra-thecal Methotrexate Cytarabine Thiotepa Hydrocortisone Ommaya reservoir • Small SC reservoir connected to a small catheter leading to lateral ventricle • The device is named for the U.S. neurosurgeon Ayub Ommaya
- 67. Routes Of Administration Topical • Topical 5-FU for actinic keratoses
- 68. Take Home Message • Multimodality therapy has become the mainstay in the treatment of the vast majority of solid malignant tumors. • Combination drug regimens to prevent the development of resistance. • Concurrent chemo-radiotherapy has shown its benefit in many solid malignant tumors. • Moving towards more rational, tailored design of a patient`s treatment, ultimately leading to personalised medicine for each patient. (Cytotoxic to Targeted approach)
- 69. • THANK YOU