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A, B, Cs of CHEMOTHERAPY

This educational series explores the various stages of the cell cycle, protein synthesis, and tumor growth. It also discusses the kinetics of chemotherapy and strategies for preventing relapse.

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A, B, Cs of CHEMOTHERAPY

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  1. A, B, Cs of CHEMOTHERAPY Pediatric Resident Education Series

  2. THE CELL CYCLE G1 PROTEIN SYNTHESIS S DNA SYNTHESIS G2 PREMITOSIS M MITOSIS Go RESTING S Go G1 G2 M CELLS THAT DIE OR MATURE DO NOT CONTRIBUTE (ARE “LOST”) TO TUMOR GROWTH CELL LOSS

  3. TUMOR GROWTH A. ALL CELLS IN CYCLE DT DOUBLING TIME CT AVERAGE CYCLE TIME GF GROWTH FRACTION CL CELL LOSS DT = CT B. A FRACTION IN CYCLE DT = CT GF C. A FRACTION IN CYCLE WITH CELL LOSS WHEN CL IS > 0.5 GROWTH OF A TUMOR CEASES DT = CT GF x CL

  4. LUNG METASTASIS GROWTH LOG # TUMOR CELLS TMO TIME METASTASIS ORIGIN TMD TIME METASTASIS DIAGNOSED TPD TIME PRIMARY DIAGNOSED TMO TMD TPD TIME

  5. TUMOR GROWTH CONTROLS • Large tumors grow slowly because of limitations in oxygen/nutrient supply and waste elimination solution: tumor angiogenesis • Mid-sized tumors grow logarithmically • Small tumors grow slowly because of residual normal growth control mechanisms solution: additional mutations increase growth independence

  6. MICROMETASTASES AT THE TIME OF PRIMARY TUMOR DIAGNOSIS MICROSCOPIC METASTATIC TUMOR DEPOSITS ARE PRESENT IN MOST PATIENTS WILMS TUMOR: WITHOUT CHEMOTHERAPY, 80 % OF NEWLY DIAGNOSED PATIENTS WITH NORMAL CXR DEVELOP LUNG METASTASES DESPITE IMMEDIATE NEPHRECTOMY OSTEOSARCOMA: WITHOUT CHEMOTHERAPY, 90 % OF NEWLY DIAGNOSED PATIENTS WITH NORMAL CXR DEVELOP LUNG METASTASES DESPITE IMMEDIATE AMPUTATION ALL: WITHOUT CNS “PROPHYLAXIS”, 70 % OF NEWLY DIAGNOSED PATIENTS WITH A NORMAL CSF DEVELOP CNS LEUKEMIA

  7. CHEMOTHERAPY KINETICS Tumor cell kill depends upon drug dose. For many agents the dose response curve is steep. LOG KILL HYPOTHESIS: in log phase growth, the fraction of cells killed is dependent on drug dose and is independent of tumor cell numbers Example: 2 log cell kill 106104 104102 4 log cell kill 106 102 104 100

  8. CHEMOTHERAPY KINETICS 4 LOG CELL KILL STARTING CELL # 106 104 FREQUENCY 0 1 10 100 1000 RESIDUAL TUMOR CELLS CURE IS MORE LIKELY WHEN THERE IS A LOWER TUMOR CELL BURDEN AT THE INITIATION OF THERAPY

  9. CHEMOTHERAPY KINETICS MUTATIONS AT SPECIFIC LOCUS OCCUR AT A FREQUENCY OF 1/1,000,000 CELL DIVISIONS 100 % SENSITIVE CELLS STARTING CELL # 106 104 0 TIME or CELL DIVISIONS

  10. CHEOTHERAPY KINETICS i.e., TREATMENT IS USUALLY MOST EFFECTIVE WHEN: DOSES ARE HIGH [INTENSIVE THERAPY] TUMOR BURDEN IS LOW [MINIMAL DISEASE] THIS STRATEGY WORKS BY SEVERAL MECHANISMS: ELIMINATION OF SENSITIVE CELLS PREVENTING DEVELOPMENT OF RESISTANT CELLS TREATMENT OF RESISTANT CELLS

  11. CHEMOTHERAPY KINETICS 1012 1010 [REMISSION] LOG TUMOR CELLS SENSITIVE CELLS RESISTANT CELLS TOTAL CELLS 0 TIME WHAT STRATEGY IS BEST TO PREVENT RELAPSE?

  12. CHEMOTHERAPY STRATEGY Given a series of drugs (or drug combinations), what is the optimal strategy: • AAAAAAAAAA……relapse…BBBBB… ? • AAAAABBBBBAAAAABBBBB… ? • ABABABABABABABABABAB… ?

  13. GOLDIE-COLDMAN HYPOTHESIS Optimal tumor treatment would use a large series of non-repeating drugs or drug combinations ABCDEFGHIJKL… This hypothesis is based on several assumptions: Log growth of tumor cells X Equal effectiveness of drugs X Different mechanisms of action of drugs X Different toxicities of drugs X ASSUMPTIONS MARKED X ARE NOT MET IN MOST CLINICAL SETTINGS

  14. DRUG SCHEDULE Many patient, disease and treatment factors affect the efficacy and toxicities of drugs DOSE ROUTE FREQUENCY TIMING CONCOMMITANT MEDICATIONS METABOLIZING ENZYMES HEPATIC, RENAL FUNCTION NUTRITION SENSITIVITY

  15. DRUG SYNERGY, ANTAGONISM, and ADDITIVE EFFECTS • Drug effects are additive when their use in combination gives results equivalent to their sequential independent use. • Lesser effects suggest antagonism. • Greater effects suggest synergism.

  16. DRUG SYNERGY, ANTAGONISM, and ADDITIVE EFFECTS • Drug A 60 % response • Drug B 30 % response • Drug A + B 60 respond to A 12 respond to B [30 % of 40 non-responders to A] 72 % = additive response rate A lower response rate would suggest antagonism; a higher response rate would suggest synergism

  17. SYNERGY, ANTAGONISM, and ADDITIVE EFFECTS: OSTEOSARCOMA • No chemotherapy: 10 % EFS • High dose methotrexate: 50% EFS • Doxorubicin: 50% EFS • Methotrexate + doxorubicin: 50 % EFS EXPLANATION: because of overlapping toxicities, both drugs had to be scheduled at longer intervals than when used alone

  18. DRUG SYNERGY, ANTAGONISM, and ADDITIVE EFFECTS: ALL • Methotrexate [Mtx] followed by asparaginase is synergistic • Asparaginase [Asn] followed by methotrexate is antagonistic EXPLANATION: Mtx kills in S phase; this recruits cells into G1 where they are most susceptible to Asn.With initial Asn, cells are killed in G1 leaving few to enter S where Mtx is most effective.

  19. GENERAL APPROACHES TO CHEMOTHERAPY PROTOCOL DESIGN • Intensify the use of chemotherapeutic agents known to be effective • Modify therapy based on disease response to initial treatment and/or risk factors for recurrent disease • Add new agents targeting a specific cell, antigen, or enzyme/metabolic pathway

  20. CREDITS • Bruce Camitta MD

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