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According to the log-kill hypothesis, chemotherapeutic agents kill a constant fraction of cells (first order kinetics), rather than a specific number of cells, after each dose
1. Solid cancer tumors - generally have a low growth fraction thus respond poorly to chemotherapy & in most cases need to be removed by surgery 2. Disseminated cancers- generally have a high growth fraction & generally respond well to chemotherapy.
The tumor is detected (using conventional techniques) when the tumor burden reaches 109 cells
The patient is symptomatic at 1010-1011 cells
Dies at 1012 cells.
EFFECT OF CELL CYCLE
CELL CYCLE SPECIFIC AGENTS (CCS) CELL CYCLE NONSPECIFIC AGENTS (CCNS)
Kills cells in cell cycle KILLS BOTH G0 and cycling cells (although cycling cells are more specific)Useful in High growth fraction tumors (hematological malignancies, Burkitt’s lymphoma, trophoblastic choriocarcinoma)
Useful in both High growth fraction & low growth fraction tumors (solid tumors)
More specifically kills tumor cells Kills both normal and malignant cells to the same extentGiven in continuous infusion or frequent small doses Intermittent high dose therapy G1 Asparginase, corticosteroids S ANTIMETABOLITES ANTHRACYCLINS (doxorubicin, daunorubicin) HYDROXYUREA G2 BLEOMYCIN CAMPTOTHECINS (Irenotecan, topotecan) EPIPODOPHYLLOTOXINS ( Etopside) M VINCA ALKALOIDS TAXANES
prophylactic ALLOPURINOL (xanthine oxidase inhibitor)alternatively RASBURICASE (uricase)Aggressive hydrationHigh urine outputAlkalinization of urine not recommended/controvvertialDiuresis is reserved for well hydrated patientsHEMODIALYSIS (if above fails)
(1) AML (All subtypes except M3)INDUCTION CHEMOTHERAPY: With cytarabine (ara-C) and an anthracycline (such as daunorubicin or idarubicin).[32] This induction chemotherapy regimen is known as "7+3" (or "3+7"), because the cytarabine is given as a continuous IV infusion for seven consecutive days while the anthracycline is given for three consecutive days as an IV pushThe goal of the induction phase is to reach a complete remission. Complete remission does not mean that the disease has been cured; rather, it signifies that no disease can be detected with available diagnostic methodsCONSOLIDATION THERAPY: Even after complete remission is achieved, leukemic cells likely remain in numbers too small to be detected with current diagnostic techniques. If no further post remission or consolidation therapy is given, almost all patients will eventually relapse. Therefore, more therapy is necessary to eliminate non-detectable disease and prevent relapse that is, to achieve a cure. The specific type of post remission therapy is individualized based on a patient's prognostic factors and general health.
Good prognosis inv(16), t(8;21), and t(15;17) 3-5 course of consolidation chemotherapyIntermediate risk normal cytogenetics or cytogenetic changes not falling
into good-risk or high-risk groupsDepends on specific situation like age, health, suitable donor
High risk with high-risk cytogenetics, underlying MDS, or therapy-related AML
If suitable donor is available Allogenic stem cell transplantIf donor is not available Consolidation chemo followed by Immunotherapy with
a combination of histamine dihydrochloride (Ceplene) and interleukin-2 (Proleukin)
(2) M3 SUBTYPE AML (ACUTE PROMYELOCYTIC LEUKEMIA):ATRA (all-trans-retinoic acid) in addition to induction chemotherapy
(3) RELAPSED AML:If no further post remission or consolidation therapy is given, almost all patients will eventually relapse. For patients with relapsed AML, the only proven potentially curative therapy is a stem cell transplant, if one has not already been performed. A newer drug, gemtuzumab ozogamicin, which combines an antibody with a chemotherapy drug as an attempt to specifically "target" the leukemia cells, is effective in some people after relapse has occurred.Arsenic trioxide is used in relapsed cases of acute promyelocytic leukemia.
(4) ALLINDUCTION CHEMOTHERAPY: Combination of Prednisolone or dexamethasone, vincristine, asparaginase (better tolerance in pediatric patients), and daunorubicin (used in Adult ALL) is used to induce remissionCONSOLIDATION/INTENSIFICATION: vincristine, cyclophosphamide, cytarabine, daunorubicin, etoposide, thioguanine or mercaptopurine given as blocks in different combinations. For CNS protection, intrathecal methotrexate or cytarabine is usually used combined with or without cranio-spinal irradiationMAINTENANCE: daily oral mercaptopurine, once weekly oral methotrexate, once monthly 5-day course of intravenous vincristine and oral corticosteroids are usually used.
(5) CML:(6) CLL: Generally considered incurable. Combinations of fludarabine with alkylating agents (cyclophosphamide) produce higher response rates and a longer progression-
free survival than single agents: * FC (fludarabine with cyclophosphamide) * FR (fludarabine with rituximab) * FCR (fludarabine, cyclophosphamide, and rituximab)
(7) REFRACTORY CLL: In this case more aggressive therapies, including lenalidomide (thalidomide derivative), flavopiridol (cyclin dependent kinase inhibitor), and bone marrow (stem cell) transplantation, are considered. The monoclonal antibody, alemtuzumab (directed against CD52), may be used in patients with refractory, bone marrow-based disease.