Most important adverse effect of Bleomycin is?

ANSWER: (C) Pulmonary fibrosisREF: KDT 6 'b edition page No: 827, Harrison 17th ed chapter 81See APPENDIX-37 below for "CLASSIFICATION OF CANCER CHEMOTHERAPY AGENTS"The most feared and most common complication of bleomycin treatment is pulmonary fibrosis, which increases in incidence at > 300 cumulative units administered and is minimally responsive to treatment (e.g., glucocorticoids)."The most common early symptoms of bleomycin-induced pulmonary toxicity are cough and dyspnea"The earliest indicator of an adverse effect is a decline in the DLCO, although cessation of drug immediately upon documentation of a decrease in DLCO may not prevent further decline in pulmonary function.Risk factors of developing Bleomycin induced pulmonary fibrosis are:Elderly patientsCo existing lung diseasePrevious radiation therapyHigh doses of bleomycin (>150mg/m2) APPENDIX - 37Classification of Cancer Chemotherapy Agents:GroupSubgroups & AgentsAcute ToxicityDelayed ToxicityUsesAlkylatingAgentsNitrogen Mustard Alkylation of DNA at N7 &06 position of Guanine -DNA crosslinking I; b/n 2 strands - prevents duplication(1) Mechiorethamine(First anticancer drug)CINV-chemo induced nausea vomiting (4hr- 48hrs)MyelosuppressionMyelosuppression (delayed type-onset = 7d, Nadir = 10-14d, reco%rerv = 21-28d)AlopeciaMOPP-HodgkinslymphomaAA are commonly used in chronic leukemia(2) Cyclophosphamide1CP - 4hydroxyCP -aldophosphamide- Acrolein (toxic) & phosphamide mustard (active)]CINVMyelosuppression(CP>Ifo)Myelosuppression (CP>Ifo) Alopecia, SIADHHemorrhagic cystitis (Ifo>CP)Sec cancer-transitional cell cancer of bladderWagner'sgranulomatosis DOC CMF-Breast, small cell lung ca Broad spectrumAA are nonphase specific(3) Ifosfamide 4hydroxy ifosfamide (active)CINVMyelosuppression(CP>Ifo)Myelosuppression(CP>Ifo)AlopeciaHemorrhagic cystitis (Ifo>CP)Broad spectrum Lung, breast, ovary, sarcoma, testis, germ cell tumorAA causes secondary leukemia in 4-5 years(4) Melphanamino acid derivative ofmechloretamineCINVMyelosuppressionMyelosuppression No alopeciaMultiple myeloma DOCCan replace C in CMF (5) ChlorambucilMyelosuppression CINV is rareMyelosuppression No alopeciaCLL, Hodgkin's Nitrosoureas(lipophilic-crosses BBB) Nitrosoureas causes delayedMyelosuppression (onset-15d, Nadir-4wks, recovery-6wks) (1) Carmustine (BCNU- bis chloro nitroso urea)CINV (severe-2hrs)Myelosuppression, male infertility,Pulmonary fibrosisBrain tumors DOC(Glioblastomamultiforme.Astrocytoma,Medulloblastoma) (2) Lomustine (CCNU)CINV (severe-2hrs)Myelosuppression Interstitial lung diseasedo (3) Semustine (methyl CCNU)CINV (severe-2hrs)Myelosuppressiondo (4) Streptozocin (methylation of protein & nucleic acid)CINV (severe-2 hrs)No MyelosuppressionPancreatic islet cell tumorCarcinoid tumor Alkyl Sulfonates(Intra strand cross linking of DNA by 2 N7 Guanine) BUSULFAN {Dealkylating agent)Hyperuricemia(MC)Sterility, gynecomastia, seizures, Skin pigmentation, Adrenal insufficiency Pulmonary fibrosis (specific)CM L-DOC until imatinibConditioning of BM transplant Ethyl Enimines Thiotepa(Organophosphorous)CINVMyelosuppressionSeldom used nowNon ClassicalAlkylatingAgentsTriazenes Acts on RNA &Protein synthesis not/ mild DNADacarbazine (Active- methyl carbonium ion)CINV-severePermanent sterility Myelos uppre ssion (early/classical)MAID-sarcoma, ABVD-Hodgkins Malignant melanoma (most active agent) Procarbazine (autoxidize spontaneously, Active- Azoprocarbazine, crosses BBB)CINV, MAO inhibitor Disulfiram like reactionMyelosuppression,DermatitisLeukenogenic,teratogenicMOPP-Hodgkin'sPCV-Glioblastoma AltretamineCINV-severe HypotensionNeuro toxic NephrotoxicRefractory ovarian cancerAlkylating Like AgentsPlatinum Compounds 1st gen platinum Inactivated by aluminumCisplatinCINV (most emitogenic)Hypo Mg, K, Ca sec to hypo Mg)Myelosuppression N ephrotoxicity, Ototoxicity Secondary leukemiaCMF-Solidmalignancies2nc generation platinum, Cross resistance- cisplatinCarboplatinCINV (cis>carbo)Myelosuppression(carbo>ds)No nephrotoxicityLess potent than cisplatin (1:4) GemCarco-Iung cancer3rd generation platinum No cross resistanceOxaliplatinPSN pathy (reversible hand & foot, temp loss)Neurotoxicity (dose limiting)No nephrotoxicity PSN pathyflrreversible, hand, foot, leg, arm, temp loss, propio loss)FOLFOX- colon cancerCis/carboplatin resistance AntimetabolitesFolate Antagonists S phase specificMethotrexate HepatotoxicityMyelosuppressionMucositisChoriocarcinoma DOC, ALL, Osteosarcoma. RA, ectopic Myasthenia, psoriasis, meningeal leukemia (intrathecal route)Inhibits DMA syn thesisPemetrexed : Mesothelioma, nonsmall cell lungNo acute toxicidesPurine Analogue Commonly used in acute leukemias6 THIO Guanine MyelosuppressionHepatotoxicityAdult acute leukemia 6 Mercapto Purine Myelosupp ression, hepatotoxicityChildhood acute leukemia Fludrabine Myelosuppression, Flu like symptom (fever, myalgia, arthralgia) Cladribine Myelosuppression, Nephrotoxic, ClXVHairy cell leukemia Pentostatin NephrotoxicHairy cell leukemia Pyrimidine Analogue 5 Fluorouracil (5-FU) GI upset-diarrhea (MC) Hand foot syndrome, CINVMyelosuppression, neurotoxicity Cerebellar ataxia Cytrabine Stomatitis, CINV, Cerebellar ataxia MyelosuppressionAML Capecitabine CINV, Diarrhea, Hand foot syndrome Myelosupp ression (<5FU)Metastatic breast cancer, Metastatic colorectal cancer Gamecitabine CINV, Myelosuppression (dose limiting)Pancreatic cancer DOC Bladder & Nonsmall cell lung CaAntibioticsAnthracyclinsTopoisomerase 2 inhibitor (me)Quinone Free radical injury & intercalation b/n DNA strandsMembrane binding (responsible for cardiotoxicity) Doxorubicin (Adriamycin)CINV, AlopeciaMyelosuppression (dose limiting, neutropenia >th rombocytopenia) Cardiotoxicity(cardiomy opathy, CHF)Radiation recall Hand foot syndromeBroad spectrum Solid tumors & sarcomas (rhabdo/ leiomyosarcoma, Kaposi sarcoma) DaunorubcinCl MV, AlopeciaMyelosuppression, cardiotoxicity, radiation recallNarrow spectrum AML Idarubcin (synthetic Daunorubicin analogue)CINV, Alopecia, Red urine (not hematuria)Myelosuppression, cardiotoxicity, radiation recallAML (more efficacious than daunorubicin) MitoxantroneCINV, Bluish discoloration of nailsMyelosuppression (dose limiting)Lower cardiotoxicity? Other Antibiotics Bleomycin(Glyco peptide Antibiotic) Free radical injury - ds- ss DMA breaks, have both DNA & Fe binding domainAllergic reaction HypotensionPulmonary fibrosis (dose limiting)Mucocutaneous toxicity? Marrow sparingHL, NHL, SCC Malignant pleural effusionAscitis (sclerosing agent) Mitomycin- CActs as alkylating agentCINVHemolytic uremic syndrome. Pulmonary- fibrosis, 8th nerve damageRadiosensitizer- DOC, SCC Dactinomycin Inhibits all forms of DMA dependent RMA synthesis, r-RNA most sensitiveCINVMyelosupp ression Alopecia Radiation recallPediatric tumors (Ewing's, witm's, Rhabdomyosarcoma) Radiosensitizer ActinomycinCINVDesquamationMyelosuppressionAlopeciaPediatric tumors (Ewing's, wilm's, Rhab domyosarcoma) Radiosensitizer PlicamycinCINV EnzymeL-ASPARGINASE (inhibits protein synthesis of tumor cell by depletion of L-Aspargine)Anaphylaxis/ hyper sensitivity- fever, chills, rash, urticaria (brochospasm, hypotension if severe)Hypercoagulable state Pancreatitis, Hepatotoxicity Marrow sparing, no alopeciaALLIneffective in solid tumors(normal cells spared)Plant DerivedVinca AlkaloidsM phase specificInhibits tubulin polymerizationMitotic inhibitors VincristineAlopeciaPSNpathySIADH, Marrow sparingLymphosarcoma, wilm's, Ewing's Remission of childhood acute leukemia. VinblastineAlopecia (Vc >Vb)PSNpathy (Vc >Vb) MyelosuppressionHodgkin s, testicular carcinoma EpipodophylotoxinsTopoisomerase 2 inhibitor Etopside (VP-16)CINV, HypotensionMyelosuppression, early onset secondary leukemia (1-3 years) alopecia Teniposide (VP-26) TaxansM phase specificEnhance tubulin polymerizationSpindle poison PaclitaxelHypersensitivityPSNpathy (stocking glove type) Myelosuppression,Cisplatin resistance Relapse &resistant breast/ovary ca Docetaxel (more potent)HypersensitivityMyelosuppression, PSNpathy (is less frequent)Cisplatin resistance, Relapse-resistant br/ovary ca CamptothecinTopoisomerase 1 inhibitorss DNA breaks TopothecanCINVMyelosuppression (dose limiting) Irinothecan (active = SN-38)CINV, Cholinergic syndrome (SLUDGE) including early diarrhea-24hrsMyelosuppression, cholinergic syndrome (SLUDGE) including late diarrhea 3-10d (dose limiting)Advanced colorectal ca- DOCMiscellaneousArsenic Trioxide (degradation of PM LI & RARa protein)Headache, lightheadednessCINVCardiotoxicity (QT prolongation, arrhythmias), Myelosuppression Syndrome-fever, fluid retention, wt gain, rashAPL-induction in tretinoin relapse and refractoryHydroxyurea has 100% oral bioavailabilityHydroxyurea (inhibits ribonucleotide reductase - inhibits DMA synthesis)CINVMyelosuppression (dose limiting)HyperpigmentationCMLAML-blast crisis Imatinib (Bcr-Abl Tyrosine kinase inhibitor)CINVFluid retention, Ankle & perioral edemaCML-chronic phase GIST with Ckit tyrosine kinase Dasatinib & Nilotinib (novel agents- TK inhibitors) CML- imatinibresistance/intoleranceAnticancer Drug Toxicities:MYELOSUPPRESSIONAll except Asparginase, Vincristine, BleomycinCARDIOTONICAnthracyclins, arsenic trioxideNEPHROTOXICPlatinum compounds (cisplatin>carboplatin>oxaliplatin)PULMONARY FIBROSISBleomycin. Busulfan, CarmustinePERIPHERAL NEUROPATHYGxaliplatin, vincristine Taxans (stoking & glove type)HAEMORRHAGIC CYSTITISCyclophosphamide, IfosfamideHAND FOOT SYNDROME5FU, Capecitabine, DoxorubicinCEREBELLAR ATAXIAPyrimidine analogs like Cytrabine & 5FUSIADHCyclophosphamide, VincristineSECONDARY LEUKEMIAAll alkylating agents & alkylating like agents (in 4-5 years) E topside (in 1-3 years)STERLITYAlkylating agentsDISULFIRAM LIKE REACTIONProcarbazineCHOLINERGIC SYNDROMEIrinitecanRADIATION RECALL SYNDROMEAnthracydinsAnticancer Drugs Toxic Amelioration:ToxicityMeasuresMethotrexateFolinic acidAlkalization of urine (Mtz is weak acid & reabsorbed in acidic urine)Hemorrhagic cystitis (cyclophosphamide, ifosfamide)ME SNA (2 mercapto ethyl sulfonyl sodium) systemic ACETYLCYSTEINE irrigation of bladderHigh fluid intakeFrequent voidingCINV (Cytotoxic drug induced nausea Stvomiting )Ondansetron (5HT3 Antagonist)Cytotoxic drug induced MucositisPabfermin (human recombinant keratinocyte growth factor)TUMOR LYSIS SYNDROME (hyperkalemia, hypophosphatemia, hyperuricemia, hypemricosuria, hypocalcaemia, acute renal failure)prophylactic ALLOPURINOL (xanthine oxidase inhibitor)alternatively RASBURICASE (urkase)Aggressive hydrationHigh urine outputAlkalization of urine not recommended/controversialDiuresis is reserved for well hydrated patientsHEMODIALYSIS (if above fails) MYE LOS OPPRESSIONFor AnemiaERYTHROPOIETIN (recombinant)For NeutropeniaFILGRASTIM- Granulocyte colony-stimulating factor (G-CSF) analogSARGRAMOSTTM - Recombinant granulocyte macrophage colony stimulating factor (GM-CSF)For ThrombocytopeniaOPRELVEKIN (IL-11)BONE MARROW TRANSPLANT (for extreme suppression)CANCER CACHEXIATHALIDOMIDECYTOPROTECTION of normal tissueAMIFOSTINE= WTR-2721=prodrug(active = free thiol=WR-1065. activation normal tissue)USES=cispIatin based chemotherapy & radiation therapyAnthracyclins induced CARDIOTOXICITYDEXRAZOXAXE (ICRF-187) Iron chelating agent Cardio protective agent, derivative of EDTA