CANCER CHEMOTHERAPY

ACRONYM OF REGIMEN

Hodgkin's lymphoma(stage 3 & 4)

ABVD Adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine

BEACOPP Bleomycin, etoposide, Adriamycin (doxorubicin), cyclophosphamide, Oncovin (vincristine), procarbazine, prednisoneMOPP Mechlorethamine, Oncovin (vincristine), procarbazine, prednisoneStanford V Doxorubicin, mechlorethamine, bleomycin, vinblastine, vincristine, etoposide, prednisoneVAPEC-B Vincristine, Adriamycin (doxorubicin), prednisone, etoposide, cyclophosphamide, bleomycin

Non-Hodgkin lymphoma, CLL CHOP Cyclophosphamide, hydroxydoxorubicin (doxorubicin), vincristine (Oncovin), prednisone (TOC)m-BACOD Methotrexate, bleomycin, Adriamycin (doxorubicin), cyclophosphamide, Oncovin (vincristine), dexamethasoneMACOP-B Methotrexate, leucovorin (folinic acid), Adriamycin (doxorubicin), cyclophosphamide, Oncovin (vincristine), prednisone,

bleomycinCOPP Cyclophosphamide, Oncovin (vincristine), procarbazine, prednisone

Non-Hodgkin lymphoma in patients with history of cardiovascular disease

COP or CVP Cyclophosphamide, Oncovin (vincristine), prednisone

B cell non-Hodgkin lymphoma CHOP-R or R-CHOP

CHOP + rituximab

R-FCM Rituximab, fludarabine, cyclophosphamide, mitoxantroneLymphoma CBV Cyclophosphamide, BCNU (carmustine), VP-16 (etoposide)

EPOCH Etoposide, prednisone, Oncovin, cyclophosphamide, and hydroxydaunorubicinAggressive lymphomas, progressive neuroblastoma

ICE ifosfamide, carboplatin, etoposide (VP-16)

High-risk progressive or recurrent lymphomas

ICE-R ICE + rituximab

Breast cancer AC Adriamycin (doxorubicin), cyclophosphamideCA Cyclophosphamide, Adriamycin (same as AC)CAF Cyclophosphamide, Adriamycin , fluorouracil (5-FU)CMF Cyclophosphamide, methotrexate, fluorouracil (5-FU)EC Epirubicin, cyclophosphamideFEC Fluorouracil (5-FU), epirubicin, cyclophosphamide

Colorectal cancer FL (Aka- Mayo) Fluorouracil (5-FU), leucovorin (folinic acid)

FOLFOX Fluorouracil (5-FU), leucovorin (folinic acid), oxaliplatinFOLFIRI Fluorouracil (5-FU), leucovorin (folinic acid), irinotecan

Testicular cancer, germ cell tumors

BEP Bleomycin, etoposide, platinum agent (cisplatin)

EP Etoposide, platinum agent (cisplatin)VIP Etoposide, ifosfamide, platinum agent cisplatinTIP Paclitaxel, ifosfamide, platinum agent cisplatin

Multiple myeloma Thal/Dex Thalidomide, dexamethasoneVAD Vincristine, Adriamycin (doxorubicin), dexamethasone

Brain tumors PCV Procarbazine, CCNU (lomustine), vincristineLung cancer CAV Cyclophosphamide, Adriamycin (doxorubicin), vincristineRhabdomyosarcoma VAC Vincristine, Actinomycin, CyclophosphamideGastric cancer and oesophageal cancer

ECF Epirubicin, cisplatin, fluorouracil (5-FU)

Sarcoma MAID Mesna, Adriamycin (doxorubicin),ifosfamide, dacarbazine

LOG KILL HYPOTHESIS

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

ALKYLATING AGENTSANTICANCER ANTIBODIESPLATIMUM AMALOGS

TOXICITIES

MYELOSUPPRESSION All except Asparginase, Vincristine, BleomycinCARDIOTOXIC Anthracyclins, arsenic trioxideNEPHROTOXIC Platinum compounds (cisplatin>carboplatin>oxaliplatin)PULMONARY FIBROSIS Bleomycin, Bsulfan, CarmustinePERIPHERAL NEUROPATHY Oxaliplatin, vincristine

Taxans (stoking & glove type)HAEMORRHAGIC CYSTITIS Cyclophosphamide, IfosfamideHAND FOOT SYNDROME 5FU, Capecitabine, DoxorubicinCEREBELLAR ATAXIA Pyrimidine analogs like Cytrabine & 5FUSIADH Cyclophosphamide, VincristineSECONDARY LEUKEMIA All alkylating agents & alkylating like agents (in 4-5 years)

Etopside(in 1-3 years)STERLITY Alkylating agentsDISULFIRAM LIKE REACTION ProcarbazineCHOLINERGIC SYNDROME IrinitecanRADIATION RECALL SYNDROME Anthracyclins

TOXIC AMELIORATION

TOXICITY MEASURESMethotrexate Folinic acid

Alkalynization of urine (Mtz is weak acid &reabsorbed in acidic urine)Hemorrhagic cystitis (cyclophosphamide, ifosfamide) MESNA ( 2 mercapto ethyl sulfonyl sodium) systemic

ACETYLCYSTEINE irrigation of bladderHigh fluid intakeFrequent voiding

CINV (Cytotoxic drug induced nausea &vomiting ) Ondansetron (5HT3 Antagonist)TUMOR LYSIS SYNDROME (hyperkalemia, hyperphosphatemia, hyperuricemia, hyperuricosuria, hypocalcemia, acute renal failure)

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)

MYELOSUPPRESSION SARGRAMOSTIMRecombinant GM-CSF/G-CSFBONE MARROW TRANSPLANT (for extreme suppression)

CANCER CACHEXIA THALIDOMIDECYTOPROTECTION of normal tissue AMIFOSTINE= WR-2721=prodrug

(active= free thiol=WR-1065, activation @normal tissue)USES=cisplatin based chemotherapy & radiation therapy

Anthracyclin induced CARDIOTOXICITY DEXRAZOXANE (ICRF-187) Iron chelating agentCardio protective agent, derivative of EDTA

CLASSIFICATION

ALKYLATING AGENTS NITROGEN MUSTARD ACUTE TOXICITY DELAYED TOXICITY USES

(Alkylation of DNA at N7 & O6 position of Guanine→DNA cross linking b/n 2 strands→ prevents duplication

(1)MECHLORETHAMINE(First anticancer drug)

CINV-chemo induced nausea vomiting (4hr-48hrs)Myelosuppression

Myelosuppression (delayed type-onset=7d, Nadir=10-14d, recovery=21-28d)Alopecia

MOPP-hodgkins lymphoma

AA are commonly used in chronic leukemia

(2)CYCLOPHOSPHAMIDE[CP→4hydroxyCP↔aldophosphamide→ Acrolein (toxic) & phosphamide mustard (active)]

CINVMyelosuppression(CP>Ifo)

Myelosuppression (CP>Ifo) Alopecia, SIADHHemorrhagic cystitis (Ifo>CP)Sec cancer-transitional cell cancer of bladder

Wagners granulomatosis DOCCMF-Breast, small cell lung caBroad spectrum

AA are non phase specific

(3)IFOSFAMIDE4hydroxy ifosfamide (active)

CINVMyelosuppression (CP>Ifo)

Myelosuppression (CP>Ifo)AlopeciaHemorrhagic cystitis (Ifo>CP)

Broad spectrumLung, breast, ovary, sarcoma, testis, germ cell tumour

AA causes secondary leukemia in 4-5 years

(4)MELPHAN amino acid derivative of mechloretamine

CINVMyelosuppression

MyelosuppressionNo alopecia

Multiple lyeloma DOCCan replace C in CMF

(5)CHLORAMBUCIL MyelosuppressionCINV is rare

MyelosuppressionNo alopecia

CLL, Hodgkins

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 fibrosis

Brain tumors DOC(Glioblastoma multiforme, astrocytoma,medulloblastoma)

(2)LOMUSTINE (CCNU) CINV (severe-2hrs) MyelosuppressionInterstitial lung disease

do

(3)SEMUSTINE (methyl CCNU) CINV (severe-2hrs) myelosuppression do(4)STREPTOZOCIN (methylation of protein & nucleic acid)

CINV (severe-2hrs) No myelosuppression Pancreatic islet cell tumourCarcinoid tumour

ALKYL SULFONATES (Intra strand cross linking of DNA by 2 N7 Guanine)BUSULFAN (Dealkylating agent) Hyperuricemia (MC) Sterlity, gynecomastia, seizures, Skin

pigmentation, Adrenal insufficiencyPulmonary fibrosis (specific)

CML-DOC until imatinibConditioning of BM transplant

ETHYL ENIMINESTHIOTEPA (Organophosphorous) CINV myelosuppression Seldom used now

NON CLASSICAL ALKYLATING AGENTS

TRIAZENES

Acts on RNA &Protein synthesis not/mild DNA

DACARBAZINE (Active-methyl carbonium ion)

CINV-severe Permanent sterilityMyelosuppression (early/classical)

MAID-sarcoma, ABVD-hodgkinsMalignant melanoma (most active agent)

PROCARBAZINE (autoxidize spontaneously, Active-Azoprocarbazine, crosses BBB)

CINV, MAO inhibitorDisulfiram like reaction

Myelosuppression, DermatitisLeukenogenic, teratogenic

MOPP-hodgkinsPCV-glioblastoma

ALTRETAMINE CINV-severeHypotension

NeurotoxicNephrotoxic

Refractory ovarian cancer

ALKYLATING LIKE AGENTS

PLATINUM COMPOUNDS

1ST gen platinumInactivated by aluminum

CISPLATIN CINV (most emitogenic)Hypo Mg, K, Ca sec to hypo Mg)

MyelosuppressionNephrotoxicity,OtotoxicitySecondary leukemia

CMF-Solid malignancies

2nd generation platinum, Cross resistance-cisplatin

CARBOPLATIN CINV (cis>carbo) Myelosuppression (carbo>cis)No nephrotoxicity

Less potent than cisplatin (1:4)GemCarco-lung cancer

3rd generation platinumNo cross resistance

OXALIPLATIN PSN pathy (reversible hand & foot, temp loss)

Neurotoxicity (dose limiting)No nephrotoxicityPSN pathy(irreversible, hand, foot, leg, arm, temp loss, propio loss)

FOLFOX- colon cancerCis/carboplatin resistance

ANTIMETABOLITES FOLATE ANTAGONISTSS phase specific METHOTREXATE Hepatotoxicity

MyelosuppressionMucositis

Choriocarcinoma DOCALL, Osteosarcoma, RA, ectopic Myasthenia, psoriasis, meningeal leukemia (intrathecal route)

Inhibits DNA synthesis PEMETREXED Mesothelioma, non small cell lung

No acute toxicities PURINE ANALOGUECommonly used in acute leukemias

6 THIO GUANINE MyelosuppressionHepatotoxicity

Adult acute leukemia

6 MERCAPTO PURIME Myelosuppression, hepatotoxicity Childhood acute leukemiaFLUDRABINE Myelosuppression, Flu like symptom

(fever, myalgia,arthralgia)CLADRIBINE Myelosuppression, Hairy cell leukemia

Nephrotoxic, CINVPENTOSTATIN Nephrotoxic Hairy cell leukemiaPYRIMIDINE ANALOGUE5 FLUOROURACIL (5FU) GI upset-diarrhoea (MC)

Hand foot syndrome, CINVMyelosuppression, neurotoxicityCerebellar ataxia

CYTRABINE Stomatitis, CINV, Cerebellar ataxia myelosuppression

AML

CAPECITABINE CINV,Diarrhoea,Hand foot syndromeMyelosuppression (<5FU)

Metastatic breast cancerMetastatic colorectal cancer

GAMECITABINE CINV, Myelosuppression (dose limiting)

Pancreatic cancer DOC Bladder & Non small cell lung Ca

ANTIBIOTICS ANTHRACYCLINS Topoisomerase 2 inhibitor (mc)

Quione Free radical injury & intercalation b/n DNA strands

Membrane binding (responsible for cardiotoxicity)

DOXORUBICIN (ADRIAMYCIN) CINV, Alopecia Myelosuppression (dose limiting, neutropenia>thrombocytopenia)Cardiotoxicity(cardiomyopathy,CHF)Radiation recallHand foot syndrome

Broad spectrumSolid tumors & sarcomas (rhabdo/ leiomyosarcoma, Kaposi sarcoma)

DAUNORUBICIN CINV, Alopecia Myelosuppression, cardiotoxicity, radiation recall

Narrow spectrumAML

IDARUBICIN (synthetic Daunorubicin analogue)

CINV, Alopecia, Red urine(not hematuria)

Myelosuppression, cardiotoxicity, radiation recall

AML (more efficacious than daunorubicin)

MITOXANTRONE CINV, Bluish discoloration of nails

Myelosuppression (dose limiting)Lower cardiotoxicity

OTHER ANTIBIOTICSBLEOMYCIN(Glyco peptide Antibiotic)Free radical injury→ds-ss DNA breaks, have both DNA & Fe binding domain

Allergic reactionHypotension

Pulmonary fibrosis (dose limiting)Mucocutaneous toxicityMarrow sparing

HL, NHL, SCCMalignant pleural effusionAscitis (sclerosing agent)

MITOMYCIN- CActs as alkylating agent

CINV Hemolytic uremic syndromePulmonary fibrosis8th nerve damage

Radiosensitizer-DOCSCC

DACTINOMYCINInhibits all forms of DNA dependent RNA synthesis, r-RNA most sensitive

CINV MyelosuppressionAlopeciaRadiation recall

Pediatric tumors (Ewing’s, wilm’s, Rhabdomyosarcoma)Radiosensitizer

ACTINOMYCIN CINVDesquamation

MyelosuppressionAlopecia

Pediatric tumors (Ewing’s, wilm’s, Rhabdomyosarcoma)Radiosensitizer

PLICAMYCIN CINVENZYME L-ASPARGINASE (inhibits protein

synthesis of tumor cell by depletion of L-Aspargine)

Anaphylaxis/hypersensitivity-fever,chills,rash,uticaria (brobchospasm,hypotension if severe)

Hypercoagulable statePancreatitis, HepatotoxicityMarrow sparing, no alopecia

ALLIneffective in solid tumors(normal cells spared)

PLANT DERIVED VINCA ALKALOIDS M phase specific Inhibits tubulin polymerization Mitotic inhibitorsVINCRISTINE Alopecia PSNpathy

SIADH, Marrow sparingLymphosarcoma, wilm’s, Ewing’sRemission of childhood acute leukemia.

VINBLASTINE Alopecia (Vc>Vb) PSNpathy (Vc>Vb)Myelosuppression

Hodgkin’s, testicular carcinoma

EPIPODOPHYLOTOXINS Topoisomerase 2 inhibitorETOPSIDE (VP-16) CINV, Hypotension Myelosuppression, early onset

secondary leukemia (1-3 years) alopecia

TENIPOSIDE (VP-26)TAXANS M phase specific Enhance tubulin polymerization Spindle poisonPACLITAXEL Hypersensitivity PSNpathy (stocking glove type)

Myelosuppression ,Cisplatin resistanceRelapse &resistant breast/ovary ca

DOCETAXEL (more potent) Hypersensitivity Myelosuppression, PSNpathy (is less frequent)

Cisplatin resistance,Relapse-resistant br/ovary ca

CAMPTOTHECIN Topoisomerase 1 inhibitor ss DNA breaksTOPOTHECAN CINV Myelosuppression (dose limiting)IRINOTHECAN (active= SN-38) CINV, Cholinergic syndrome

(SLUDGE) including early diarrhea-24hrs

Myelosuppression, cholinergic syndrome (SLUDGE) including late diarrhea 3-10d (dose limiting)

Advanced colorectal ca- DOC

MISCELLANIOUS ARSENIC TRIOXIDE (degradation of PMLI & RARα protein)

Headache, light headednessCINV

Cardiotoxic (QT prolongation, arrhythmias), myelosuppressionSyndrome-fever, fluid retention, wt gain, rash

APL-induction in tretinoin relapse and refractory

Hydroxyurea has 100% oral bioavailability

HYDROXYUREA (inhibits ribonucleotide reductase→inhibits DNA synthesis)

CINV Myelosuppression (dose limiting)Hyperpigmentation

CMLAML-blast crisis

IMATINIB (Bcr-Abl Tyrosine kinase inhibitor)

CINV Fluid retention, Ankle & perioral edema

CML-chronic phaseGIST with Ckit tyrosine kinase

DASATINIB & NILOTINIB (novel agents- TK inhibitors)

CML- imatinib resistance/intolerance

SPECIFIC CHEMOTHERAPY REGIMENS

(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.