Nancy T. Sklarin, MD, MS
Director of Chemotherapy Practice MSKCC
The following material is intended for MSKCC internal med...
 Develop a framework for understanding
antineoplastic chemo and biotherapeutic agents
 Review basic chemotherapy princip...
 Surgery
 Radiation
 Mechanical
 Cytotoxic chemotherapy
 Molecularly targeted therapies
 Immunologic therapy
 Hormo...
 Surgery
• Localized disease
 Often the most effective and definitive curative therapy
 Local control of mass even in s...
 Cure
• As an adjunct to surgery
• As an adjunct to radiation
• Curative single modality therapy
 Prevention
• Hormonal ...
 Adjuvant Therapy
• Treatment given after the primary treatment to lower the risk of
recurrence caused by micrometastatic...
 Palliative therapy
• Treatment not curative, but given to relieve symptoms and reduce
suffering caused by the disease
 ...
 Therapeutic Index
• Ratio of the doses that cause therapeutic effect versus toxicity
 Dose Limiting Toxicity (DLT)
• A ...
 Phase I
• First time using the drug in humans
• Evaluate safety, toxicities and establish safe dose of the agent
 Phase...
 Narrow therapeutic-safety index
• Small Δ dose  Large Δ toxicity
 Potentially lethal toxicities
• Marrow, pulmonary, h...
Cancer cells lose regulatory mechanisms for differentiation, growth
arrest, and self-renewal capacity that allows for loss...
 Growth fraction:
Percentage of cells that are growing starts at
100% and declines exponentially over time
with increasin...
Most cancers have
found a mechanism
to evade the normal
checkpoints of the
cell cycle.
 Non-Cell cycle-specific agents
• Kill both resting and replicating cells
• Induce apoptosis through DNA damage
• Interru...
CHEMOTHERAPY TARGETED THERAPY
Antimetabolites Tyrosine kinase inhibitors
Alkylators mTOR inhibitors
Topoisomerase inhibito...
 Structural analogues of cellular substrates
• Incorporated into DNA & RNA causing transcription to
halt purine or pyrimi...
 Methotrexate
• Competitively inhibits DHFR & inhibits conversion
of FH2 FH4 necessary for reduced folates.
• Leukemia, ...
• Leucovorin starts 24 hours after moderate-high doses
methotrexate to “rescue” normal cells
• High-dose:
 Metabolized to...
 Pemetrexed
• Mesothelioma
• Myelosuppression, mucositis, rash
• Must give folic acid & B12
 Pralatrexate
• Peripheral T...
 6 Mercaptopurine
• ALL, AML
• If give with allopurinol, must decrease mercaptopurine by 75%
• Myelosuppression, mucositi...
 Cladribine
• Hairy cell leukemia. Waldenström's, CLL
• Myelosuppression, neuropathy, fever, fatigue
 Pentostatin (2-deo...
 5-Fluorouracil
• Inhibits thymidylate synthase & inhibits conversion of dUMP dTMP
• Colon, gastric, breast, pancreatic,...
 Capecitabine
• Oral drug converted to 5-FU
• Breast, colon
• Diarrhea, mucositis, myelosuppression, coronary spasm,
palm...
 Cytosine arabinoside (ara-C)
• AML, lymphomas, MDS, ALL
• Myelosuppression, cerebellar, mucositis, hepatic, conjunctivit...
 Alkyl groups covalently bind to DNA
strands
• Leads to cross-linking of DNA strands, abnormal base
pairing, and breaks i...
 Mechlorethamine
• Hodgkin, Lymphoma, mycosis fungoides
• ++nausea
 Cyclophosphamide
• Breast, lymphoma, myeloma, ITP, R...
 Chlorambucil
• CLL, Waldenstrom’s, lymphoma
• oral
 Melphalan
• Myeloma
• Oral/IV
 Bendamustine
• CLL
• Delayed myelos...
Lipophilic, late nadir
 Carmustine (BCNU)
• Brain, Melanoma, lymphoma
• Pneumonitis, hepatotoxicity
 Lomustine (CCNU)
• ...
 Busulfan
• CML, transplant
• Lipophilic
• Pneumonitis, skin, wasting
Aziridine
 Thiotepa
• Transplant
• Intrathecal
 Dacarbazine
• Hodgkin, sarcoma, neuroblastoma, melanoma
• ++ nausea, flu-like
 Procarbazine
• Hodgkin, lymphoma
• Oral
...
 Cause cross-links in DNA
• Causes strand breaks
 Toxicities
• Peripheral neuropathy
• Nephrotoxic
• Myelosuppression
• ...
 Cisplatin
• Ovarian, germ cell, lung, H/N
• Nephrotoxicity, ototoxicity, ++nausea
• Requires large amts of hydration + m...
 Intercalate into DNA directly
• Disrupt transcription & replication
• Generate free radicals damage DNA
• Topoisomerase ...
 Life-time cumulative dose dependent
• Varies by drug
 Get echocardiogram or MUGA prior to therapy
 Heart failure may b...
 Doxorubicin
• Breast, sarcoma, lymphoma, myeloma, bladder, thyroid, endometrial
 Daunorubicin
• AML, ALL, lymphoma
 Ep...
 Bleomycin
• Lymphoma, germ cell, H&N, skin
• Pulmonary, fever, hypersensitivity
 Mitomycin
• Gastric, H/N, bladder, lun...
 Mechanism
• Topoisomerase I: creates single strand breaks in DNA
• Topoisomerase II: creates double strand breaks in DNA...
 Irinotecan
• Colorectal, lung, breast
 Topotecan
• Ovarian, small cell lung
• Flu-like
Topoisomerase II
 Etoposide
• L...
Vinca alkaloids
 Mechanism
• Depolymerize microtubules & interfere w/mitotic
function
 Excretion: biliary
 Toxicities
•...
Vincristine
• ALL, lymphoma, Hodgkin, myeloma, neuroblastoma, Ewi
ng’s, Wilms
• SIADH, no myelosuppression
Vinblastine
•...
 Mechanism
• Prevent microtubule disassembly
 Excretion: biliary
Toxicities
• Hypersensitivity
• Neutropenia
• Peripher...
 Paclitaxel
• Ovarian, breast, lung, GI, H/N, bladder, esophagus, KS
• Need Premeds: steroid, antihistamines 1 & 2
 Doce...
 Eribulin
• Inhibits tubulin polymerization
• Breast
• Myelosuppression, fatigue
• Modify dose in biliary or renal diseas...
 L-asparaginase
• ALL
• Hypersensitivity, fever, chills, coagulopathy, pancreatitis,
LFTs, CNS
 Hydroxyurea
• CML, P. ve...
 Thalidomide
• Myeloma, melanoma, e. nodosum
• Category X, rash, somnolence
 Lenalidomide
• Myeloma, MDS
• Pulm emboli
 Aldesleukin, Interleukin
• Renal, Melanoma
• rHu-IL2 - enhances lymphocyte activity
• flu-like, capillary leak, somnolen...
SOS
Akt
MAPK
P
SurvivalNucleus
PI3-K
MEK
Proliferation
Mobility Invasiveness
VEGF
erlotinib
gefitinib
mTOR
FKHR GSK-3
Bad
...
TARGET DRUG (generic) DRUG (brand) DISEASE
HER2 lapatinib Tykerb® Breast
trastuzumab Herceptin® Breast, Gastric
pertuzumab...
TARGET DRUG (generic) DRUG (brand) DISEASE
Histone deacetylase vorinostat Zolinza® CTCL
romidepsin Istodax® CTCL
Retinoid ...
TARGET DRUG (generic) DRUG (brand) DISEASE
CTLA-4 ipilimumab Yervoy® Melanoma
CD20 rituximab Rituxan® Lymphoma
ofatumumab ...
 Reduce dose
 Improve elimination of metabolites
• Hydration / diuresis
 Alter schedule of therapy
• Frequent low dose
...
 Tumor heterogeneity
 Efflux pumps
 Increased rate of DNA repair
 Changes in the drug sensitivity
of a target enzyme
...
 Drugs
• Vesicants - anthracyclines, vinca alkaloids
• Irritants - taxanes
 Signs/Symptoms
• Pain, Redness, Swelling
• D...
GUIDELINE ORDER SET
 Goal
• Target cells not equally sensitive to a single drug
• Avoid selection of resistant cell lines
 Choosing drugs fo...
 CHOP: lymphoma
• cyclophosphamide, doxorubicin, vincristine, prednisone
 FOLFIRI: colon
• leucovorin 5-FU, irinotecan
...
Chemotherapy 101
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Chemotherapy 101

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Chemotherapy 101

  1. 1. Nancy T. Sklarin, MD, MS Director of Chemotherapy Practice MSKCC The following material is intended for MSKCC internal medicine house staff teaching purposes only. The slides were updated for the LibGuide in 2013-2014.
  2. 2.  Develop a framework for understanding antineoplastic chemo and biotherapeutic agents  Review basic chemotherapy principles  Discuss some common chemotherapeutic agents and side effects
  3. 3.  Surgery  Radiation  Mechanical  Cytotoxic chemotherapy  Molecularly targeted therapies  Immunologic therapy  Hormonal therapy Local/Regional Systemic
  4. 4.  Surgery • Localized disease  Often the most effective and definitive curative therapy  Local control of mass even in setting of metastases • Metastatic disease  Curative in rare cases – solitary liver metastasis in colon cancer  Relief of compression - solitary brain, spinal cord  Bowel obstruction  Radiation • Cure or control of localized disease • Prophylaxis of sites at high risk for metastasis • Palliation for relief of  pain, spinal cord compression, brain metastases, organ obstruction, bleeding mass  Mechanical • Stents to bypass obstructions • Radiofrequency ablation of isolated lung metastases • Embolization of bleeding tumor or liver metastasis
  5. 5.  Cure • As an adjunct to surgery • As an adjunct to radiation • Curative single modality therapy  Prevention • Hormonal therapy as chemoprophylaxis for breast cancer • Imatinib in CML  Improved survival in metastatic disease  Palliation of symptoms
  6. 6.  Adjuvant Therapy • Treatment given after the primary treatment to lower the risk of recurrence caused by micrometastatic or residual disease; • Usually with curative intent  Neoadjuvant therapy • Treatment to shrink tumor before main treatment; usually surgery • Goals:  Improve operability  Preserve anatomic structure: larynx, anal sphincter, breast  Assess responsiveness of tumor to chemotherapy  Salvage therapy • Treatment given after the cancer has not responded to other treatments. • May be for curative intent
  7. 7.  Palliative therapy • Treatment not curative, but given to relieve symptoms and reduce suffering caused by the disease  Dose-dense or Accelerated therapy • Chemotherapy given more frequently or at higher dose to attempt to kill tumor cells early in the regrowth phase • Requires colony stimulating factor support  High-dose therapy  Regimen given at doses so high that counts would not recover on their own  Requires stem cell support
  8. 8.  Therapeutic Index • Ratio of the doses that cause therapeutic effect versus toxicity  Dose Limiting Toxicity (DLT) • A dose that yields greater than acceptable toxicity  Maximal Tolerated Dose (MTD) • Dose just lower than DLT; usually the dose suitable for phase II trials  NCI Common Toxicity Criteria • Standard toxicity definitions used to communicate level of toxicity
  9. 9.  Phase I • First time using the drug in humans • Evaluate safety, toxicities and establish safe dose of the agent  Phase II • Is the drug effective • Establish further dosing and safety data  Phase III • Confirm effectiveness • Monitor side effects • Compare to established agents
  10. 10.  Narrow therapeutic-safety index • Small Δ dose  Large Δ toxicity  Potentially lethal toxicities • Marrow, pulmonary, hepatic  Wide range of dosing for some drugs • Appropriate methotrexate dose can be 12mg or 12,000 mg • More difficult to judge if orders are correct  Complex regimens • Multidrug, multiday  Many research protocols • Unfamiliar drugs and schedules
  11. 11. Cancer cells lose regulatory mechanisms for differentiation, growth arrest, and self-renewal capacity that allows for loss of tissue architecture and homeostasis.
  12. 12.  Growth fraction: Percentage of cells that are growing starts at 100% and declines exponentially over time with increasing tumor burden  Growth rate: Slowly progresses to an exponential phase, and slows again as the size of the tumor outstrips it blood supply  Treatment Challenge: Treatment results in an increase in the growth fraction and growth rate  Chemotherapy is given in cycles: To allow recovery from toxicity and address regrowth of cancer cells
  13. 13. Most cancers have found a mechanism to evade the normal checkpoints of the cell cycle.
  14. 14.  Non-Cell cycle-specific agents • Kill both resting and replicating cells • Induce apoptosis through DNA damage • Interrupt transcription, translation, and protein synthesis necessary for cellular replication and function • eg: Alkylating agents, Antitumor antibiotics  Cell cycle-specific agents • Block specific parts of the cycle as cells divide • S phase - Antimetabolites • S and G2 phase - Topoisomerase Inhibitors • G2 and M phase - Mitotic Spindle Inhibitors
  15. 15. CHEMOTHERAPY TARGETED THERAPY Antimetabolites Tyrosine kinase inhibitors Alkylators mTOR inhibitors Topoisomerase inhibitors Proteasome inhibitors Antibiotics Histone deacetylase inhibitors Antimicrotubular agents Retinoic acid receptor activators Biologic Response Modifiers Angiogenesis inhibitors Miscellaneous Monoclonal antibodies Vaccines
  16. 16.  Structural analogues of cellular substrates • Incorporated into DNA & RNA causing transcription to halt purine or pyrimidine synthesis • Inhibit enzymes in DNA replication & repair  Toxicities • Myelosuppression • Stomatitis • Diarrhea
  17. 17.  Methotrexate • Competitively inhibits DHFR & inhibits conversion of FH2 FH4 necessary for reduced folates. • Leukemia, lymphoma, breast cancer, head & neck cancers, gestational trophoblastic disease, rheumatologic diseases • Intrathecal route or high-dose IV can penetrate CNS • Toxicities:  Related to length of exposure  Don’t give w/ascites of effusion because accumulates in 3rd space & released over time  Myelosuppression, hepatoxicity, nephrotoxicity, hypersensitivity pneumonitis
  18. 18. • Leucovorin starts 24 hours after moderate-high doses methotrexate to “rescue” normal cells • High-dose:  Metabolized to insoluble form at physiologic pH  Must alkalinize blood & urine to eliminate the drug for mod-high dose  Monitor urine pH, output, creatinine, methotrexate levels daily  Clearly sign out need to follow up urinalyses to covering night staff  Service attending to be notified about decrease in urine pH or oliguria
  19. 19.  Pemetrexed • Mesothelioma • Myelosuppression, mucositis, rash • Must give folic acid & B12  Pralatrexate • Peripheral T-cell lymphoma • Mucositis, ↓ plts, nausea, fatigue • Must give folic acid & B12
  20. 20.  6 Mercaptopurine • ALL, AML • If give with allopurinol, must decrease mercaptopurine by 75% • Myelosuppression, mucositis, jaundice  Nelarabine • T-ALL, T-lymphoblastic lymphoma • Neurotoxic, N/V, myelosuppression, cough  6 Thioguanine • AML, CML, ALL • myelosuppression
  21. 21.  Cladribine • Hairy cell leukemia. Waldenström's, CLL • Myelosuppression, neuropathy, fever, fatigue  Pentostatin (2-deoxycoformycin) • Hairy cell leukemia, CLL • Myelosuppression, renal • Contraindicated with fludarabine (fatal pulmonary toxicity)  Fludarabine • B-cell malignancies • Myelosuppression, immunosuppression, encephalopathy • Contraindicated with pentostatin (fatal pulmonary toxicity)
  22. 22.  5-Fluorouracil • Inhibits thymidylate synthase & inhibits conversion of dUMP dTMP • Colon, gastric, breast, pancreatic, squamous cell • Mucositis, diarrhea, coronary spasm • Leucovorin is synergistic
  23. 23.  Capecitabine • Oral drug converted to 5-FU • Breast, colon • Diarrhea, mucositis, myelosuppression, coronary spasm, palmar-plantar erythrodysesthesia • Warfarin interaction – significantly ↑s INR  Floxuridine • Intrahepatic infusion, intraperitoneal • Colon • Hepatic, myelosuppression, palmar-plantar erythrodysesthesia  Gemcitabine • Pancreatic, lung, breast, bladder, lymphoma • Myelosuppression, malaise, jaundice, hyperpigmentation
  24. 24.  Cytosine arabinoside (ara-C) • AML, lymphomas, MDS, ALL • Myelosuppression, cerebellar, mucositis, hepatic, conjunctiviti s in hi-dose (Rx w steroid drops) • Can be given intrathecally  5-azacytidine • MDS • Myelosuppression, nausea  Decitabine • MDS • Edema, neuro, myelosuppression, hyperglycemia, nausea, con stipation
  25. 25.  Alkyl groups covalently bind to DNA strands • Leads to cross-linking of DNA strands, abnormal base pairing, and breaks in the DNA • Inhibits transcription causing cell-cycle arrest and apoptosis • No discrimination between resting or dividing cells  Toxicities • Myelosuppression • Alopecia • Mucositis • Pulmonary toxicity • Infertility • Immunosuppression • Mutagenic
  26. 26.  Mechlorethamine • Hodgkin, Lymphoma, mycosis fungoides • ++nausea  Cyclophosphamide • Breast, lymphoma, myeloma, ITP, RA • Cystitis, SIADH  Ifosfamide • Sarcoma, germ cell, lymphoma, lung, bladder • Must use mesna to prevent hemorrhagic cystitis • Encephalopathy, SIADH
  27. 27.  Chlorambucil • CLL, Waldenstrom’s, lymphoma • oral  Melphalan • Myeloma • Oral/IV  Bendamustine • CLL • Delayed myelosuppression, fever
  28. 28. Lipophilic, late nadir  Carmustine (BCNU) • Brain, Melanoma, lymphoma • Pneumonitis, hepatotoxicity  Lomustine (CCNU) • Hodgkin, brain, lymphoma • ++nausea  Streptozocin Pancreatic islet, carcinoid Renal, hyperglycemia
  29. 29.  Busulfan • CML, transplant • Lipophilic • Pneumonitis, skin, wasting Aziridine  Thiotepa • Transplant • Intrathecal
  30. 30.  Dacarbazine • Hodgkin, sarcoma, neuroblastoma, melanoma • ++ nausea, flu-like  Procarbazine • Hodgkin, lymphoma • Oral • Avoid MAO inhibitors, TCAs, ETOH  Temozolomide • Glioblastoma, melanoma • Fatigue
  31. 31.  Cause cross-links in DNA • Causes strand breaks  Toxicities • Peripheral neuropathy • Nephrotoxic • Myelosuppression • Nausea/vomiting • Ototoxicity • Hypersensitivity • Electrolyte wasting
  32. 32.  Cisplatin • Ovarian, germ cell, lung, H/N • Nephrotoxicity, ototoxicity, ++nausea • Requires large amts of hydration + mannitol  Carboplatin • Ovarian, lung, germ cell, breast • Milder toxicity  Oxaliplatin • Colorectal, lymphoma • “cold” neuropathy
  33. 33.  Intercalate into DNA directly • Disrupt transcription & replication • Generate free radicals damage DNA • Topoisomerase II inhibitors  Toxicities • Nausea/vomiting • Myelosuppression • Cardiotoxicity • Biliary excretion • Anthracyclines are vesicants
  34. 34.  Life-time cumulative dose dependent • Varies by drug  Get echocardiogram or MUGA prior to therapy  Heart failure may be seen decades afterwards  Dexrazoxane used as cardioprotective agent
  35. 35.  Doxorubicin • Breast, sarcoma, lymphoma, myeloma, bladder, thyroid, endometrial  Daunorubicin • AML, ALL, lymphoma  Epirubicin • Breast, gastric,  Idarubicin • AML, ALL, lymphoma  Liposomal doxorubicin • Kaposi’s sarcoma, breast, ovarian • Hypersensitivity, hand foot
  36. 36.  Bleomycin • Lymphoma, germ cell, H&N, skin • Pulmonary, fever, hypersensitivity  Mitomycin • Gastric, H/N, bladder, lung • Late nadir, HUS  Mitoxantrone • Prostate, ALL, lymphoma • Milder toxicity  Dactinomycin • Ewing’s sarcoma, GTD • ++nausea
  37. 37.  Mechanism • Topoisomerase I: creates single strand breaks in DNA • Topoisomerase II: creates double strand breaks in DNA • Interferes with DNA’s capacity to unwind and allow for normal replication or transcription  Toxicities • Myelosuppression • Mucositis • Secretory diarrhea  Rx w/anticholinergics
  38. 38.  Irinotecan • Colorectal, lung, breast  Topotecan • Ovarian, small cell lung • Flu-like Topoisomerase II  Etoposide • Lung, germ cell, Kaposi’s, AML, lymphoma • Liver metabolism, renal excretion • hypoT is given fast  Antibiotics Topoisomerase I
  39. 39. Vinca alkaloids  Mechanism • Depolymerize microtubules & interfere w/mitotic function  Excretion: biliary  Toxicities • Peripheral neuropathy  glove-and-stocking parasthesias, adynamic ileus, jaw pain • Vesicant  potential for extravasation injuries
  40. 40. Vincristine • ALL, lymphoma, Hodgkin, myeloma, neuroblastoma, Ewi ng’s, Wilms • SIADH, no myelosuppression Vinblastine • Lymphoma, Hodgkin, germ cell, Kaposi’s • Vascular Vinorelbine • Breast, lung
  41. 41.  Mechanism • Prevent microtubule disassembly  Excretion: biliary Toxicities • Hypersensitivity • Neutropenia • Peripheral neuropathy • Venous irritant • Onycholysis
  42. 42.  Paclitaxel • Ovarian, breast, lung, GI, H/N, bladder, esophagus, KS • Need Premeds: steroid, antihistamines 1 & 2  Docetaxel • Ovarian, breast, lung, GI, H/N, bladder, • Severe fluid retention • Need steroid premed  Albumin-bound paclitaxel • Breast, lung • No premeds  Cabazitaxel • Prostate
  43. 43.  Eribulin • Inhibits tubulin polymerization • Breast • Myelosuppression, fatigue • Modify dose in biliary or renal disease Epothilone analogue  Ixabepilone • Enhances tubular polymerization • Breast • Excretion: hepatic Halichondrin B analogue
  44. 44.  L-asparaginase • ALL • Hypersensitivity, fever, chills, coagulopathy, pancreatitis, LFTs, CNS  Hydroxyurea • CML, P. vera, AML blast crisis • Controls counts • Myelosuppression, rash  Arsenic • APL • APL syndrome, fluid overload, n/v, long QT
  45. 45.  Thalidomide • Myeloma, melanoma, e. nodosum • Category X, rash, somnolence  Lenalidomide • Myeloma, MDS • Pulm emboli
  46. 46.  Aldesleukin, Interleukin • Renal, Melanoma • rHu-IL2 - enhances lymphocyte activity • flu-like, capillary leak, somnolence, thyroid  Denileukin diftitox • Cutaneous T-cell Lymphoma, Mycosis Fungoides • diptheria toxin fused to IL-2 • flu-like, hypersensitivity, capillary leak  Interferon alpha-2b • Renal • flu-like
  47. 47. SOS Akt MAPK P SurvivalNucleus PI3-K MEK Proliferation Mobility Invasiveness VEGF erlotinib gefitinib mTOR FKHR GSK-3 Bad Cyclin D1 RAS RAFP Cycle progression Dimerization Tyrosine Kinase phosphorylation Signal transduction Cell activity bevacizumab hsp90 PTEN Protein synthesis Ligand binding temsirolimus everolimus Bcr-Abl imatinib dasatinib rituximab ibritumumab tositumumab C D 2 0 C D 3 3 C D 5 2 gemtuzumab alemtuzumab 26s proteasome bortezomib sorafenib sunitinib TARGETED THERAPY
  48. 48. TARGET DRUG (generic) DRUG (brand) DISEASE HER2 lapatinib Tykerb® Breast trastuzumab Herceptin® Breast, Gastric pertuzumab Perjeta® Breast HER1 (EGFR) erlotinib Tarceva® Lung gefitinib Iressa® Lung cetuximab Erbitux® Colorectal, H&N panitumumab Vectibix® Colorectal VEGF, EGFR vandetanib Caprelsa® Medullary Thyroid VEGF axitinib Inlyta® Renal BCR-abl, PDGF imatinib Gleevec® CML, GIST dasatinib Sprycel® CML nilotinib Tasigna® CML Serine threonine (mTOR) temsirolimus Toricel® Renal everolimus Afinitor® Renal ALK crizotinib Xalkori® NSCLC BRAF kinase vemurafenib Zelboraf® Melanoma JAK ruxolitinib Jakafi® Myelofibrosis Signal transduction inhibitors
  49. 49. TARGET DRUG (generic) DRUG (brand) DISEASE Histone deacetylase vorinostat Zolinza® CTCL romidepsin Istodax® CTCL Retinoid X receptors bexarotene Targretin® CTCL tretinoin Vesanoid® APL Modify proteins regulating gene expression Induce apoptosis TARGET DRUG (generic) DRUG (brand) DISEASE Proteasome bortezomib Velcade® Multiple myeloma Block angiogenesis TARGET DRUG (generic) DRUG (brand) DISEASE VEGF bevacizumab Avastin® GYN, Glioblastoma PDGFR, VEGFR sorafenib Nexavar® Renal sunitinib Sutent® Renal, GIST pazopanib Votrient® Renal, Sarcoma
  50. 50. TARGET DRUG (generic) DRUG (brand) DISEASE CTLA-4 ipilimumab Yervoy® Melanoma CD20 rituximab Rituxan® Lymphoma ofatumumab Arzerra® CLL CD52 alemtuzumab Campath® CLL MoAbs that help immune system kill cells MoAbs that deliver toxic molecules TARGET DRUG (generic) DRUG (brand) DISEASE CD20 ibritumomab tiuxetan Zevalin® Lymphoma tositumomab Bexxar® Lymphoma CD30 brentuximab Adcetris® ALCL, HD denileukin diftitox Ontak® CTCL MoAb that stops cells destruction TARGET DRUG (generic) DRUG (brand) DISEASE C5 eculizumab Soliris® PNH
  51. 51.  Reduce dose  Improve elimination of metabolites • Hydration / diuresis  Alter schedule of therapy • Frequent low dose • Increasing length of time between cycles  Limit extent of delivery • Perfuse tumor locally (hepatic pump)  Minimize effect of drug on other tissue • Leucovorin rescue with MTX  Improve recovery from toxicities • G-CSF (Neupogen, Neulasta)
  52. 52.  Tumor heterogeneity  Efflux pumps  Increased rate of DNA repair  Changes in the drug sensitivity of a target enzyme  Decreased activation of pro-drugs (precursors)  Inactivation of anticancer drugs by enzymes
  53. 53.  Drugs • Vesicants - anthracyclines, vinca alkaloids • Irritants - taxanes  Signs/Symptoms • Pain, Redness, Swelling • Decreased range of motion • Change in sensation • Change in skin temperature  Management • Stop infusion • Elevate the extremity • Contact attending physician for plan of care and to obtain antidote orders • Apply cold or warm compresses per MSKCC guidelines • Consider topical or systemic antibiotics as needed • Consider plastic surgery consult
  54. 54. GUIDELINE ORDER SET
  55. 55.  Goal • Target cells not equally sensitive to a single drug • Avoid selection of resistant cell lines  Choosing drugs for regimen • Each with activity against this cancer type • Have different mechanisms of action • Non-cross-resistance • Non-overlapping toxicities
  56. 56.  CHOP: lymphoma • cyclophosphamide, doxorubicin, vincristine, prednisone  FOLFIRI: colon • leucovorin 5-FU, irinotecan  ACT: breast • doxorubicin, cyclophosphamide, paclitaxel  EP: lung, germ cell, GTD • etoposide, cisplatin  AIM: sarcoma • doxorubicin, ifosfamide, mesna  Gem/Carbo: ovarian, H/N, lung, breast • Gemcitabine, carboplatin  BEAM: transplant • carmustine, etoposide, cytarabine, melphalan  VAD: myeloma • vincristine, doxorubicin, dexamethasone

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