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.  Develop a framework for understanding
antineoplastic chemo and biotherapeutic agents
 Review basic chemotherapy principles
 Discuss some common chemotherapeutic agents
and side effects

3.  Surgery
 Radiation
 Mechanical
 Cytotoxic chemotherapy
 Molecularly targeted therapies
 Immunologic therapy
 Hormonal therapy
Local/Regional
Systemic

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.  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.  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.  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.  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.  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.  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. Cancer cells lose regulatory mechanisms for differentiation, growth
arrest, and self-renewal capacity that allows for loss of tissue
architecture and homeostasis.

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. Most cancers have
found a mechanism
to evade the normal
checkpoints of the
cell cycle.

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

16. 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

17.  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

18.  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

19. • 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

20.  Pemetrexed
• Mesothelioma
• Myelosuppression, mucositis, rash
• Must give folic acid & B12
 Pralatrexate
• Peripheral T-cell lymphoma
• Mucositis, ↓ plts, nausea, fatigue
• Must give folic acid & B12

21.  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

22.  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)

23.  5-Fluorouracil
• Inhibits thymidylate synthase & inhibits conversion of dUMP dTMP
• Colon, gastric, breast, pancreatic, squamous cell
• Mucositis, diarrhea, coronary spasm
• Leucovorin is synergistic

24.  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

25.  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

26.  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

27.  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

28.  Chlorambucil
• CLL, Waldenstrom’s, lymphoma
• oral
 Melphalan
• Myeloma
• Oral/IV
 Bendamustine
• CLL
• Delayed myelosuppression, fever

29. Lipophilic, late nadir
 Carmustine (BCNU)
• Brain, Melanoma, lymphoma
• Pneumonitis, hepatotoxicity
 Lomustine (CCNU)
• Hodgkin, brain, lymphoma
• ++nausea
 Streptozocin
Pancreatic islet, carcinoid
Renal, hyperglycemia

30.  Busulfan
• CML, transplant
• Lipophilic
• Pneumonitis, skin, wasting
Aziridine
 Thiotepa
• Transplant
• Intrathecal

31.  Dacarbazine
• Hodgkin, sarcoma, neuroblastoma, melanoma
• ++ nausea, flu-like
 Procarbazine
• Hodgkin, lymphoma
• Oral
• Avoid MAO inhibitors, TCAs, ETOH
 Temozolomide
• Glioblastoma, melanoma
• Fatigue

32.  Cause cross-links in DNA
• Causes strand breaks
 Toxicities
• Peripheral neuropathy
• Nephrotoxic
• Myelosuppression
• Nausea/vomiting
• Ototoxicity
• Hypersensitivity
• Electrolyte wasting

33.  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

34.  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

35.  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

36.  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

37.  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

38.  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

39.  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

40. 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

41. Vincristine
• ALL, lymphoma, Hodgkin, myeloma, neuroblastoma, Ewi
ng’s, Wilms
• SIADH, no myelosuppression
Vinblastine
• Lymphoma, Hodgkin, germ cell, Kaposi’s
• Vascular
Vinorelbine
• Breast, lung

42.  Mechanism
• Prevent microtubule disassembly
 Excretion: biliary
Toxicities
• Hypersensitivity
• Neutropenia
• Peripheral neuropathy
• Venous irritant
• Onycholysis

43.  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

44.  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

45.  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

46.  Thalidomide
• Myeloma, melanoma, e. nodosum
• Category X, rash, somnolence
 Lenalidomide
• Myeloma, MDS
• Pulm emboli

47.  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

48. 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

49. 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

50. 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

51. 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

52.  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)

53.  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

54.  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

55. GUIDELINE ORDER SET

56.  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

57.  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