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Chemotherapy 101
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
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
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
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
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
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
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
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
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