The following material is intended for MSKCC internal medicine housestaff teaching purposesonly. The slides were updated for the LibGuide in 2011-2012.
Develop a framework for understanding chemotherapeutic agents Review basic chemotherapy principles Discuss some common chemotherapeutic agents and side effects
Surgery In localized disease, surgery is often the most effective and definitive curative therapy May also play a role in metastatic disease Solitary brain metastases Resectable liver or lung lesions Palliation Radiation Cure or control of localized disease Palliation Systemic Chemotherapy
Adjuvant Chemotherapy: Used after surgery to reduce the risk of disease recurrence Operates under the assumption that micro-metastases exist and not removed by surgery Sometimes surgery is useful to “debulk” the amount of tumor cells Neo-adjuvant chemotherapy: Used prior to surgery in order to eliminate micrometastatic disease Useful to shrink tumors for anatomic preservation (larynx, anal sphincter)
Cure of cancer: Ultimate goal of chemo is CURE, though that requires elimination of every last neoplastic cell As an adjunct to surgery As an adjunct to radiation Curative chemotherapy alone Long-term control of cancer Using Gleevec in CML Hormonal therapy for breast/prostate cancer Palliation of symptoms of cancer
Main Barriers: Re-growth of tumor cells Chemotherapy Toxicities Cell-Cycle Specific Resistance
Cancer stem cells: cells that are reversibly not in cycle are capable ofreplenishing tumor cells physically removed or damaged by radiationand chemotherapy
Tumor growth follows a Gompertzian growth curve: growth fraction of a tumor starts at 100% and declines exponentially over time and with tumor burden Tumor size increases slowly, goes through an exponential phase, and slows again as the tumor reaches the size at which limitation of nutrients occur Efforts to treat the tumor results in an increase in the growth fraction and an increase in growth rate
The Log-Kill Hypothesis A given dose kills a constant proportion of a cell population rather than a constant number of cells, usually by three orders of magnitude If 109 leukemia cells x 99.999% kill (5-log kill) After a dose of chemotherapy, then 104 cells will still remain Will be induced to grow again -> 105 or 106 cells before long
Infections Myelosuppression Organ failure Debilitation Etc…
Some Definitions: Therapeutic Index: ratio of the amt that causes the therapeutic effect versus the amt that causes toxicity Dose Limiting Toxicity (DLT): a dose that yields greater toxicity than is acceptable in practice Maximal Tolerated Dose (MTD) : dose just lower than DLT, usually the dose suitable for phase II trials
Tumors consist of cells that are either actively dividing or not dividing at the moment Drugs are sometimes effective only in a particular phase of the cell cycle. Other drugs kill tumor cells in both dividing and resting phases of the cell cycle
Antimetabolites – S phaseTopoisomerase Inhibitors – S andG2 phaseMitotic Spindle Inhibitors – M andG2 phase
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
What is the solution to killing resting cells and overcoming limitations with killing on a constant fraction of cells? CYCLES of chemotherapy Recruitment Initially use a cell-cycle nonspecific (CCNS) drug to achieve initial log kill recruits resting cells to start dividing subsequently use cell-cycle specific (CCS) against dividing cells
Minimize toxicities: Perfuse tumor locally (hepatic pump) Hydration / diuresis Leucovorin rescue with MTX Pulse Therapy Intermittent treatment with very high doses of a drug that’s too toxic to be used continuously Stem cell rescue (BMT) allows for high doses of chemo that would otherwise kill the patient G-CSF (Neupogen, Neulasta)
Combination Therapy Target tumor cells that are not equally sensitive to a single drug Prevents/slows development of resistant cell lines
Kill both resting (non-dividing cells) as well as cells in replication Though dividing cells often more susceptible Alkylating agents Platinum agents Antitumor antibiotics Steroids Kill non-dividing cells
Mechanism Add alkyl groups and covalently bind to DNA bases Leads to cross-linking of DNA strands, abnormal base pairing, and breaks in the DNA No discrimination between resting or dividing cells Decreased transcription, translation, protein synthesis DNA damage -> apoptosis• Nitrogen Mustards • Nitrosureas – Mechlorethamine – Carmustine (BCNU) – Cyclophosphamide – Lomustine (CCNU – Ifosfamide – Streptozocin – Chlorambucil • Alkylsulfonates – Melphalan – Busulfan
Toxicities Myelosuppression Alopecia Mucositis Pulmonary toxicity Can cause secondary neoplasms many years later (particularly leukemia)
Used in breast, lymphoma, myeloma, BMT, rheumatic diseases Metabolized by P450 then further break down to phosphoramide mustard and acrolein Clinical issues: (aside from myelosuppression, secondary malignancies, sterility) Acrolein irritates bladder causing hemorrhagic cystitis Must hydrate patients Give mesna (2-Mercaptoethane sulfonate Na) which binds acrolein Patients must be on PCP prophylaxis due to high rates of immunosuppression and PCP infection, in particular
Melphalan Used prominently in Multiple Myeloma, BMT Busulfan Used in transplant prep regimens Pulmonary toxicity
Similar to alkylating agents: cause cross-links in DNA Used in: lung, head & neck, testicular cancers Cisplatin – extremely toxic, but efficacious Carboplatin – developed as a less toxic alternative
Toxicities: Nausea & vomiting (the most emetogenic drug) Neurotoxicity: stocking/glove paresthesias, weakness Nephrotoxicity Ototoxicity Clinical Issues: Watch out for aminoglycosides with similar toxicity May require more antiemetics, hydration Hypomagnesemia, hypocalcemia
Mechanism Produced by bacteria that naturally provide chemical defenses against other hostile microorganisms Intercalate into DNA directly -> disrupt transcription & replication Also generate free radicals that damage DNA Drugs: Anthracyclines (also inhibits topoisomerase II) Daunorubicin Doxorubicin Epirubicin Idarubicin Mitoxantrone Bleomycin Mitomycin
Toxicities & Clinical Issues Myelosuppression Cardiotoxicity Cardiac tissue low in superoxide dismutase & catalase, so susceptible to oxidative damage Heart failure may be seen decades afterwards Dose-dependent Get echocardiogram or MUGA prior to therapy Extravasation injury Dexrazoxane is antidote (may be cardioprotective)
35 yo F with early-stage breast cancer Treated with lumpectomy & XRT ER/PR positive Her2 negative SLN biopsy negative Oncotype DX shows HIGH RISK The patient receives adjuvant treatment with hormonal treatment and AC-T Adriamycin Cyclophosphamide Taxol Is subsequently started on tamoxifen
4 years later, the patient has anemia & thrombocytopenia Work-up reveals AML Is poor-risk, due to likelihood that this is therapy- related Adriamycin topo-isomerase II inhibitor; typically 1-5 years post-tx Cyclophosphamide alkylating agent; typically 5-10 years post-tx Taxol
Stop the infusionAssess site for signs of extravasationo Rednesso Swellingo Paino Decreased range of motiono Change in sensationo Change in skin temperatureElevate the extremityContact the attending physician for plan ofcare and to obtain antidote orders asindicatedApply cold or warm pack as outlined inMSKCC guidelinesConsider topical or systemic antibiotics asneededPlastic Surgery evaluation as outlined below
Antimetabolites – S phase Topoisomerase Inhibitors – S and G2 phase Mitotic Spindle Inhibitors – M and G2 phase
Mechanism Compounds with structural similarity to precursors of purines or pyrimidines Compounds that interfere with purine or pyrimidine synthesis Causes DNA damage indirectly, through mis- incorporation into DNA, abnormal DNA synthesis
CO2 + PRPP Glutamine ATP Carbamoyl IMP phosphateAMP -> GMP -> UMP dUMP ATP GTP Thymidylate synthase Xanthine UTP dTMP Uric acid CTP
Toxicities Myelosuppression Stomatitis Diarrhea Not associated with second malignancies
Folic acid analog that competitively inhibits the enzyme dihydrofolate reductase, thereby inhibiting the conversion of dihydrofolate to tetrahydrofolate . Without the ability to replenish a supply of reduced folates, purine & pyrimidine synthesis is interrupted Can be sequestered in third-space collections Uses: Leukemia, lymphoma, breast cancer, head & neck cancers, rheumatologic diseases, gestational trophoblastic disease Crosses the blood-brain barrier, so is useful in CNS disease
Toxicities: Myelosuppression, Hepatoxicity, Nephrotoxicity, Hypersensiti vity pneumonitis, encephalopathy, rashClinical Issues:- Often given intrathecally for leptomeningeal disease- At high doses, can penetrate the blood-brain barrier and is useful in the prophylaxis or treatment of CNS disease- May need to avoid in ascites- Metabolized to insoluble form at physiologic pH, so must alkalinize the blood & urine to eliminate- Leucovorin started 24 hours afterward moderate or high doses of methotrexate to “rescue” normal cells Lippincott’s Pharmacology. Ed. Harvey & Champe. 2000.
Toxicities: Myelosuppression HepatoxicityClinical Issues:- Doesn’t penetrate blood-brain barrier, so often given intrathecally for CNS disease- May need to avoid in ascites- Metabolized to insoluble form at physiologic pH, so must alkalinize the blood & urine to eliminate- Leucovorin used to “rescue” normal cells Lippincott’s Pharmacology. Ed. Harvey & Champe. 2000.
Supportive Medications Pre-dose: Infuse 1 liter D5W + 100 mEq sodium bicarbonate over 4 hours Urine output should be >150 ml/hour and urine pH >7.5 ( ≥ 7 for patients on neurology service) prior to the start of the high-dose methotrexate. Notify MD/NP if these criteria are not met. For continuous infusions: Infuse D5W + 50 mEq sodium bicarbonate/ liter @150 ml/hour throughout infusion Post-dose Infuse D5W + 50 mEq sodium bicarbonate/ liter @150 ml/hour x 72 hours Sodium bicarbonate tablets 1300 mg PO x 1 or 50 mEq in 25 ml D5W IV x 1 for each urinalysis with pH less than 7.5 Obtain specific order from Attending MD/NP for dose and schedule of Leucovorin
56 year-old male with DLBCL and leptomeningeal involvement.Admitted Feb 2011 for high-dose methotrexate…
Thorough evaluation failed to reveal other causes of renal failure, and thiswas attributed to MTX nephrotoxicity.The patient temporarily required hemodialysis.
Teaching Points:It is important to monitor urine pH, urine output, renal function and daily methotrexate levels in patients receiving high-dose methotrexate.Inform any covering individual (e.g. night float) that a patient has received methotrexate, and clearly sign out the need to follow up any urinalyses.Service attending should be notified about drops in urine pH or oliguria associated with high-dose methotrexate.
Pyrimidine analog with fluorine Inhibits thymidilate synthase, so inhibits conversion of dUMP to dTMP Uses: Colon, gastric, pancreatic Toxicities: N/V/D, alopecia Hand-foot syndrome
Clinical issues: Vasospasm – more with infusional administration than with bolus - discontinue drug - consider a CCB
• Capecitabine (Xeloda): Used in breast, colon cancers oral drug converted to 5-FU Still has concern for vasospasm• Gemcitabine: Analog of cytidine• Cytarabine (Ara-C): Analog of cytidine Used in AML, ALL Clinical issue: conjunctivitis For high dose therapy (> 2000 mg/m2/day): Dexamethasone eye drops 0.1%; administer 2 drops to each eye 6 hours before infusion and continue every 6 hours until 24 hours post therapy.
Mechanism (natural products) Topoisomerase I: creates SS breaks allowing for unwinding of DNA strand Topoisomerase II: creates DS breaks through which another Interference with DNA’s capacity to unwind and allow for normal replication or transcription Toxicities Myelosuppression Mucositis Secretory diarrhea
Topoisomerase I Camptothecin Topotecan Irinotecan From Camptotheca Chinese ornamental tree
Topoisomerase II Etoposide From Podophyllum Peltatum (American Mayapple)
Clinical issues: Used in FOLFIRI regimen (colon cancer) Patients may develop a severe diarrhea, often requiring hospitalization and intensive fluid resuscitation - Still look for infectious causes
Mechanism Plant alkaloids or derived from natural products Microtubules form the mitotic spindle, which allows for migration of the chromosomes and cell division Toxicities Peripheral nerve damage (glove-and-stocking neuropathy, paralytic ileus, paresthesias, jaw pain) Extravasation injuries
Vinca Alkaloids blocks assembly of microtubules Vincristine “Oncovin” – the “O” in CHOP Bad neuropathy, extravasation injury Vinblastine
Taxanes prevents microtubule disassembly bark of Pacific Yew Tree (Taxus Brevifolia) paclitaxel (Taxol) Breast cancer, Ovarian cancer Docetaxel (Taxotere) Clinical issues: HYPERSENSITIVITY NEUTROPENIA Peripheral neuropathy
1) Each drug should be active when used alone against the particular cancer2) Drugs should have different mechanisms of action3) Cross-resistance between drugs should be minimal4) Drugs should have different toxic effects
Non-Hodgkin’s Lymphoma CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Predniso ne) An alkylating agent, an anthracycline, a vinka alkaloid, and a steroid Cyclophosphamide: Hemorrhagic cystitis (need IVF & UA); PCP Doxorubicin: Extravasation injury; Cardiotoxicity Vincristine: Extravasation injury; Neuropathy
Colon Cancer FOLFIRI - Leucovorin (FOL), 5-FU (F), Irinotecan (IRI) An antimetabolite, synergistic agent, topoisomerase inhibitor 5-FU: Hand-foot syndrome & cardiotoxicity/vasospasm Irinotecan: Bad diarrhea
Standard chemotherapy regimens are given every 3-4 weeks, in order to allow healthy cells to recover between cycles (blood counts, mucosa) However, given Gompertzian growth curve, during this 3-week break, the smaller number of tumor cells are already rapidly-dividing again By administering the same doses, but on a 2-week interval, we can catch the tumor cells in this early rapid growth phase Concerns about toxicity & marrow suppression have been mediated by growth factors, etc.