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Chemotherapeutic Agents. Introduction n Classification of Drugs n Cell-cycle specificity n Mechanism of Action n Indication n Side effects.

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Presentation on theme: "Chemotherapeutic Agents. Introduction n Classification of Drugs n Cell-cycle specificity n Mechanism of Action n Indication n Side effects."— Presentation transcript:

1 Chemotherapeutic Agents

2 Introduction n Classification of Drugs n Cell-cycle specificity n Mechanism of Action n Indication n Side effects

3 Antimetabolites n Cell-cycle specific n Act in S-phase n Inhibit enzyme production for DNA synthesis n Lead to strand breaks or incomplete DNA strands

4 Cytosine Arabinoside n Also called Ara-C or Cytarabine n Treatment for Leukemias and Lymphomas n Variety of dose schedules/routes n Myelosuppression, alopecia (dose dependant), N&V, mucositis, diarrhea, conjunctivitis, acral redness, liver and kidney dysfunction, neurologic dysfunction (high dose) n Non-vesicant

5 5-Flurouracil (5-FU) n Treatment for GI, breast, and ovarian cancers n Variety of dose schedules n Mucositis and Diarrhea, mild alopecia, photosensitivity, darkening and sclerosing of veins, skin changes, mild to no N&V n Potentiates radiation therapy--may be given concurrently n Leucovorin increases toxicity n Non-vesicant

6 Methotrexate n Treatment for lymphomas, leukemias, ovarian, breast, lung, testicular, cervical, and CNS mets n May be given for non-cancer dx n Variety of dose schedules/routes n Mucositis and diarrhea, N&V, alopecia, Myelosuppression, photosensitivity, renal toxicity n Given with Leucovorin (rescue) n Non-vesicant

7 Fludarabine n Treatment for CLL n 25 mg/m2 IV for 5 days n Given as 30 minute infusion n Myelosuppression, nausea, slight alopecia, rash, diarrhea

8 Capecitabine (Xeloda) n Treatment for breast cancer n Pro-drug -- turns to 5-FU in body n 2,500 mg/m2 orally for 14 days on and 7 days off n Take with food n Diarrhea, Mucositis, numbness, tingling, itching of hands and feet (hand and foot syndrome)

9 Gemcitabine (Gemzar) n Treatment for pancreatic, lung, and many other cancers n 1000mg/m2 IV every week up to 7 weeks in a row n Given as a 30 minute infusion-- longer infusions increase toxicity n Myelosuppression, N&V, fatigue, increased liver enyzmes, alopecia n Non-vesicant

10 Vinca Alkaloids n Cell-cycle Specific n Act in late G2 phase, M phase, and S phase n Block DNA and RNA production, prevent cell division, inhibit microtubule formation

11 Vinorelbine (Navelbine) n Treatment for lung, breast cancer n 30 mg/m2 IV weekly n VESICANT n Given IV push over min through side port of fast running IV (furthest from IV site), f/b 100 cc flush n Myelosuppression, Peripheral neuropathy, N&V, mild alopecia

12 Vincristine (Oncovin) n Treatment for leukemias, breast, lymphoma, SCLC, sarcoma n 1.4mg/m2 IV weekly n DOSE NOT TO EXCEED 2 mg n VESICANT n Peripheral neuropathy, constipation, paralytic ileus, jaw pain n Neuropathy is cumulative n FATAL IF GIVEN INTRATHECALLY

13 Vinblastine (Velban) n Testicular, Head and neck cancer, Hodgkin’s disease, Kaposi’s sarcoma n mg/m2 IV weekly n VESICANT n Peripheral neuropathy, constipation, myelosuppression, mild alopecia, jaw pain n Less neuropathy than vincristine

14 Epipodophyllotoxins n Cell-cycle specific n Work in late G2 and S phase n Interfere with topoisomerase II enzyme n Stops cell replication in pre-mitotic phase

15 Etoposide (VP-16) n Breast, testicular, SCLC, lymphomas n 100 mg/m2/day x 3 days q 28 days n Non-vesicant n Myelosuppression, N&V, alopecia, orthostatic hypotension n Rapid infusion causes hypotension-given over min n Must be dilute or will precipitate

16 Taxanes n Cell-cycle specific n Active in G2 and M phase n Stabilize the microtubule structure n Cells cannot divide

17 Paclitaxel (Taxol) n Breast, ovarian, SCLC n Given IV over 24hrs, 3 hrs, or 1 hr n Myelosuppression, alopecia (severe), peripheral neuropathy, hypersensitivity rxns, myalgias, severe fatigue n Pre-meds: Dexamethasone 20 mg po 12 & 6 hrs prior, Pepcid or Tagamet, Benedryl plus anti-emetic n Need NON-PVC tubing with 0.2 micron in-line filter -- NON-PVC bag or bottle n IRRITANT n When given with other chemo drugs; give Taxol first

18 Docetaxel (Taxotere) n Breast, NSCLC, head and neck, ovarian n 60 to 100 mg/m2 IV every 3 weeks n Myelosuppression, myalgias, hypersensitivity, peripheral neuropathy, alopecia (severe) n Pre-med: Dexamethasone 8 mg po bid starting 1 day prior and continuing 4 days after n Non-PVC tubing and bottle (no filter)

19 Camptothecins n Cell-cycle specific n Act in S phase n Inhibit topoisomerase I n Causes double-strand DNA changes

20 Topotecan (Hycamtin) n Ovarian, salvage therapy n 1.5 mg/m2 IV daily x 5 days q 3 weeks n Myelosuppression, diarrhea, mild alopecia

21 Irinotecan (Camptosar) n Metastatic colon and rectum n 125 mg/m2 IV weekly x 4 weeks n Diarrhea (severe), Myelosuppression, alopecia n Diarrhea MUST be treated -- patients need to go home with antidiarrheal and know how to use it

22 Miscellaneous n Cell-cycle specific n Work in a variety of ways u Inhibit Protein synthesis u Act in S phase u Inhibit RNA and DNA synthesis

23 L-Asparginase (Elspar) n Leukemia n 1, ,000 IU/m2 IM n Hypersensitivity, anaphylaxis, hepatoxicity, N&V (slight), fever n ALWAYS give test dose prior to initial dose-test dose given intradermally n Also give test dose if pt has not had in more than 1 week n IM administration decreases hypersensitivity reactions

24 Pegaspargase (Oncaspar) n Leukemics who are sensitive to Elspar n 2,500 IU/m2 IM every 14 days n Hepatotoxicity, coagulopathy, may have some hypersensitivity rxns n Less hypersensitivity than Elspar - may not need test dose n VERY expensive

25 Hydroxyurea (Hydrea) n Leukemias, Malignant melanoma, head and neck cancer, ovarian n mg/kg PO q day n Myelosuppression, N&V (mild), mucositis, constipation or diarrhea n Dose is adjusted based on blood counts

26 Alkylating Agents n Cell-cycle Nonspecific n Break DNA helix strand n Interfere with DNA replication

27 Cisplatin n GU cancers, lung, head and neck, sarcomas, testicular, renal cell, esophageal n Doses no higher than 100 mg/m2 n Monitor K+, Mg+, Creatinine n Severe and prolonged N&V, nephrotoxocity, ototoxicity, myelosuppression, alopecia (mild) n Rigorous hydration needed to prevent renal toxicity n Irritant

28 Carboplatin n Ovarian, testicular, head and neck, lung, cervical n Varied dosing; sometimes ordered as AUC (area under the curve) n Thrombocytopenia, N&V, hyper- sensitivity, myelosuppression, renal/hepatic toxicity n No need for rigorous pre- or post- hydration

29 Oxaliplatin n Second line therapy for metatstatic colorectal cancer n Neuropathy starting within hours exacerbated by exposure to cold u Acute and chronic neuropathy n Neutropenia (  w/ 5-FU), Anemia Thrombocytopenia n Renally excreted n Irritant – use central line

30 Cyclophosphamide (Cytoxan) n Breast, lung, prostate, ovary, leukemias, lymphomas, Multiple Myeloma, head and neck n Varied dosing schedule/route n Hemorrhagic cystitis, myelosuppression, N&V, alopecia, SIADH, nasal burning n Patient should drink glasses of water per day

31 Ifosfamide (Ifex) n Lung, testicular, lymphomas, sarcomas n 1.2 gm/m2 IV days 1-5 q 3-4 wks n ALWAYS given with Mesna n Hermorrhagic cystitis, N&V, alopecia, myelosuppression, neurotoxicity n Mesna dose should be 20% of the Ifosfamide dose

32 Mechlorethamine HCl (Nitrogen Mustard) n Leukemias, lymphomas n 6 mg/m2 IV on day 1 and day 8 q 4 weeks n Myelosuppression, N&V, chills, fever, pain at IV site n VESICANT n Flush with cc NS n Stable for only 10 to 15 minutes; use immediately after mixing

33 Dacarbazine (DTIC) n Lymphomas, Sarcoma, Melanoma n mg/m2 n Myelosuppression, N&V, alopecia, flu-like syndrome, renal and liver toxicity, diarrhea n VESICANT

34 Thiotepa n Bladder, breast, ovarian, lymphomas n mg/kg IV at wk intervals; mg/kg for bladder (intracavitary) administration n Myelosuppression, rash, fever, N&V n Monitor renal function if given IV

35 Anti-tumor Antibiotics n Cell-cycle Nonspecific n Bind with DNA n Inhibit DNA and RNA synthesis

36 Doxorubicin (Adriamycin) n Breast, ovary, prostate, stomach, lung, liver, head and neck, multiple myeloma, lymphomas, leukemias n mg/m2 q 3 weeks n Myelosuppression, N&V, alopecia, mucositis, cardiotoxicity, radiation recall, photosensitivity, red urine n VESICANT n May cause flare reaction n MUGA / Echocardiogram before dosing n Lifetime cumulative dose mg/m2

37 Liposomal Doxorubicin (Doxil) n Refractory ovarian, Kaposi’s sarcoma n 50 mg/m2 IV q 4 weeks n Myelosuppression, palmar-plantar erythrodysesthesia, cardiotoxicity, mucositis, N&V, rash, alopecia n Start infusion at 1 mg/min and check for flushing, SOB, facial swelling, hypotension. If none, give over minutes n Irritant; not vesicant

38 Bleomycin (Blenoxane) n Lung, head and neck, cervical, GYN cancers, GU cancers, lymphomas n units/m2 IV, IM, or SQ 1-2 times per week n Hypersensitivity, anaphylaxis, alopecia, photosensitivity, renal/hepatotoxicity, fever, chills, pulmonary fibrosis n Test dose of 1-2 units before 1st dose n Cumulative lifetime dose ~ 400 units due to risk for pulmonary fibrosis

39 Mitomycin - C n GI tumors, breast, lung, head and neck, esophageal, bladder, multiple myeloma n 20 mg/m2 IV q 6-8 weeks n Myelosuppression, alopecia, mucositis, renal / pulmonary toxicity, fatigue n VESICANT n Nadir is 4 to 8 weeks n Brochospasm can occur when given simultaneously or after Vinca alkaloid n Extravasation can occur distant from IV site

40 Mitoxantrone (Novantrone) n Breast, lymphomas, leukemia (ALL) n mg/m2 every 21 days n Myelosuppression, alopecia, cardiotoxicity n Urine blue-green with 1st post void n VESICANT

41 Hormonal Therapy n Cell-cycle Nonspecific n Interfere with hormone receptors n Interfere with protein synthesis in all phases of cell cycle

42 Glucocorticoids n Prednisone, dexamethasone, etc. n Breast, lymphomas, multiple myeloma, leukemias, CNS tumors or mets n Various dosing schedules n Fluid retention, hyperglycemia, GI irritation, masks infections, mood swings, moon face, osteoporosis, perineal burning with rapid infusion

43 Tamoxifen n ER+, postmenopausal breast cancer n 10 mg tab po BID n Vaginal bleeding/discharge, hot flashes, N&V, risk of uterine cancer n Usually given for 5 years-no evidence for continued use n Given as preventative in high-risk women

44 Progestins n Depo-Provera ; Megace n Breast, renal cell n Depo-Provera: 400-1,000 mg IM q wk; Megace: mg/day in divided doses PO n Fluid retention, headache, vaginal bleeding/spotting, increased appetite, thrombophlebitis n Megace used as appetite stimulant n Depo-provera used to prevent menses in thrombocytopenic patients

45 Leuprolide (Lupron) n Prostate, breast cancer n Dose varies with protocol n Gynecomastia, hot flashes, N&V, headache, bone pain n Symptoms may worsen in first few weeks of therapy.

46 Goserelin acetate (Zoladex) n Prostate, breast cancer n Dose varies with protocol n Hot flashes, gynecomastia, N&V n Given as depot injection SQ into abdomen (with gauge needle) once a month or every 3 months

47 Nitrosoureas n Cell-cycle Nonspecific n Break DNA helix n Interfere with DNA replication n Cross blood-brain barrier

48 Carmustine (BCNU) n Lymphomas, CNS tumors, multiple myeloma, melanoma, BMT n mg/m2 IV x 2 days or 200 mg/m2 IV single dose q 6-8 wks n N&V, myelosuppression, renal/liver toxicity, pulmonary fibrosis n Nadir: 4-6 weeks n Crosses blood/brain barrier n Rapid infusion causes facial flushing and hypotension

49 Monoclonal Antibodies n Cell-cycle Nonspecific n Uses antibody to target specific cells n Bind to markers on cell surface n Induce cell death (apoptosis) n Initiate complement system which results in cell phagocytosis

50 Antibodies/Antigens CELL Antigens Antibodies

51 How Antibodies Work

52 How MoAbs Are Produced

53 Various Types of MoAbs Adapted from LoBuglio A, et al. Crit Rev Oncol Hematol. 1992;13:273.

54 Monoclonal Antibodies (MoAbs) n “momab”- murine antibody n “ximab”- chimeric antibody n “xumab”- humanized antibody

55 Rituximab (Rituxan) n Leukemias, lymphomas, ITP, Waldenstrom’s macroglobulinemia n 375mg/m2 IV; schedule varies n Start at 50 mg/hr; increase gradually if no reaction. n Infusion-related side effects; fever with rigors, hypotension, allergic reactions, N&V, pain n Pre-med: Tylenol and Benedryl

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57 Ibritumomab (Zevalin) n Anti-CD 20 antibody bound to Tiuxetan—which binds to Yittrium 90 or Indium 111 n Dose = 0.4 mCi/kg n Given in Nuclear Medicine n Cannot be given if platelets < 100,000 u Dose reductions based on platelet count

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59 Trastuzumab (Herceptin) n Breast, prostate n Dose varies with protocol n Cardiotoxicity, myelosuppression, allergic reactions, infusion reactions (chills, fever, headache) common with 1st infusion- give over 30 min n When given with other chemo- therapeutic agents-give first n MUGA or Echocardiogram before 1st dose n Pre-med with Tylenol and Benedryl

60 Gemtuzumab (Mylotarg) n AML (leukemia) n Antibody + calicheamicin (antitumor antibiotic) n Mylosuppression, longstanding thrombocytopenia, fatigue, myalgias, anorexia, chills and fever n Given over 2 hours x 2 doses 7 days apart n Pre-med with Tylenol and Benedryl

61 Alemtuzumab (Campath) n Chronic Lymphocytic Leukemia u Failed first line therapy with Fludarabine n T-cell Leukemia, Mycosis Fungoides, NHL n Binds to CD-52  cell lysis n Severe Myelosuppression n Start at 3 mg daily over 2 hours n When no reactions, increase to 10 mg n When tolerated increase to 30 mg M-W-F for 12 weeks. n Severe infusion related reactions n Premedicate with Tylenol, Benedryl, and Hydrocortisone

62 Biologic Response Modifiers n Cell-cycle Nonspecific n Stimulate immune system-primarily lymphocytes n Cause release of cytokines n Not effective as single agents

63 Interferons n Leukemias, lymphomas, multiple myeloma, melanoma, hepatitis, renal cell, Kaposi’s sarcoma n Dose varies depending on formulation and disease n Flu-like syndrome, fever, malaise, anorexia, diarrhea, rash n Usually self-administered; best taken at HS n Pre-med with Tylenol

64 Aldesleukin (IL-2) n Renal cell, malignant melanoma n Dose varies depending on protocol n Toxicity is dose related n Capillary-leak syndrome, hypotension, cardiac arrhythmias, pulmonary edema, mental status changes, rash with pruritis, diarrhea, lymphocytosis, weight gain,edema n Pre-medicate as ordered

65 Immunoglobulin (IgG) n ITP, TTP, anemias, leukemias, post BMT n Dose varies with manufacturer n Chills, fever, hypotension, dyspnea, anaphylaxis, urticaria, edema of lips and tongue n Monitor vs q 15 min x 4; then q hr n Start at slow rate and increase q min until MAX rate (dependes on manufacturer)

66 Chemoprotectants n Not chemotherapy n Given with chemotherapy protocol to decrease toxicities n Side effects vary with drug n Protect healthy cells but not cancer cells

67 Mesna (Mesnex) n Prophylaxis of acrolein-induced hemorrhagic cystitis n IV bolus injection equal to 20% Ifex dose 15-30min prior to Ifex and 4 and 8 hours after Ifex n May be given concurrently as CI n Run for 12 hours after Ifex done n Oral dose n Diarrhea, headache, nausea, fatigue (all mild)

68 Amifostine (Ethyol) n Reduction of renal toxicity from Cisplatin administration n Protects salivary glands from RT n Hypotension and nausea, lowers Ca++ n Run NS at 500 cc/hr x 2 hrs n Ondansetron 32 mg IV Dexamethasone 20 mg IV and Ativan 1 mg IV 1 hour prior to drug n Give over ~10 minutes approx 30 min. prior to Cisplatin-pt should be supine n Stop infusion if systolic BP drops significantly from baseline

69 Dexrazoxane (Zinecard) n Reduces incidence and severity of cardiomyopathy from Adriamycin n 10:1 Zinecard to Adriamycin n Slow IV push or fast IV infusion 30 min prior to Adriamycin n Not recommended with initiation of treatment; used after Adriamycin cumulative dose > 300mg/m2 n May lower response rate

70 Leucovorin n Given with Methotrexate to reduce toxicity to healthy cells n A form of folic acid n Taken up preferentially by healthy cells instead of Methotrexate which is taken up more by cancer n For HD Methotrexate, given until methotrexate level in safe range n Increases toxicity of 5-FU

71 5HT3 receptor antagonists n Ondansetron (Zofran) 32 mg IV or 4 to 8 mg po TID n Granisetron (Kytril) 10 mcg/kg IV or 2 mg PO daily n Dolasetron (Anzemet) 1.8 mg/kg IV or 100 mg po n Work prophylactically in chemo Rx n Less useful for delayed N&V

72 Emend END


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