Introduction to Antineoplastic Prescribing

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1 Introduction to Antineoplastic Prescribing Robert Bradbury, R.Ph., BCPS Clinical Coordinator H. Lee Moffitt Cancer Center

2 Objectives Meet the following goals concerning antineoplastic prescribing: Understand the basis for chemotherapy. Be able to identify appropriate dosage ranges. Be able to identify major toxicities. Learn the skill of prescribing chemotherapy.

3 Overview Cell Cycle Kinetics Pharmacologic Classification of Antineoplastic Agents Review of Agents Review of Combination Therapy

4 The Cell Cycle Mitosis (Cell Division) Premitotic Phase RNA Synthesis G 2 S M G 1 G 0 Resting Phase Cell Death DNA Synthesis Cell Maturation

5 Therapy Concepts Phase Specific drugs work only on a specific phase of cell growth most effective in rapidly growing cells Phase Non-Specific drugs work on more than one phase of cell growth most effective in rapidly growing cells

6 Therapy Concepts Chemotherapy Terminology Induction- drug therapy used as primary treatment (leukemia) Consolidation - drug therapy used as follow up after remission from induction (leukemia) Adjuvant- drug therapy after surgery or XRT Neo-adjuvant - drug therapy before surgery or XRT which is not adequate alone. Salvage - drug therapy when primary drug treatment after relapse.

7 Therapy Concepts Chemotherapy Terminology (cont) Regional - drug therapy localized to a specific area (e.g. limb perfusion, intrathecal, intraperitoneal) Maintenance - drug therapy used to maintain stable disease or remission. High Dose - doses above the standard range used primarily in combo with bone marrow rescue. Assumption that dose-intensity is effective. Palliation - drug therapy given to reduce symptoms without an intent to cure disease.

8 Therapy Concepts Response Criteria Complete Response - Complete disappearance of signs and symptoms for at least 1 month. Partial Response - >50% reduction of tumor mass of all measured lesions and no new lesions. Stable Disease - No significant change in tumor mass neither increasing or decreasing by 25%. Progressive Disease- More than 25% increase in tumor mass

9 Therapy Concepts Gompertzian Model of Tumor Growth Growth rate of tumor cells decreases with time Response to chemotherapy is during rapid growth phase. Plateau Rapid rate of tumor growth Time

10 Therapy Concepts Goldie-Coldman Hypothesis A fraction of tumor cells will develop resistance after treatment. This clone will continue to grow even though the patient appears to respond. Alternating combinations of chemotherapy agents early in treatment is necessary to prevent development resistant clones.

11 Therapy Concepts Worst-Drug Rule - Day Drug A works better than drug B against a tumor. Use Drug B first to shrink tumor. Use Drug A sequentially to overcome resistance. Assumes all tumors of resistant clones. Some tumors respond best to sequential therapy allowing for sparing of toxicity.

12 Combination Therapy Goals Maximum cell kill with tolerable toxicity Broad coverage of resistant cell lines Prevent development of resistance Method Use only effective drugs Use optimal scheduling and dose Limit overlapping toxicities

13 Combination Therapy Disadvantages Multiple toxicities. Reduction or holding of doses due to toxicity will limit effectiveness. Complicated to administer. Expensive

14 Combination Therapy Toxicity - CAF Toxicity Alopecia Cardiotoxicity Cystitis Mucositis Myelosuppression Responsible Drug C, A A C A, F C,A,F

15 Factors Affecting Tumor Response Tumor Burden Tumor Site Tumor Heterogeneity Drug Resistance Dose Intensity Patient Specific Factors Apoptosis

16 Cell Cycle Specific Drugs S Phase Specific Drugs Antimetabolites Folate antagonists(methotrexate) Purine antagonists (cladribine) Pyrimidine antagonists (cytrarbine,fluorouracil)

17 Cell Cycle Specific Drugs Mitosis Phase Specific Drugs Vinca Alkaloids (vincristine, vinblastine) Taxanes (paclitaxel, docetaxel) G2 Phase Specific Agents Topoisomerase I Inhibitors (irinotecan) Topoisomerase II Inhibitors (etoposide) G1 Phase Specific Agents Enzymes (asparaginase)

18 Cell Cycle Non-Specific Drugs Alkylating Agents Cyclophosphamide, busulfan Anthracyclines Doxorubicin, daunorubicin, idarubicin Antibiotics Mitomycin, dactinomycin Tryosine Kinase Inhibitors Imatinib

19 Cell Cycle Non-Specific Drugs Biologic Agents Immunomodulators (Interferon, Interleukin-2) Monoclonal Antibodies Rituximab, Trastuzumab Gemtuzumab Ozogamicin, Alemtuzumab, Ibritumomab Tiuxetan Yttrium-90, Cetuximab, Bevacizumab Hormones Tamoxifen, leuprolide, flutamide

20 Alkylating Agents Mechanism: Bind to DNA causing breaks Cell Cycle Non-Specific Major Toxicity: Myelosuppression, alopecia Examples: Busulfan (Myleran) Dacarbazine (DTIC) Cyclophosphamide, Ifosfamide Melphalan

21 Busulfan ( Myleran) 1.8mg/m2 PO daily or 0.06 mg/kg one time. BMT: 4mg/kg/d PO 3.2mg/kg/d IV CML CLL BMT Myelosuppression Pulmonary fibrosis CNS Hepatic (VOD)

22 Dacarbazine (DTIC) 250mg/m2 x 5 days Sarcoma Melanoma Myelosuppression Photosensitivity Flu-like symptom N/V Irritant Hepatic (vascular) VOD

23 Cyclophosphamide (Cytoxan) IV: mg per m 2 Max: 100mg/kg/48H PO: mg/m2 daily ALL Breast CLL NHL Hodgkins Myelosuppression N/V Cardiac (HD) Hemm. Cystitis SIADH

24 Ifosfamide (Ifex) 1-2gm/m2 daily x 4 IV Only Sarcoma NHL Ovarian Testicular Myelosuppression N/V Hemm. Cystitis (Requires Mesna) CNS

25 Melphalan (Alkeran) Oral: 9mg/m2 Daily PO BMT: mg/m2 IV Isolated Limb Perfusion: mg/kg M.Myleoma Breast Ovarian Melanoma Myelosuppression Secondary leukemia Pulmonary fibrosis

26 Other Alkylating Agents Procarbazine(Matulane) Chlorambucil (Leukeran) Mechlorethamine (Mustargen)

27 Nitrosoureas Mechanism: Bind to DNA causing breaks Cell Cycle Non-Specific Examples Carmustine (BCNU) Lomustine (CeeNu) Streptozocin (Zanosar)

28 Carmustine (BCNU) mg/m2/day x 2days CNS Tumors Sarcoma Hodgkins NHL Delayed Myelosuppression (6 week nadir) N/V Pulmonary fibrosis

29 Platinum Analogues Mechanism: Form Crosslinks in DNA,RNA Cell Cycle Non-Specific Major Toxicity: Renal and N/V Examples: Cisplatin (Platinol) Carboplatin (Paraplatin)

30 Cisplatin (Platinol) mg/m2 I V q 21 days Lung Testicular Head & Neck Bladder Ovarian Renal- hydrate Electrolyte Abnormality N/V - Severe Peripheral Neuropathy Ototoxicity

31 Carboplatin ( Paraplatin) mg/m2 IV or AUC Dose 5-7mg/mlxmin Dose = AUC(CrCl+25) Lung Testicular Head & Neck Breast Bladder Ovarian Myelosuppression N/V CNS Hypersensitivity

32 Oxaliplatin (Eloxatin ) 85mg/m2 IV over 2 hours every 2 weeks combined with 5FU+ LV Colon 90% Neuropathy Myelosuppression

33 Anthracyclines Mechanism: Intercalate DNA base pairs Cell Cycle Non-Specific Major Toxicity: Cardiac, Vesicant, Alopecia Examples: Doxorubicin (Adriamycin) Daunorubicin (Cerubidine) Idarubicin (Idamycin) Epirubicin (Ellence) Mitoxantrone (Novantrone)

34 Doxorubicin (Adriamycin) mg/m2 IV Q21 days MAX: 450mg/m2 with XRT 300mg/m2 Breast Bladder NHL Hodgkins Sarcoma Myeloma Lung AML Myelosuppression Cardiac Toxicity N/V Mucositis Vesicant

35 Daunorubicin (Cerubidine) mg/m2/day x3-5 days MAX: 550mg/m2 in adults AML ALL NHL Wilm s Tumor Neuroblastoma Myelosuppression Cardiac Toxicity N/V Mucositis Vesicant

36 Idarubicin (Idamycin) 12 mg/m2/day x 3 days MAX: 120mg/m2 AML ALL Myelosuppression N/V Cardiac Vesicant

37 Epirubicin (Ellence) IV: mg/m2 IVP MAX: 700mg/m2 Breast Cardiac Myelosuppression N/V Alopecia Vesicant

38 Mitoxantrone ( Novantrone ) 12 mg/m2/day x 3-5 days for AML 12mg/m2 IV Q 21 days for solid tumors. MAX: 160mg/m2 AML NHL Breast Myelosuppression Mucositis N/V Cardiac

39 Cardiotoxicity Agent Doxorubicin Daunorubici EKG Arrhythmia CHF Myopathy CHG Idarubicin Epirubicin Mitoxantrone Cytoxan Ifosfamide Paclitaxel ++ ++

40 Antibiotics Mechanism: DNA breakage Cell Cycle Non-Specific Major Toxicity: Pulmonary and Renal Examples: Mitomycin Bleomycin

41 Mitomycin (Mutamycin) mg/m2 Q 6 weeks MAX: 60mg/m2 Total Bladder Breast Lung Myelosuppression HUS(dose related) Pulmonary (avoid high O 2 levels) Vesicant

42 Bleomycin (Blenoxane) U/m2 IV or IM 1-2 x per week Pleurodesis: 60 units MAX: 400 U Total Testicular NHL Malignant Pleural Effusions Pulmonary fibrosis (avoid high O 2 levels) Anaphylaxis Fever Hyperpimentation

43 Pulmonary Toxicity Bleomycin Avoid high 02 concentrations for several weeks post chemo Incidence is 1-3% when doses >400 units Symptoms include dyspnea and dry cough Carmustine 20-30% lung fibrosis with doses >600mg/m2 Mitomycin C Incidence 3-12% when doses exceed 60 mg Busulfan Incidence of fibrosis 3% when >500mg

44 Antimetabolites: Folate Antagonists Mechanism: Blocks tetrahydrofolic acid production Cell Cycle Specific: S Phase Major Toxicity: Myelosuppression & GI Example Methotrexate Edatrexate Pemetrexed

45 Methotrexate (Mexate, MTX) Low: mg/m2 Inter: 1-2 g/m2 High: g/m2 Intrathecal: 12mg Breast NHL Sarcoma ALL Myelosuppression Mucositis Radiation Sensitizer Renal- alkalinize urine CNS (Leucovorin Rescue)

46 Pemetrexed ( Alimta) 500mg/m2 Every 21 days Requires Folic Acid and B12 Supplements Mesothelioma NSCLC Neutropenia 24% N/V 30% Fatigue 25%

47 Antimetabolites: Pyrimidine Antagonists Mechanism: Block DNA production Cell Cycle Specific: S Phase Major Toxicity: Myelosuppression Examples Cytarabine Fluorouracil Capecitabine Gemcitabine

48 Cytarabine ( Cytosar, Ara-C) mg/m2/day x 5-7 days CIVI 1-3 g/m2 Q 12 hrs bolus 10-30mg/m2 intrathecal AML ALL CML NHL Myelosuppression Cerebellar (High Dose) Ocular (High Dose) Pulmonary Hepatic (VOD)

49 Fluorouracil (5-FU, Adrucil) IV: mg/m2 weekly mg/m2/day x 5-7 days Colon Breast Head & Neck Gastric Myelosuppression Mucositis (CIVI) Diarrhea Cardiac Rash CNS

50 Capecitabine (Xeloda) Oral: 1250mg/m2 BID x 14 days With 1-2 week rest Breast Colon Diarrhea Hand/Foot Syndrome

51 Gemcitabine (Gemzar) IV: 1000mg/m2 over 30 min weekly X 3 Pancreatic Breast Lung Myelosuppression N/V Rash Hepatic

52 Antimetabolites: Purine Antagonists Mechanism: Block DNA production Cell Cycle Specific: S Phase Major Toxicity: Myelosuppression Examples Cladribine Fludarabine Mercaptopurine

53 Cladribine (2-CDA, Leustatin) 0.1mg/kg daily x 7 CIVI Hairy Cell Leukemia NHL CLL Waldenstrom Myelosuppression Fever Rash

54 Fludarabine (Fludara) IV: 25mg/m2 daily x 5 NHL CLL AML Myelosuppression Encephalopathy Pulmonary

55 Mercaptopurine (Purinethol, 6-MP) 6 PO: mg/m2 or 2.5mg/kg daily Hodgkins ALL CML NHL AML Myelosuppression Hepatic (VOD) Interacts with Allopurinol

56 Vinca Alkaloids Mechanism: Inhibits spindle formation Cell Cycle Specific: M Phase Major Toxicity: Neuropathy, alopecia, vesicants Examples Vincristine Vinblastine Vinorelbine

57 Vincristine (Oncovin) IV: mg/m2 weekly MAX: 2mg weekly ALL NHL CLL Breast Hodgkins Neuroblastoma Neuropathy Constipation Ileus Vesicant SIADH DEATH with overdose or intrathecal use

58 Vinblastine (Velban) IV: 4-10 mg/m2 weekly Hodgkins NHL CML Breast Myelosuppression Neuropathy Vesicant

59 Vinorelbine (Navelbine) IV 30mg/m2 weekly Breast NSCLC Ovarian Myelosuppression Neuropathy Constipation SIADH Vesicant (flush vein)

60 Vesicants Irritants Dactinomycin Daunorubicin Doxorubicin Epirubicin Idarubicin Mechlorethamine Mitomycin C Dactinomycin Vincristine Vinblastine Vinorelbine Cisplatin Carboplatin Docetaxel Etoposide Mitoxantrone Paclitaxel Teniposide

61 Extravasation

62 Treatment of Extravasations Stop Infusion Leave catheter in place Remove tubing Aspirate as much as possible from site Instill antidote if indicated Remove needle Inject SQ antidote into site in 3-6 areas around site Sodium thiosulfate 1/6 M for mechlorethamine,cisplatin, carboplatin Hyaluronidase units for vinca alkaloids Apply cold compress 45 minutes on 15 min off for 24 hr Apply warm compress for vincas, etoposide and taxanes

63 Topoisomerase I Inhibitors: Camptothecins Mechanism: Inhibit Topoisomerase I Cell Cycle Specific: G2 Phase Major Toxicity:Diarrhea,Myelosuppression Examples Irinotecan Topotecan

64 Irinotecan (Camptosar,, CPT-11) IV: 125 mg/m2 weekly x 4 Or 350mg/m2 Q 21 days Colon SCLC Pancreatic Gastric Diarrhea (Loperamide) Myelosuppression Flushing N/V Alopecia

65 Topotecan (Hycamtin) 1.5mg/m2 daily x5 Lung Ovarian Myelosuppression Diarrhea Headache

66 Diarrhea Causative agents Irinotecan Topotecan Cytarabine Fluorouracil Methotrexate Gemcitabine Treatment Loperamide Octreotide

67 Topoisomerase II Inhibitors: Epipodophyllotoxins Mechanism: Inhibit Topoisomerase II Cell Cycle Specific: G2 Phase Major Toxicity: Myelosuppression, Mucositis Examples Etoposide Teniposide

68 Etoposide (Vepesid) IV: mg/m2/day x 1-5 days PO: 50% Absorbed mg/m2 daily Lung NHL Breast AML ALL Myelosuppression Mucositis Alopecia Infusion-related: Hypotension

69 Teniposide (Vumon) IV: ALL: 165mg/m2 twice a week Solid Tumors: mg/m2 ALL Neuroblastoma NHL Myelosuppression Mucositis

70 Taxanes Mechanism: Stabilizes Microtubules Cell Cycle Specific: M Phase Major Toxicity: Myelosuppression, Neuropathy, Allergic Reactions, Alopecia Examples Paclitaxel Docetaxel

71 Paclitaxel (Taxol) IV: mg/m2 Q21 days or 80mg/m2 weekly Breast Lung Ovarian Head & Neck Bladder Myelosuppression Hypersensitivity Neuropathy Myalgia Alopecia

72 Docetaxel (Taxotere) mg/m2 Q 21 days Breast Lung H+N Ovarian Myelosuppression Pleural Effusions Peripheral Edema Angioedema Hypersensitivity Mucositis Alopecia

73 Immunomodulators Mechanism: Enhance immune function Cell Cycle Non- Specific Major Toxicity:Myalgia, hypotension Examples Interferon Aldesleukin (IL-2)

74 Interferon (Roferon( A, Intron A) IM or SQ: 3-10 Million Units 3 times a week. Melanoma CML Flu Symptoms Myalgia Fever N/V, Anorexia Depression Cough

75 Aldesleukin ( Proleukin,, IL-2) IV: High-dose 600,000 Units/Kg Q 8 Hrs Low-dose 2million/m2 daily x 4 as CIVI Renal Cell Melanoma Hypotension ( with high dose) Fever, chills Edema, Effusions Liver Toxocity

76 Monoclonal Antibodies Mechanism: Destroy specific cells with antigenic markers Cell Cycle Non- Specific Major Toxicity: Infusion-related toxicity Examples: Rituximab Trastuzumab Gemtuzumab Ozogamicin Alemtuzumab Ibritumomab Tiuxetan Yttrium-90 Cetuximab Bevacizumab

77 Rituximab ( Rituxan) IV: 375mg/m2 slowly Q week NHL (CD-20 +) Fever, chills (1st infusion worst) Hypotension Bronchospasm TLS (large tumor)

78 Trastuzumab (Herceptin) IV: Load: 4mg/kg over 90 min. Maint: 2mg/kg over 30 min. Q week Breast (Her-2 overexpression) Fever, Chills (1st Infusion) Cardiac (CHF) MUGA N/V, Diarrhea Rash

79 Gemtuzumab Ozogamicin (Mylotarg) IV: 9mg/m2 over 2 hours on Day 1 and 15. AML for patients> 60 year Fever, Chills, Hypotension, Neutropenia, Thrombocytopenia, Anemia, Tumor Lysis

80 Alemtuzumab (Campath) IV: 3mg IV daily over 2 hours then 10mg daily, then 30mg 3x a week Anti CD-52 B-cell CLL failed Fludarabine Fever, Chills, Hypotension, Neutropenia, Thrombocytopenia, Anemia, Tumor Lysis HSV AND PCP x 2 months

81 Ibritumomab Tiuxetan Y-90 (Zevalin( Zevalin) Radioimmunotherapy IV: mCi/kg once Refractory low-grade CD20+ NHL Neutropenia 63%, Thrombocytopenia 60%, Anemia 17%

82 Cetuximab (Erbitux) IV: 400mg/m2 Over 2 hrs x1, Then 250mg/m2 Over 1 hr Weekly. EGFR + Colorectal Irinotecan refractory Infusion Reaction 3% Bronchospasm, Anaphylaxis Inter. Lung Dis. 1% Severe Acne 14% Fever 5%

83 Bevacizumab (Avastin) IV: 5mg/kg Over 90 min. every 14 days. Metastatic Colorectal Anti-VEGF Infusion Reactions GI Perforation 2% Hemorrhage Nephrotic Syndrome CHF 14% Neutropenia 21% Hypertension 60%

84 Tyrosine Kinase Inhibitor Mechanism: Inhibits tyrosine kinase regulation of cell growth Cell Cycle Non- Specific Major Toxicity: Variable Examples: Imatinib Erlotinib

85 Imatinib ( Gleevec) PO: mg daily CML: Ph +, chronic, accelerated phases, and blast crisis Neutropenia 33-60% Thrombocytopenia 16-60% Anemia 4-50% Hepatotoxicity 1-3% Fluid Retention1-5%

86 Erlotinib (Tarceva) PO: mg daily NSCLC Pancreatic Interstitial Lung Disease 1% Hepatotoxicity Rash Fatigue

87 Hormonal Agents Mechanism: Block or prevent hormonal effects on tumor cells Cell Cycle Non- Specific Major Toxicity: Hormonal dysfunction Examples: Tamoxifen Leuprolide Bicalutimide

88 Tamoxifen (Nolvadex) PO: 10-20mg PO BID Breast Hot Flashes N/V Flare Reaction VTE Category D:PRF

89 Anastrazole (Arimidex) PO: 1mg daily Breast Hot Flashes N/V Flare Reaction VTE Preg Category D:

90 Leuprolide (Lupron) IM: 7.5mg monthly or 22.5mg q3 months Prostate Hot flashes Impotence Decreased Libido Tumor Flare

91 Flutamide (Eulexin ) PO: 250mg tid Prostate Hepatotoxicity Gynecomastia Diarrhea Myalgia

92 Bicalutamide (Casodex) PO: mg daily Prostate Hepatotoxicity Gynecomastia Diarrhea Myalgia

93 Calculations: Body Surface Area BSA (m2) = Height (cm) x Weight (Kg) 3600 Estimated Creatinine Clearance GFR Males = (140-age) x Weight ( Kg) 72 x SCr GFR Females = GFR Males X 0.85

Medication Review. Cancer Chemotherapy Drugs. Pharmacy Technician Training Systems Passassured, LLC

Medication Review. Cancer Chemotherapy Drugs. Pharmacy Technician Training Systems Passassured, LLC Medication Review Cancer Chemotherapy Drugs Pharmacy Technician Training Systems Passassured, LLC Medication Review, Cancer Chemotherapy Drugs PassAssured's Pharmacy Technician Training Program Medication