Introduction to Antineoplastic Prescribing Robert Bradbury, R.Ph., BCPS Clinical Coordinator H. Lee Moffitt Cancer Center
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.
Overview Cell Cycle Kinetics Pharmacologic Classification of Antineoplastic Agents Review of Agents Review of Combination Therapy
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
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
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.
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.
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
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
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.
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.
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
Combination Therapy Disadvantages Multiple toxicities. Reduction or holding of doses due to toxicity will limit effectiveness. Complicated to administer. Expensive
Combination Therapy Toxicity - CAF Toxicity Alopecia Cardiotoxicity Cystitis Mucositis Myelosuppression Responsible Drug C, A A C A, F C,A,F
Factors Affecting Tumor Response Tumor Burden Tumor Site Tumor Heterogeneity Drug Resistance Dose Intensity Patient Specific Factors Apoptosis
Cell Cycle Specific Drugs S Phase Specific Drugs Antimetabolites Folate antagonists(methotrexate) Purine antagonists (cladribine) Pyrimidine antagonists (cytrarbine,fluorouracil)
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)
Cell Cycle Non-Specific Drugs Alkylating Agents Cyclophosphamide, busulfan Anthracyclines Doxorubicin, daunorubicin, idarubicin Antibiotics Mitomycin, dactinomycin Tryosine Kinase Inhibitors Imatinib
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
Alkylating Agents Mechanism: Bind to DNA causing breaks Cell Cycle Non-Specific Major Toxicity: Myelosuppression, alopecia Examples: Busulfan (Myleran) Dacarbazine (DTIC) Cyclophosphamide, Ifosfamide Melphalan
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)
Dacarbazine (DTIC) 250mg/m2 x 5 days Sarcoma Melanoma Myelosuppression Photosensitivity Flu-like symptom N/V Irritant Hepatic (vascular) VOD
Cyclophosphamide (Cytoxan) IV: 500-2000mg per m 2 Max: 100mg/kg/48H PO: 50-400mg/m2 daily ALL Breast CLL NHL Hodgkins Myelosuppression N/V Cardiac (HD) Hemm. Cystitis SIADH
Ifosfamide (Ifex) 1-2gm/m2 daily x 4 IV Only Sarcoma NHL Ovarian Testicular Myelosuppression N/V Hemm. Cystitis (Requires Mesna) CNS
Melphalan (Alkeran) Oral: 9mg/m2 Daily PO BMT: 50-140mg/m2 IV Isolated Limb Perfusion: 0.8-1.5mg/kg M.Myleoma Breast Ovarian Melanoma Myelosuppression Secondary leukemia Pulmonary fibrosis
Other Alkylating Agents Procarbazine(Matulane) Chlorambucil (Leukeran) Mechlorethamine (Mustargen)
Nitrosoureas Mechanism: Bind to DNA causing breaks Cell Cycle Non-Specific Examples Carmustine (BCNU) Lomustine (CeeNu) Streptozocin (Zanosar)
Carmustine (BCNU) 75-100 mg/m2/day x 2days CNS Tumors Sarcoma Hodgkins NHL Delayed Myelosuppression (6 week nadir) N/V Pulmonary fibrosis
Platinum Analogues Mechanism: Form Crosslinks in DNA,RNA Cell Cycle Non-Specific Major Toxicity: Renal and N/V Examples: Cisplatin (Platinol) Carboplatin (Paraplatin)
Cisplatin (Platinol) 60-100 mg/m2 I V q 21 days Lung Testicular Head & Neck Bladder Ovarian Renal- hydrate Electrolyte Abnormality N/V - Severe Peripheral Neuropathy Ototoxicity
Carboplatin ( Paraplatin) 300-400 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
Oxaliplatin (Eloxatin ) 85mg/m2 IV over 2 hours every 2 weeks combined with 5FU+ LV Colon 90% Neuropathy Myelosuppression
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)
Doxorubicin (Adriamycin) 60-100 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
Daunorubicin (Cerubidine) 30-60 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
Idarubicin (Idamycin) 12 mg/m2/day x 3 days MAX: 120mg/m2 AML ALL Myelosuppression N/V Cardiac Vesicant
Epirubicin (Ellence) IV: 60-100mg/m2 IVP MAX: 700mg/m2 Breast Cardiac Myelosuppression N/V Alopecia Vesicant
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
Cardiotoxicity Agent Doxorubicin Daunorubici EKG Arrhythmia CHF Myopathy CHG ++ ++ +++ +++ Idarubicin ++ ++ ++ ++ Epirubicin + + ++ ++ Mitoxantrone + ++ + Cytoxan Ifosfamide ++ ++ Paclitaxel ++ ++
Antibiotics Mechanism: DNA breakage Cell Cycle Non-Specific Major Toxicity: Pulmonary and Renal Examples: Mitomycin Bleomycin
Mitomycin (Mutamycin) 10-20 mg/m2 Q 6 weeks MAX: 60mg/m2 Total Bladder Breast Lung Myelosuppression HUS(dose related) Pulmonary (avoid high O 2 levels) Vesicant
Bleomycin (Blenoxane) 10-20 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
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
Antimetabolites: Folate Antagonists Mechanism: Blocks tetrahydrofolic acid production Cell Cycle Specific: S Phase Major Toxicity: Myelosuppression & GI Example Methotrexate Edatrexate Pemetrexed
Methotrexate (Mexate, MTX) Low: 10-100mg/m2 Inter: 1-2 g/m2 High: 10-12 g/m2 Intrathecal: 12mg Breast NHL Sarcoma ALL Myelosuppression Mucositis Radiation Sensitizer Renal- alkalinize urine CNS (Leucovorin Rescue)
Pemetrexed ( Alimta) 500mg/m2 Every 21 days Requires Folic Acid and B12 Supplements Mesothelioma NSCLC Neutropenia 24% N/V 30% Fatigue 25%
Antimetabolites: Pyrimidine Antagonists Mechanism: Block DNA production Cell Cycle Specific: S Phase Major Toxicity: Myelosuppression Examples Cytarabine Fluorouracil Capecitabine Gemcitabine
Cytarabine ( Cytosar, Ara-C) 100-200 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)
Fluorouracil (5-FU, Adrucil) IV: 400-500 mg/m2 weekly 300-1000 mg/m2/day x 5-7 days Colon Breast Head & Neck Gastric Myelosuppression Mucositis (CIVI) Diarrhea Cardiac Rash CNS
Capecitabine (Xeloda) Oral: 1250mg/m2 BID x 14 days With 1-2 week rest Breast Colon Diarrhea Hand/Foot Syndrome
Gemcitabine (Gemzar) IV: 1000mg/m2 over 30 min weekly X 3 Pancreatic Breast Lung Myelosuppression N/V Rash Hepatic
Antimetabolites: Purine Antagonists Mechanism: Block DNA production Cell Cycle Specific: S Phase Major Toxicity: Myelosuppression Examples Cladribine Fludarabine Mercaptopurine
Cladribine (2-CDA, Leustatin) 0.1mg/kg daily x 7 CIVI Hairy Cell Leukemia NHL CLL Waldenstrom Myelosuppression Fever Rash
Fludarabine (Fludara) IV: 25mg/m2 daily x 5 NHL CLL AML Myelosuppression Encephalopathy Pulmonary
Mercaptopurine (Purinethol, 6-MP) 6 PO: 70-100mg/m2 or 2.5mg/kg daily Hodgkins ALL CML NHL AML Myelosuppression Hepatic (VOD) Interacts with Allopurinol
Vinca Alkaloids Mechanism: Inhibits spindle formation Cell Cycle Specific: M Phase Major Toxicity: Neuropathy, alopecia, vesicants Examples Vincristine Vinblastine Vinorelbine
Vincristine (Oncovin) IV: 0.4-1.4 mg/m2 weekly MAX: 2mg weekly ALL NHL CLL Breast Hodgkins Neuroblastoma Neuropathy Constipation Ileus Vesicant SIADH DEATH with overdose or intrathecal use
Vinblastine (Velban) IV: 4-10 mg/m2 weekly Hodgkins NHL CML Breast Myelosuppression Neuropathy Vesicant
Vinorelbine (Navelbine) IV 30mg/m2 weekly Breast NSCLC Ovarian Myelosuppression Neuropathy Constipation SIADH Vesicant (flush vein)
Vesicants Irritants Dactinomycin Daunorubicin Doxorubicin Epirubicin Idarubicin Mechlorethamine Mitomycin C Dactinomycin Vincristine Vinblastine Vinorelbine Cisplatin Carboplatin Docetaxel Etoposide Mitoxantrone Paclitaxel Teniposide
Extravasation
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 150-900 units for vinca alkaloids Apply cold compress 45 minutes on 15 min off for 24 hr Apply warm compress for vincas, etoposide and taxanes
Topoisomerase I Inhibitors: Camptothecins Mechanism: Inhibit Topoisomerase I Cell Cycle Specific: G2 Phase Major Toxicity:Diarrhea,Myelosuppression Examples Irinotecan Topotecan
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
Topotecan (Hycamtin) 1.5mg/m2 daily x5 Lung Ovarian Myelosuppression Diarrhea Headache
Diarrhea Causative agents Irinotecan Topotecan Cytarabine Fluorouracil Methotrexate Gemcitabine Treatment Loperamide Octreotide
Topoisomerase II Inhibitors: Epipodophyllotoxins Mechanism: Inhibit Topoisomerase II Cell Cycle Specific: G2 Phase Major Toxicity: Myelosuppression, Mucositis Examples Etoposide Teniposide
Etoposide (Vepesid) IV: 30-120 mg/m2/day x 1-5 days PO: 50% Absorbed. 50-100 mg/m2 daily Lung NHL Breast AML ALL Myelosuppression Mucositis Alopecia Infusion-related: Hypotension
Teniposide (Vumon) IV: ALL: 165mg/m2 twice a week Solid Tumors: 60-90 mg/m2 ALL Neuroblastoma NHL Myelosuppression Mucositis
Taxanes Mechanism: Stabilizes Microtubules Cell Cycle Specific: M Phase Major Toxicity: Myelosuppression, Neuropathy, Allergic Reactions, Alopecia Examples Paclitaxel Docetaxel
Paclitaxel (Taxol) IV: 135-250 mg/m2 Q21 days or 80mg/m2 weekly Breast Lung Ovarian Head & Neck Bladder Myelosuppression Hypersensitivity Neuropathy Myalgia Alopecia
Docetaxel (Taxotere) 60-100 mg/m2 Q 21 days Breast Lung H+N Ovarian Myelosuppression Pleural Effusions Peripheral Edema Angioedema Hypersensitivity Mucositis Alopecia
Immunomodulators Mechanism: Enhance immune function Cell Cycle Non- Specific Major Toxicity:Myalgia, hypotension Examples Interferon Aldesleukin (IL-2)
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
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
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
Rituximab ( Rituxan) IV: 375mg/m2 slowly Q week NHL (CD-20 +) Fever, chills (1st infusion worst) Hypotension Bronchospasm TLS (large tumor)
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
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
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
Ibritumomab Tiuxetan Y-90 (Zevalin( Zevalin) Radioimmunotherapy IV: 0.3-0.4mCi/kg once Refractory low-grade CD20+ NHL Neutropenia 63%, Thrombocytopenia 60%, Anemia 17%
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%
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%
Tyrosine Kinase Inhibitor Mechanism: Inhibits tyrosine kinase regulation of cell growth Cell Cycle Non- Specific Major Toxicity: Variable Examples: Imatinib Erlotinib
Imatinib ( Gleevec) PO: 400-800 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%
Erlotinib (Tarceva) PO: 100-150 mg daily NSCLC Pancreatic Interstitial Lung Disease 1% Hepatotoxicity Rash Fatigue
Hormonal Agents Mechanism: Block or prevent hormonal effects on tumor cells Cell Cycle Non- Specific Major Toxicity: Hormonal dysfunction Examples: Tamoxifen Leuprolide Bicalutimide
Tamoxifen (Nolvadex) PO: 10-20mg PO BID Breast Hot Flashes N/V Flare Reaction VTE Category D:PRF
Anastrazole (Arimidex) PO: 1mg daily Breast Hot Flashes N/V Flare Reaction VTE Preg Category D:
Leuprolide (Lupron) IM: 7.5mg monthly or 22.5mg q3 months Prostate Hot flashes Impotence Decreased Libido Tumor Flare
Flutamide (Eulexin ) PO: 250mg tid Prostate Hepatotoxicity Gynecomastia Diarrhea Myalgia
Bicalutamide (Casodex) PO: 50-150 mg daily Prostate Hepatotoxicity Gynecomastia Diarrhea Myalgia
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