Antineoplastic Prescribing I Brian Boulmay, MD LSU- Section of HemOnc

It’s the dose that makes a poison. Paracelcus AD 1520

Objectives Understand the basis for chemotherapy. Be able to identify appropriate dosage ranges. Be able to identify major toxicities. Learn the skill of prescribing chemotherapy.

To be a monk, you have to cook a lot of rice. -David Lee Roth

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

The Cell Cycle Mitosis Premitotic M RNA Synthesis Protein Synthesis G2 DNA Synthesis

Therapy Basics Phase Specific drugs Phase Non-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

Chemotherapy terms Induction 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 for cure Salvage- drug therapy when primary drug treatment fails Definitive- Chemotherapy used for cure

Chemotherapy terms 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.

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

Chemotherapy- Acute lymphoblastic leukemia Single agents- late 1940’s Antimetobolites or nitrogen mustards= Short remissions NCI/ Roswell Park/ Childrens’ Buffalo- 1950’s Methotrexate + 6-mercaptopurine= Longer remissions

Therapy Concepts Goldie-Coldman Hypothesis– A fraction of tumor cells will develop resistance after treatment. This clone will continue to grow even in responders. Alternating combinations of chemotherapy agents= prevent resistant clones

Combination Chemotherapy- Acute lymphoblastic leukemia Multiple agents: Vincristine + amethopterin + 6MP + prednisone= Cure 21st century: Children: Cure is the rule Adults: 40% cure rate

Combination chemotherapy DeVita- MOPP for stage IV Hodgkin lymphoma= Cure Bonnadonna- CMF chemotherapy after breast cancer surgery= More cures than with surgery

Combination chemotherapy- Advantages Maximum cell kill Broad coverage of resistant cell lines Prevent development of resistance Method –Use only effective drugs –Use optimal scheduling and dose Limit overlapping toxicities

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

Combination Therapy Toxicity Combination Therapy Toxicity- FAC 5-Fluorouracil, Adriamycin, Cytoxan (cyclophosphamide) Toxicity Responsible Drug Alopecia C,A Cardiotoxicity A Cystitis C Myelosuppression C, A, F Mucositis 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 ??? Purine antagonists ??? Pyrimidine antagonists ???

Cell Cycle Specific Drugs S Phase Specific Drugs Antimetabolites: Folate antagonists (methotrexate) Purine antagonists (cladribine, fludarabine) Pyrimidine antagonists (cytarabine, 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 Anthracyclines Antibiotics Tyrosine Kinase Inhibitors

Alkylating Agents Cell Cycle Non-Specific Major Toxicity: Myelosuppression, alopecia Examples: Busulfan (Myleran) Dacarbazine (DTIC) Cyclophosphamide, Ifosfamide Melphalan

Alkylating Agents Mustards: Ifosfamide, cyclophosphamide, nitrogen mustard Alkylation: Addition of an alkyl group to guanine Prevents coiling or uncoiling of DNA by crosslinking guanine H C H H Methyl group

Alkylating Agents Dacarbazine Indications Toxicities Hodgkin Lymphoma Myelosuppression Nausea, nausea Irritant Dacarbazine

Alkylating Agents Indications Toxicities ALL Cystitis Breast Myelosuppression NHL Irritant Nausea, nausea cyclophosphamide (Cytoxan)

Cyclophosphamide Cyclophosphamide Liver Aldophosphamide Phosphoramide mustard (active metabolite) Acrolein (cause of hemorrhagic cystitis)

Ifosfamide Indications Common Toxicities Sarcoma Myelosuppression NHL Nausea, nausea Testicular Cystitis Ifos Brain

(cause of neuro compromise) Ifosfamide Ifosfamide chloroacetaldehyde (cause of neuro compromise) aldoifosfamide acrolein isophosphoramide mustard

Alkylating Agents Other alkylators: Procarbazine Chlorambucil Mechlorethamine

Nitrosureas Mechanism: Bind to DNA causing breaks/ alkylators Cell Cycle Non-Specific Examples Carmustine (BCNU) Lomustine (CCNU)

Nitrosureas Indications Toxicity CNS Tumors delayed neutropenia (3-5 weeks after dose) nausea irritant Administered IV BCNU (carmustine)

Nitrosureas Indications Toxicity CNS Tumors delayed neutropenia (3-5 weeks after dose) nausea irritant Administered PO CCNU (lomustine)

Platinum Analogues Mechanism: Form Crosslinks in DNA, RNA Cell Cycle Non-Specific Major Toxicity: Renal and nausea/vomiting Examples: Cisplatin Carboplatin Oxaliplatin

Cisplatin cis-diamminedichloroplatinum (CDDP) Through a process of ‘aquation,’ platinum is able to bind DNA bases (guanine) A second binding to another guanine results in “cross-linking’ of DNA.

Cisplatin 25% of a dose is excreted in the urine within 1 hour of a dose 75% rapidly distributes in skin, muscle and liver. cisplatin can be measured in urine months after a single dose Extensive protein and RBC binding Important for dosing methodology (versus carboplatin)

Cisplatin Indications Toxicity Lung Renal dysfunction Testicular Hypomagnesemia Head and neck Nausea Bladder Neuro-ototoxcity Ovarian Peripheral neuropathy (prolonged use)

Carboplatin cis-diammine(1,1-cyclobutanedicarboxylato)platinum Lower reactivity, less protein binding than cisplatin More stable in D5W rather than NS

Carboplatin Renal function and other physiologic variables can affect excretion: Carboplatin typically dosed by the area under the curve (AUC) mg/ml x min mg/m2 a less reliable method: hematologic toxicity higher Calvert Equation: dose=Target AUC x [GFR+25]

Carboplatin Percentage reduction in platelet count linearly correllates with the AUC. AUC6 targets plt count nadir 100K Advantages of AUC: Avoids subtherapeutic dosing for patients with high GFR Avoids overdosing those with renal impairment Calvert JCO 1989

Platinum Analogues Oxaliplatin Indications Common Toxicities Colon cancer 90% neuropathy myelosuppression Oxaliplatin

Anthracyclines Mechanism: Intercalate DNA base pairs; generates iron mediated free O radicals Cell Cycle Non-Specific Major Toxicity: Cardiac, Vesicant, Alopecia Examples: Doxorubicin (Adriamycin) ----Red Daunorubicin ----Red Idarubicin (Idamycin) ----Red Epirubicin (Ellence) ----Red Mitoxantrone (Novantrone) ----Blue

Anthracyclines Toxicity: Cardiac toxicity possibly related to inhibition of topoisomerase II in cardiomyocytes. Typically dose related

Anthracyclines Drug Lifetime Dose Doxorubicin 500-550mg/m2 Daunorubicin 500-600mg/m2 Doxorubicin+cyclophophosphamide 450mg/m2 Epirubicin 830-920mg/m2 Epirubicin+cyclophosphamide 750mg/m2 Idarubicin ~120mg/m2 Mitoxantrone 160mg/m2 Keefe Semin Oncol 2001

Anthracyclines Conversion Table: Drug Conversion Factor Doxorubicin- 5% HF at 450mg/m2 1 Daunorubicin- 5% HF at 900mg/m2 0.5 Epirubicin- 5% HF at 935mg/m2 Idarubicin- 5% HF at 225mg/m2 2 Mitoxantrone- 5% HF at 200mg/m2 2.2

Anthracyclines Drug considerations: Vesicant Hepatically cleared: T bili >1.5 or AST >2x ULN: dose adjustment necessary Contraindicated in heart failure

Anthracyclines Adriamycin “Red Drug” Idarubicin Indications Toxicity Breast Myelosuppression Bladder Nausea NHL Mucositis Hodgkin Vesicant Sarcoma Indications Common Toxicities AML Myelosuppression ALL Nausea Cardiac dysfunction Adriamycin “Red Drug” Idarubicin

Antibiotics Mechanism: DNA breakage- exact mechnism of action still unclear. Cell Cycle Non-Specific Major Toxicity: Pulmonary and Renal Examples: Mitomycin Bleomycin

Antibiotics Mitomycin Bleomycin Indication Common Toxicity Anal Myelosuppression HUS Vesicant Indications Toxicity Testicular Pulmonary fibrosis* NHL Anaphylaxis Fever Mitomycin Bleomycin

A few words on 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 Incidence of pulmonary toxicity with bleomycin increased from 9% to 26% with use of growth factors and ABVD (Martin JCO 2005) At what threshold of FEV1 or DLCO do you hold bleomycin?

A few words on 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 Incidence of pulmonary toxicity with bleomycin increased from 9% to 26% with use of growth factors and ABVD (Martin JCO 2005) At what threshold of FEV1 or DLCO do you hold bleomycin? Unknown: ‘Bleomycin was discontinued if the patient manifested clinical or radiographic evidence of pulmonary fibrosis (rales or inspiratory lag) or significant deterioration of pulmonary diffusion capacity. ‘ (Nichols JCO 1998)

Antimetabolites: Folate Antagonists Mechanism: Inhibits dihydrofolate reductase Inhibits tetrahydrofolic acid production Cell Cycle Specific: S Phase Major Toxicity: Myelosuppression & GI Example Methotrexate Pemetrexed

Antimetabolites: Folate Antagonists Indications Toxicities ALL Renal Sarcoma Mucositis NHL Head and Neck Cancer Indications Toxicities Non-small cell lung cancer Fatigue Skin Rash Conjunctival Irritation Methotrexate (MTX) Pemetrexed

Pemetrexed/ MTX- Special Considerations MTX- Effusions Pemetrexed is safe with effusions. Pemetrexed- Coadministration: with B12 q 9 weeks Daily 1mg folic acid Dickgreber Clin Cancer Researcher 2010

High Dose Methotrexate Rescue with leucovorin after completion of 24 hour infusion. Dosing nomogram based on daily MTX levels: http://www.medschool.lsuhsc.edu/internal_medicine/docs/Methotrexate%20guide.pdf Mechanism of action of leucovorin?

High Dose Methotrexate Rescue with leucovorin after completion of 24 hour infusion. Dosing nomogram based on daily MTX levels: http://www.medschool.lsuhsc.edu/internal_medicine/docs/Methotrexate%20guide.pdf Mechanism of action of leucovorin? Donates methyl groups. Allows for purine/pyrimadine synthesis.

Antimetabolites: Pyrimadine Anatagonists Mechanism: Inhibits thymidylate synthetase Cell Cycle Specific: S Phase Major Toxicity: Myelosuppression Examples Cytarabine Fluorouracil Capecitabine Gemcitabine

Antimetabolites: Pyrimadine Anatagonists Indications Common Toxicities Colon Myelosuppression Breast Mucositis (CIVI) Head and Neck Diarrhea Gastric Hand-foot syndrome Indications Toxicity AML Myelosuppression ALL Cerebellar Toxicity NHL Ocular (conjunctival) Cytarabine 5-Fluorouracil

Antimetabolites: Pyrimadine Anatagonists Indications Toxicity Breast Diarrhea Colon Hand/Foot Syndrome Capecitabine (Xeloda)

Antimetabolites: Purine Antagonists Mechanism: Inhibits ribonucleotide reducatase Cell Cycle Specific: S Phase Major Toxicity: Myelosuppression Examples Cladribine Fludarabine Mercaptopurine

Antimetabolites: Purine Antagonists Indications Toxicity Hairy Cell Leukemia Myelosuppression Fever Indications Toxicity NHL Myelosuppression CLL AML Fludarabine Cladrabine

Fludarabine- Special Considerations Leukopenia Deep and sustained Do not use G-CSF support to keep patients ‘on time’ Gets worse before it gets better. ‘AIDS-level’ drops in CD4 counts: Prophylaxis with acyclovir and Bactrim during and for at least 6 months after therapy.

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

Vinca Alkaloids Vincristine* Vinblastine Indications Toxicity Hodgkin Lymphoma Myelosuppression Neuropathy Indications Toxicity ALL Neuropathy NHL Constipation CLL Ileus Breast Vincristine* *Never give Intrathecal Vinblastine

Vesicants vs. Irritants (blistering agents) Irritants Anthracyclines (except mitoxantrone) Cisplatin Vinca alkaloids Carboplatin Mechlorethamine Taxanes Mitoxantrone Etoposide (VP-16)

Treatment of extravasation Stop infusion Do not remove catheter. Aspirate as much as possible Instill antidote into effected area: Sodium thiosulfate for mechlorethamine, platinums Hyaluronidase for 150-900 units for vincas Apply cold compresses 45 minutes on/ 15 minutes off for 24 hours Apply warm compresses for vincas, etoposide, and taxanes

Topoisomerase inhibitors: Topo 1 Mechanism: Inhibit Topoisomerase I Cell Cycle Specific: G2 Phase Major Toxicity:Diarrhea,Myelosuppression Examples Irinotecan Topotecan

Topo1 Inhibitors Topotecan Irinotecan (CPT-11) Indications Toxicity Colon Diarrhea SCLC Myelosuppression Gastric Flushing Alopecia Indications Toxicity Lung Myelosuppression Ovarian Diarrhea Topotecan Irinotecan (CPT-11)

Irinotecan- Special Considerations Diarrhea- Acute: Inhibition of acetylcholinesterase Atropine prophylactically/ secondary treatment Chronic: SN-38 secreted in bile. Loperamide, Lomotil

Topo II: Epipodophyllotoxins Mechanism: Inhibit Topoisomerase II Cell Cycle Specific: G2 Phase Major Toxicity: Myelosuppression, Mucositis Example: Etoposide

Topo II: Inhibitors Etoposide (VP-16)* Indication Toxicity Lung Myelosuppression NHL Mucositis Testicular Etoposide (VP-16)*

Topo II: Inhibitors Etoposide (VP-16)* Indication Toxicity Lung Myelosuppression NHL Mucositis Testicular Etoposide (VP-16)* *Peculiar Leukemia Risk: 1-2% AML risk at 2 years MLL gene, 11q23

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

Taxanes Paclitaxel Docetaxel Indications Toxicity Breast Neuropathy Lung Alopecia Ovarian Myelosuppression Head and Neck Indications Toxicities Breast Myelosuppression Lung Hypersensitivity Head and Neck Angioedema Alopecia Paclitaxel Docetaxel

Antineoplastics II- Next time