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Oral Chemotherapy in Dogs and Cats Cory Theberge, PhD UNE College of Pharmacy Karin Wagner, DVM, DACVIM Maine Veterinary Referral Center Scarborough, ME Learning Objectives • Relate the types of cancers seen in cats and dogs, and recall oral chemotherapy dosing and treatment strategies • Discuss oral veterinary chemotherapy options in cats and dogs, including side effects, tolerances, drug interactions and safety concerns Most Common Cancers Treated With Oral Chemotherapy • Lymphoma (including leukemia) – peripheral lymph nodes, spleen, liver in dogs; GI tract in cats • Mast cell tumors – dogs – cutaneous, less commonly visceral (spleen, GIT) • Multiple myeloma – dogs > cats – bone marrow • Histiocytic sarcoma – dogs – spleen, liver • Brain/CNS tumors Use of Chemotherapy in Veterinary Medicine • Treatment goal: “quality of life” vs “quantity of life” • Primary therapy – sole therapy for systemic cancer (lymphoma, multiple myeloma) – therapy prior to surgery or radiation therapy (RT) to decrease size of tumor or systemic effects of tumor • Adjuvant therapy – following local treatment (surgery, RT) • Palliative therapy – to control symptoms or effects of cancer to improve quality of life Mechanisms of action of chemotherapy • Targeting dividing cells to prevent growth or to induce death (apoptosis) • Targets include various steps in the cell cycle and support for tumor including blood supply, immune response, inter-cell signaling Chemotherapy Dosing Maximum tolerated dose (MTD) • Traditional use of cytotoxic drugs to have maximum, direct effect on cancer cells, ideally curative • Response directly proportional to dose • Tolerance of dose is guide, rather than efficacy • Higher doses, less frequently, allowing normal tissues to recover between doses Chemotherapy Dosing Metronomic • Lower doses, more frequently or continuously • Used for “maintenance” therapy, rather than “curative” therapy Proposed mechanisms of action: • Antiangiogenic effects • Attacking normal, support cells • Influencing immune response or tolerance to cancer (T reg cells) • Direct anti-cancer effects Advantages of Oral Chemotherapy • Convenience • Fewer hospital visits • Easier treatment of difficult patients • Possible decreased cost of treatment Disadvantages of Oral Chemotherapy • Risk of decreased efficacy due to – poor owner compliance – vomited medications – differences in bioavailability • Increased risk of exposure to chemotherapy • Decreased accuracy or flexibility of dosing due to restriction to tablet size Disadvantages of Oral Chemotherapy Compounded oral chemotherapy • Risk of inaccurate dosing greater due to low therapeutic index • Potential for changes in absorption, non-uniform distribution of drug, increased exposure to owner with liquid formulations Other factors to consider with oral chemotherapy: • Effects of food or other medications, supplements on absorption or tolerance of drugs Oral Chemotherapy Drugs Oral Chemotherapy Drugs in Veterinary Medicine Glucocorticoids Prednisone/prednisolone Alkylating Agents Cyclophosphamide (Cytoxan®) Chlorambucil (Leukeran®) Lomustine (CeeNu®) Melphalan (Alkeran®) Procarbazine Lymphoma, mast cell tumors, multiple myeloma, histiocytic sarcoma Lymphoma, metronomic tx Lymphoma, multiple myeloma Lymphoma, CNS, MCT, HS Multiple myeloma, lymphoma Lymphoma Oral Chemotherapy Drugs in Veterinary Medicine Veterinary Label TKIs Toceranib (Palladia®) Masitinib (Kinavet®) Mast cell tumors, carcinomas, sarcomas NSAIDs (Cox-2 inhibitors) Piroxicam (Feldene®) Deracoxib (Deramaxx®) Meloxicam (Metacam®) Carcinomas, metronomic tx Side Effects Side effects tend to be less common, milder, and more easily prevented than in human patients • Dosing of vet patients is designed to minimize side effects General side effects common to almost all drugs: • Myelosuppression • low WBCs, platelets, RBCs • Gastrointestinal upset • vomiting, diarrhea, inappetance Drug-Specific Side Effects Cyclophosphamide - hemorrhagic cystitis (due to contact of bladder mucosa with drug metabolite “acrolein”) – Dosing with furosemide decreases risk of cystitis significantly Lomustine – hepatotoxicity (6-20% dogs) – Concurrent S-adenosylmethionine (SAMe) may help prevent toxicity Melphalan – pulmonary fibrosis Glucocorticoids – polyuria, polydipsia, polyphagia, muscle atrophy, diabetes (insulin resistance) Toceranib – GI ulceration, lameness Masitinib - proteinuria Variations in Drug Tolerance Specific organ dysfunction causing • Decreased metabolism/elimination of active drug • Increased risk of additional toxicity Breed-associated genetic variations • MDR1 mutation in Collies, herding dogs, others • Pre-treatment genetic screening available Dogs vs cats • Differences in hepatic metabolism, nephrotoxicity Drug Interactions • Positive interactions – Combinations of chemotherapy drugs more effective treatment without additional toxicity – Overcomes natural resistance mechanisms of cancer cells – Lymphoma – CHOP protocol • Negative interactions – Glucocorticoids – suspected to cause MDR in cancer cells, avoid using more than few days prior to other chemotherapy – Compounding toxicity – myelosuppression, GI toxicity, etc Safety Concerns • For patients, family, other pets • Teratogenic – children, pregnant owners • Immunosuppressive – latent or opportunistic infections in patients • Risks of exposure – handling medications – wear gloves, wash hands, keep separate from other medications – handling excreted drug in vomit, urine, stool Case Examples of Oral Chemotherapy in Veterinary Patients “Jasmine” 10 yo FS Miniature Pinscher Presenting problems: • 6 mo hx of abnormal gait, syncope, PU/PD, bloody stool/vomit • Initially treated with prednisone with improvement in symptoms Diagnostic results: • Bloodwork - anemia, high globulin, high calcium, monoclonal gammopathy (serum electrophoresis) • Echocardiogram – hypertrophic cardiomyopathy “Jasmine” 10 yo FS Miniature Pinscher Presumptive diagnosis: • Multiple myeloma • Cancer of plasma cells • Overproduction of gamma globulins leads to hyperviscosity syndrome • Definitive diagnosis requires identifying malignant plasma cells (usually in bone marrow) • Fatal disease, but good short term prognosis with chemotherapy (MST 540 days in dogs) “Jasmine” 10 yo FS Miniature Pinscher Treatment: • Prednisone – 0.5 mg/kg PO sid x 10 days, then eod x 60 days • Melphalan – 0.1 mg/kg (0.7 mg) sid x 10 days, then 0.05 mg/kg (0.35 mg) sid • Available in 2 mg tablets compounded by Diamondback Pharmacy into 0.35 mg capsules “Jasmine” 10 yo FS Miniature Pinscher Response to treatment: • Within first 2-4 weeks • Improved neurologic symptoms, GI bleeding, energy, appetite • Normalized globulin, calcium, improved anemia • Moderate neutropenia on induction dose of melphalan, normal on maintenance dose • No other adverse effects of treatment “Jasmine” 10 yo FS Miniature Pinscher Response to treatment: • After 7 mos on melphalan, recurrence of initial symptoms (ataxia, syncope) and bloodwork abnormalities • Switched to chlorambucil at 0.15 mg/kg (1 mg) sid – avail in 2 mg tablets, compounded by Petscripts into 1 mg capsules • Clinically normal 2 yrs after starting prednisone, 1.5 years after starting melphalan/chlorambucil “Kitty Carlyle” 8 yo FS DSH cat Presenting problems: • 2 week history of progressive vomiting, inappetance, lethargy Diagnostic results: • Abdominal ultrasound: – Severe focal small intestinal thickening causing obstruction – Enlarged mesenteric lymph nodes “Kitty Carlyle” 8 yo FS DSH cat Diagnosis: Small cell lymphoma • Majority of GI lymphoma in cats, less aggressive form of LSA in cats • With chemotherapy, survival can be >2 yrs Treatment: • Surgical resection of segment of intestine • Prednisone - 2 mg/kg (6 mg) sid, taper to 0.5 mg/kg eod long term – compounded into liquid suspension by Petscripts • Chlorambucil – 20 mg/m2 (4 mg) once every 14 days – available in 2 mg tablets, filled at local pharmacy “Kitty Carlyle” 8 yo FS DSH cat Response to treatment: • Resolution of symptoms, intestinal thickening, lymph node enlargement • No apparent adverse effects • 1 year after diagnosis, recurrence of symptoms, lymph node enlargement & intestinal thickening • Switched to cyclophosphamide, 50 mg given over 2 days (25 mg tablets) every 14 days • Stable symptoms & body weight 2 years after diagnosis Quiz Q1 • What is the most common type of cancer treated with oral chemotherapy in cats and dogs? – Lymphoma (including leukemia) – Glioblastoma – Adenoma – Osteocytic sarcoma Quiz Q2 • Metromic dosing of chemotherapy drugs in cats and dogs usually involves _______ doses of drugs administered ________ frequently than with traditional chemotherapy regimens. – lower, less – lower, more – higher, less – higher, more Quiz Q3 • Which category of cancer chemotherapy medication is most often utilized in cats/dogs? • TKIs – Monoclonal antibodies – Adrenocorticoids – Alkylating agents – Epigenetics Quiz Q4 • The general side effects common to almost all oral cancer chemotherapy drugs are (Check all that apply) – Myelosuppression – Pulmonary fibrosis – Gastrointestinal upset – Multi-drug resistance (MDR) – Proteinuria Thank You!!