Download Cancer in Dogs and Cats: Oral Therapies

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!!