Cancer Care in Pets (Veterinary Oncology) Orna Kristal, DVM Dip. American College of Vet Internal Medicine (oncology) Chavat Daat, Beit Berl

Veterinary Specialty Training Requirements: DVM degree and internship Began in the US Today in Europe as well 3 yrs of working under supervision of specialists in different fields Tumor biology studies Publication, presentations Specialty examination

Specialty in Veterinary Medicine Large Animals (horses, ruminants) Internal medicine, Surgery, reproduction Small Animals Internal Medicine, oncology, cardiology, neurology Surgery Imaging Emergency medicine Ophthalmology, Dermatology, anesthesia Exotic animals (birds, reptiles, ferrets, rodents) Pathology – clinical and histopathology In Israel The Vet school in Beit Dagan qualifies specialists in most areas in the European colleges programs.

Cancer in dogs and cats No accurate incidence rates (IR) Dorn et al. 1968 – new cancer cases a yr in 2 counties in CA Dogs – 382/100,000 Cats – 156/100,000 IR today probably much higher Estimated lifetime risk of cancer Dogs – 50% Cats – 30% IR probably much higher today due to longer life expectancy as a result of better nutrition and improved health care. Also, more advanced diagnostics are being used. Cancer is therefore the leading cause of death in older animals.

Comparative aspects Humans Dogs Cats Breast/prostate Breast* Lymphoid Lung Skin (non-melanoma) Colorectal Sarcoma Testicular (intact) Lymphoid, oral tumors Most female dogs are spayed at a young age at least in the US so breast cancer is actually uncommon. In cats similar association exists but only if spayed before one yr of age. Same for testicular cancer and males but not here! This order of frequency is based on Dorn’s studies and some has probably changed. Lymphoid in cats has probably declined with the control of FeLV. Probably increased in dogs due to environmental contamination.

Genetic factors Golden Retriever Boxer Bernese Mountain Dogs 1 in 5 – Hemangiosarcoma 1 in 8 - Lymphoma Boxer Lymphoma (T-cell) Bernese Mountain Dogs Histiocytic Sarcoma Scottish Terriers Transitional Cell Carcinoma Sharpei High grade Mast Cell Tumors Scottish terriers have about 18 times the risk of bladder cancer compared with MB.

Hormonal factors Ovariohysterectomy Castration Before 2.5 yrs of age in dogs and 1 yr in cats is protective of mammary tumors Castration Reduces risk of testicular cancer Esp. in cryptorchids Increases risk of prostate cancer (still uncommon) OVH has a stronger effect in dogs and is lost earlier in cats. Neutering at a young age has been found to increase risk of OSA in male Rottweilers only, and possibly in females with MCT and HSA.

Environmental factors - Dogs Exposure may be higher in indoor pets Exposure to passive smoke  risk for lung cancer – short and medium length nose (weak)  risk for nasal cancer – long-nosed breeds Insecticides in shampoos or dips  risk of TCC, esp. if obese But not spot-ons like Frontline or Advantage Herbicides and insecticides on lawns  risk of TCC in Scottish terriers Exposure to EF may be higher in pets that spend most or all their time indoors compared with humans who go out often. No dose response relationship in the ETS respiratory cancer risk study. In obese animals increased risk - thought is inert lypohilic ingredients accumulate in body fat and may be carcinogenic. Fipronil and imidacloprid spot-ons did not increase risk. TCC Scotish – herbicides – mainly phenoxy acids One study from Italy found that residence near industrial areas and exposure to paints and solvents increased risk OR were 8.5 and 5.5 respectively (Gavazza A, JVIM 2001). Median age of dogs exposed to chemicals was also younger (from 7.5 to 6.1 yrs) which strengthens the relationship. 3) Pastor – French study found Association with waste incinerators, polluted sites and radioactive waste

Environmental factors - Cats Oral Squamous Cell CA (SCC)  risk with: High intake of canned food (RR – 3.6) and canned tuna fish (RR – 4.7) Flea collar use (RR – 5.3)  risk with flea shampoo use Lymphoma  risk with exposure to passive smoking Oral SCC is a common malignancy in older cats. Subjectively seen more commonly in the US than here. Therapy is relatively ineffective. Bertone et al looked for carcinogenic substances that the cat may eat or lick from fur while grooming, that can lead to this cancer. Controls was a population of cats with CKD. Risk of SCC was higher in smoking households but NS. Significant association with high intake of canned food and canned tuna fish Increased risk with canned food and tuna may be due to nutritional difference between them and dry food, or it is possible that cats that eat primarily canned food have more tartar buildup and worse oral hygiene that increases the risk for SCC. In humans poor oral hygiene is associated with a 2-fold increase in risk for oral SCC. To counter that, teeth brushing and Hx of dental problems was N.S. She did not try to explain the canned tuna separately from canned food. Maybe the heavy metals? Increased risk with collars – close to head? Decreased risk with shampoos – wash off carcinogenic substances? As for ETS, the connection is not strong, and may or may not exist. Interestingly the same author has shown an increase in risk of LSA in cats exposed to household ETS, with evidence of a strong dose-response relationship. – longer duration and higher quantity increased risk with a linear trend.

Why treat pets with cancer? Cancer is perceived by many to be a serious and often fatal disease Treatment in people is commonly associated with side effects leading to poor QOL Therefore treating pets with similar treatment is perceived as cruel and selfish This perception represents total misunderstanding of the treatment of cancer in animals The main goal of treating animals with cancer is to extend a good quality of life for the patient (and family) for as long as possible.

What is QOL in animals? Life without pain & daily normal activity Happy when owners come home, plays Wants to eat and drink Has control of eliminations Quality is more important than quantity Life without QOL means prolonging unnecessary suffering of the animal

How do we maintain QOL? We try to prevent treatment’s side effects Before treatment is begun risk vs. benefit is considered Often animals treated for cancer live longer and better than animals treated for other chronic disease (i.e - diabetes, chronic renal or heart disease)

Maintaining QOL If the animal develops significant treatment toxicity We can lower drug dosages Use other drugs Consider stopping treatment Treatment can be with a curative intent or palliative Know when to quit Treatment with a curative intent is usually more aggressive. In other cases we and owners choose treatment that is more palliative just to try and slow down the disease and/or improve symptoms. When treatment is no longer effective or in cases that are too advanced it is our duty to tell the owners it is time to let go.

Treatment modalities Treatment options depend on Tumor type Location in body Tumor stage (TNM) Comorbidities

Treatment modalities Surgery Radiation therapy (not in Israel) Chemotherapy Small molecule inhibitors (TKI’s) Cancer Vaccines Melanoma Multimodality Tx Symptomatic Tx Surgery is still the main modality for local tumors. If the tumor can be completely excised and has a low metastatic potential, it is the most likely treatment modality to cause a cure.

Choosing the treatment Owners ultimately choose the treatment after hearing Different options Prognosis for each option Possible side effects Cost Should they choose not to treat, they are making an educated decision Very different from humans Today I consulted on a dog with advanced MCT. Tumor is huge and disseminated. Owner NI in chemo d/t finance limitations and poor Px. He mainly wanted to know if and when to euthanize and anything palliative he can still do like prednisone.

Common signs of cancer in small animals Abnormal swellings that persist or continue to grow Sores that do not heal Weight loss Loss of appetite Bleeding or discharge from an opening Abnormal swellings that persist or continue to grow Sores that do not heal Weight loss Loss of appetitie Bleeding or discharge from any body opening Offensive odor Difficulty eating or swallowing

סימנים שכיחים של סרטן בחיות קטנות Offensive odor Loss of energy, tire easily Persistent lameness Difficulty breathing, chewing, urinating, defecating Hesitation to exercise or loss of stamina Persistent lameness or stiffness Difficulty breathing, urinating, or defecating

Aural SCC

Baaci 7 yr old spayed female Golden Retriever

Baaci Presented with enlarged lymph nodes, fever, unwell and diagnosed with lymphoma on cytology

Baaci With no treatment median survival is 4-6 weeks and QOL is poor most of this time. With CHOP based chemotherapy median survival is extended to 12 months and about 25% are alive @ 2 yrs. Drug dosages is lower than in humans. Only 20% develop grade 3-4 toxicity. Baaci’s owner chose to treat with chemo.

Baaci Achieved complete remission Treatment continued for one yr One episode of vomiting & diarrhea requiring supportive care. Still alive and happy today > 4 yrs from diagnosis.

Chaos 4 yr old female Great Dane Diagnosed with osteosarcoma (OSA) Distal radius - LFL

Osteosarcoma Many similarities to human OSA Two main differences Affects large to giant breed dogs Metaphyses of long bones most affected Most stage negative at presentation 90% are high grade Common hematogenous lung metastases Two main differences 10 times more prevalent in dogs Mean age Dog – 7rs human – 14 yrs Heavy people Rare nodal mets. ALKP is prognostic in both

Osteosarcoma Dogs Are an outbred species Have innate immune system Their cancer progresses more rapidly Combined with similarities in tumor behavior they can serve as an excellent model for research of this disease Dr. Steve Withrow - pioneer in the field Clinical trials in dogs serve a dual purpose Cancer progresses more rapidly due to accelerated aging process Research in dogs showed that in both species ionizing RT and metalic implants can lead to OSA. Withrow has developed limb sparing technology in dogs, showed IA cisplatin is safe and that pre-op chemo increases percent necrosis in tumor which in turn increases number of limb spare resections. Much of his research was applied to human medicine. Clinical trials help us improve standard of care for our patients and may also provide valuable data for therapies destined for use in people.

Chaos Had forequarter amputation To control primary tumor and relieve pain Post-operatively entered into a clinical trial 5 treatments with doxorubicin Followed by the oral trial drug vs. placebo No side effects at all Enjoyed an excellent QOL for 18 months after treatment Median survival with amputation and chemo is 10 months Sponsored by Bayer company

Slim, 7 yr old male Whippet Presented with unilateral nose bleed from the left nostril (Sept 2008) CT and biopsy – left nasal adenocarcinoma Unilateral nose bleeds in middle age to older long nosed dog – primary DD is nasal tumor.

Slim Treated with Radiation 12 X 4 Gy, 3 days a week Tumor shrunk by 30%, was stable for 2 yrs then started growing very slowly Receives low dose prednisone permanently for nasal congestion

Canine Mast Cell Tumors Common skin cancer Can be benign to malignant May swell up and shrink due to surges of histamine release

Mast cell tumors Fairly easy to diagnose by cytology Biologic behavior highly correlated with histologic grade Treatment depends on tumor grade and stage

Targeted therapy for canine MCT 33% of MCT express mutation in c-kit Toceranib Phosphate (Palladia™) KIT PDGFRβ VEGFR2 Flt3 Masitinib Mesylate (Masivet®) KIT PDGFR FGFR3 FAK (focal adhesion kinase) 2 dedicated veterinary products that are TKIs Palladia through inhibition of VEGFR2 and PDGFR inhibits angiogenesis and through KIT has direct inhibition on MCT. Blocking both R is more effective than blocking either alone. Potential for efficacy in other tumor types

In summary The main goal in treating animals with cancer is good QOL for as long as possible Every case should be evaluated individually Owners should be given all options The decision is theirs to make after weighing risk vs. benefit and cost