KetoPet Sanctuary: ketosis, cancer and canines — Part 2

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KetoPet Sanctuary: ketosis, cancer and canines — Part 2

Non-profit organization KetoPet Sanctuary has tested the feasibility of using a ketogenic diet as an adjunctive therapy in dogs with cancer. In the second part of this article, we’ll look at the overall results of the program, along with some case studies.  

Cancers exhibit an altered energy metabolism characterized by glycolytic dependency and glucose fermentation in the presence of oxygen (the Warburg effect). Studies by Poff, et al, demonstrated that this metabolic phenotype can be targeted therapeutically with co-administration of a ketogenic diet (KD) and hyperbaric oxygen therapy (HBOT). To further explore this potential therapeutic regimen, KetoPet Sanctuary (KPS) open-enrolled 40 dogs with advanced cancer, which allowed them to examine survivorship beyond initial prognosis when adjunctive therapies such as a KD and HBOT were used with standard of care. KPS was structured as an open-registry, un-blinded, case history pilot study. The trial consisted of 120 days of therapy, followed by 180 days of follow-up, for a total of 300 days.

Methods

Facility:

Opening its doors in September of 2014, KPS was located on a 53-acre plot of land in Georgetown, Texas, 25 miles north of Austin. KPS included an outside miniature water park, playground, track and specialized dog treadmills. Additionally, KPS was equipped with large indoor living and play areas, onsite veterinary care, around the clock care/monitoring, and exams rooms.

Standard of care:

All dogs received standard veterinary care to safeguard their overall health and well-being, as well as oncological standard of care defined as surgical resection, radiation, chemotherapy, and the combination thereof.

Various adjuvant supplements such as Metformin, Yunnan Baiyao, Pepcid and Benadryl were utilized on a veterinarian-monitored case-by-case basis to help dogs achieve ketosis and support standard of care.

Metabolic conditioning (MetCon):

Metabolic conditioning (MetCon) can help prevent cancer-related muscle loss and can boost the immune system while fighting cancer. Dogs at KPS were exercised one or two times per day for 20 to 30 minutes. All dogs received individual MetCon regimens based on their physical abilities or limitations.

Ketogenic diet (KD) therapy:

A ketogenic diet is any nutritional program that can be validated to induce nutritional ketosis, via twice-daily measurement of blood ketones and glucose, with glucose levels consistently around 75 mg/dL and blood ketones consistently around 0.3 mM.

KPS diets were formulated based on weight, body composition (to maintain a BCS of 4 out of 9), MetCon, most recent PET/CT results or disease progression, blood glucose/ketone results, and other diagnostics. Caloric intake and macronutrient ratios were adjusted as often as necessary to attain metabolic goals.

All dogs were fed a 0.5:1-4:1 ketogenic ratio. Dogs were fed variances of the following ingredients depending on diagnostic outcomes and personal needs:

Protein: 70/30 raw beef, ground chicken breast or ground Turkey

Fat: Medium Chain Triglyceride (MCT) powder, coconut oil powder, avocado oil, avocado mayo, unsweetened coconut cream, heavy cream, red palm oil, ghee, grass-fed butter

Low carb fibrous veggies: cabbage, green beans, broccoli, brussel Sprouts

Additions: prebiotics, probiotics, essential fatty acids, vitamins and minerals

 

Pet/CT Scans:

Using a GE Discovery,16 slice PET/CT, dogs were scanned upon arrival at KPS (Day 0), then again at 60 and 120 days into the program. Additionally, some dogs received a fourth post-treatment follow-up scan at day 300.

Hyperbaric oxygen therapy (HBOT):

Dogs receiving HBOT were administered 100% Oxygen at 2.0-2.2 ATM, in a Sechrist 2500 Chamber, for 90 minutes per session (hatch to hatch), with 60 mins spent at depth. KPS dogs received their HBOT sessions alternating three days of treatment — one day off, two days of treatment, one day off — for 120 days.

KPS open-registry results

KPS enrolled 40 dogs ranging from four to 14 years old, spanning 18 different breeds from small to large, and including 14 types of cancer, which encompassed 50 tumors. All dogs demonstrated reduced blood glucose (62.7 ±4.4 mg/dL) and elevated blood ketones (0.7±0.2 mM) while on the KD.

In collaboration with Dr. Nations, KPS demonstrated that the observed blood glucose levels of 62.7 ±4.4 mg/dL were significantly lower when compared to dogs fed kibble alone, wet food alone, or a combination of kibble and wet food. At the end of the 120-day trial, 22 of the 40 dogs completed the program, with eight dogs showing no evidence of disease; four showing decreased evidence of disease; five showing stable disease; and five showing increased evidence of disease.

Additionally, six dogs passed away from cancer; two passed away from reasons other than cancer; and ten were unable to complete the program. Over four years later, eight dogs still have no evidence of disease; three have active cancer; and 11 have passed away (five from cancer and six from other causes). Of the 22 dogs that completed the program, 11 have surpassed the original standard of care prognoses; two did not reach their prognoses; three have not yet reached their prognoses; and six were unable to receive prognoses due to lack of evidence-base on tumor type. These preliminary observations support the potential use of standard of care in combination with KD and HBOT as adjuvant therapies for dogs with advanced cancer.

KPS case studies

Arnold – Mixed Breed/Pitbull

Age: 12

Sex: male

Diagnosed with: cutaneous G2 mast cell (MCT), cutaneous hemangiosarcoma, cutaneous melanoma, papillary squamous cell carcinoma

Standard of care: Surgery

Adjuvant therapies: KD, HBOT

Additional medical issues: degenerative joint disease, idiopathic epilepsy

On 01/25/16, Arnold had surgery to remove 14 external masses, four of which came back malignant for four different types of cancer: cutaneous G2 mast cell, cutaneous hemangiosarcoma, cutaneous melanoma, and papillary squamous cell carcinoma. On 02/18/16, he received his first PET/CT scan, which showed two areas of uptake. His subsequent scans demonstrated decreasing areas of uptake and Arnold was PET/CT negative on his third scan on 06/23/16. On 09/28/16 (Day 243), three new MCTs were identified by fine needle aspirate (FNA).

Arnold suffered idiopathic seizures commencing before 01/25/16. In April 2016, he was put on Keppra, 500mg TID, to control seizures. Keppra was reduced to 500 mg BID in December 2016; 500 mg SID in January 2017; and 250 mg SID in February 2017. By March 2017, he was completely weaned off his medication with no seizure recurrence. Arnold was given a prognosis of 770 days; yet, as of 01/01/2019 (298 day beyond prognosis), he is thriving cancer- and seizure-free with his adopted family in Texas.

Cali – Vizsla

Age: ten

Sex: female

Diagnosed with: epithelioid hemangiosarcoma

Standard of care: surgery

Adjuvant therapies: KD, HBOT, IV Vitamin C

Additional medical issues: none

Cali was KPS’s first program graduate. Her cancer was discovered by her previous owner when she was pregnant. On 09/30/14, what was expected to be a large litter of puppies was revealed by ultrasound to be only one puppy and a 6 cm abdominal tumor. The vet conducted an FNA which revealed a possible epithelial neoplasm, possible carcinoma. On 10/27/14, Cali received surgery to remove the tumor, which was later diagnosed as epithelioid hemangiosarcoma. The histopathology report noted that the tumor was intimately adhered to the distal duodenum, left ureter and aorta. On 12/17/14, Cali entered the KPS program where her first PET/CT scan showed two areas of uptake suggestive of neoplasia.

Her subsequent PET/CT scans showed decreased uptake and Cali was PET/CT negative at 120 days. As of 01/01/2019, Cali has reached 1,527 days since her histopathological diagnosis, 1,476 days since the start of the program, and has surpassed her prognosis by over 1,400 days. She is thriving cancer-free with her adopted family in Texas.

Junior – Pitbull

Age: 4

Sex: male

Diagnosed with: splenic hemangiosarcoma

Standard of care: surgery

Adjuvant therapies: KD, HBOT, IV Vitamin C

Additional medical issues: none

Junior was a four-year-old pit bull who was diagnosed with splenic hemangiosarcoma on 3/21/2015 via biopsy. He entered the KPS program and received his first PET/CT scan on 04/29/15, which revealed one area of uptake. However, the scan did not show any abnormalities of the spleen.

On 7/9/15, PET/CT showed no abnormal areas of uptake. This scan was completely devoid of any abnormalities on the spleen or elsewhere. On 08/08/15, an ultrasound revealed a large cavitary splenic mass, which lead to an immediate splenectomy. About a month after his splenectomy, Junior became lethargic with white gums. An ultrasound revealed blood in his abdomen. He received a blood transfusion and his abdomen was drained to make him comfortable. An additional ultrasound revealed multiple bleeding masses in his abdomen.

On 09/07/15, Junior passed away as a result of an internal hemangiosarcoma hemorrhage. Necropsy confirmed evidence of tumors throughout much of the abdominal cavity. Even though Junior passed away due to cancer, he successfully surpassed his initial prognosis of 120 days. This case evidences the necessity of multiple diagnostic technologies in cancer detection, as certain technologies identify abnormalities in some areas of the body more effectively than others.

Conan — American Bulldog

Age: 6

Sex: Male

Diagnosed with: Stage IV Lymphoma (B-Cell)

Standard of Care: Chemotherapy Drugs: CHOP Protocol: IV Vincristine, oral Prednisone, oral Cytoxan, oral Furosemide, IV Doxorubicin

Adjuvant Therapies: KD, HBOT

Additional Medical Issues: None

On 06/09/2015, Conan, a 6-year-old American bulldog, was diagnosed with Stage IV B-Cell Lymphoma. On 06/25/15, Conan entered into the KPS program and received his first PET/CT Scan, which revealed four areas of uptake. On 07/01/2015, Conan began the CHOP chemotherapy protocol consisting of IV Vincristine, oral Prednisone, oral Cytoxan, oral Furosemide, and IV Doxorubicin. The chemotherapy regimen was initially slated to run 19 weeks; however, due to three incidences of neutropenia, the protocol was extended out an additional three weeks.

Conan’s subsequent PET/CT scans showed decreasing uptake and Conan was PET/CT negative on Day 120. Conan was discharged from KPS on 12/19/2015, at which time his lymphoma was in remission. Upon discharge, Conan resumed a standard, non-ketogenic, commercial diet. Approximately one month after his discharge, his owner noticed the formation of masses on his neck. Approximately three months after this he passed away.

Nera — Mixed Breed/Lab

Age: 15 years

Sex: Female

Diagnosed with: Lymphoblastic Lymphoma (LSA)

Standard of Care: Surgery

Adjuvant Therapies: KD, HBOT

Additional Medical Issues: None

Nera was diagnosed with lymphoma on 6/25/15 based on the results of a light microscopy biopsy. On 07/08/2015, Nera was enrolled in the KPS program and received her first PET/CT scan, which revealed two areas of uptake. Her subsequent PET/CT scans revealed disease progression.

On 10/25/15, Nera had surgery to remove a right ventral lateral mass adjacent to her thyroid. Histopathology confirmed the lymphoma diagnosis. On 2/22/16, due to the progression of her Lymphoma, Oncology recommended that Nera begin chemotherapy (19 weeks and CHOP protocol: Vincristine, Cytoxan, Prednisone, and Adriamycin); however, the protocol was never initiated. Though the PET/CT scan indicated progression of disease, Avacta tests (a type of blood test measuring the severity of lymphoma) indicated remission (03/29/16 results of 0.35 and 04/13/16 showing 0.19, the lowest possible score on the test). On 04/14/16, Nera returned home and is still doing well (last cancer status: cancer free).

Leo — Staffordshire Terrier

Age: 9

Sex: Male

Diagnosed with: Mast Cell Tumor (MCT)

Standard of Care: Surgery, Chemotherapy drugs: IV vinblastine

Adjuvant Therapies: KD, HBOT

Additional Medical Issues: Degenerative Joint Disease

On 10/13/15, Leo, a 9-year-old Staffordshire Terrier, was diagnosed with a 4.0 cm soft subcutaneous Mast Cell Tumor on the base of his tail based on an FNA. On 10/15/2015, Leo was enrolled in the KPS program and received his first PET/CT scan, which showed one area of uptake.

Leo began chemotherapy on 10/28/15 but only received two total treatments due to a massive increase in the size of the tumor. Surgery was executed on 11/6/15 to remove the tumor and tail, and a second mass on his cheek. Histopathology confirmed 2/Low Grade MCT on both his tail and cheek. On 01/07/16 and again on 03/03/16 PET/CT scans showed no areas of uptake anywhere in the body.

On 09/01/16, eight new masses were removed, four of which were determined to be low-grade recurrences of MCT. In January 2017, Leo presented with lameness, which was initially thought to be associated with partial torn ACLs, overcompensations, and degenerative joint disease. Worsening lameness resulted in a bone biopsy on 02/16/2017, which revealed a possible spindle cell carcinoma in his right distal radius.

During March 2017, CT scans were repeated as well as an additional FNA, which revealed osteosarcoma. Leo’s lameness continued to worsen, and Leo was humanely euthanized on 05/07/17. Necropsy revealed a high-grade MCT as well as osteosarcoma. No evidence of metastasis was recognized in this case, but when it occurs, it commonly metastasizes to the lung. Osteosarcoma was not evident in the examined sections of bone from the other sites. While not impossible to have osteosarcoma at multiple sites it is not common. Leo, however, had significant degenerative joint disease (cartilage erosions and peripheral proliferation) present in multiple joints and it is more likely that his multi-leg lameness was a combination of osteosarcoma, MCT, and degenerative joint disease. Osteosarcoma’s prognosis with amputation would be 3–4 months; however, it took longer to determine that Leo indeed have osteosarcoma even without amputation as his history of DJD, torn ACL disqualified him as a candidate.

Hoho — Shih Tzu

Age: 9

Sex: Male

Diagnosed with: Mast Cell Tumor

Standard of Care: Surgery

Adjuvant Therapies: KD, HBOT, IV Vitamin C

Additional Medical Issues: None

On 11/27/14, Hoho’s right fourth toe was amputated with a 4cm mass, which histopathology revealed to be high-grade MCT. On 12/17/14, Hoho was enrolled at KPS, where his PET/CT scan revealed two areas of uptake. Hoho’s subsequent PET/CT scans showed progression of disease. Hoho underwent surgery on 05/20/16 to remove the MCT tumor on his right thigh (Area #1), which had obstructed blood flow to the area, resulting in infection. Surgeons determined that full amputation of the right hind leg was necessary due to large volumes of puss found at the incision point. Upon further exploration of infection in the upper leg and lower abdomen surgeons decided the best course of action was euthanasia.

Summary

Case studies (see below) selected from KetoPet Sanctuary represent the most dramatic examples of what can be learned from integrating novel adjuvant therapies with standard of care when addressing various tumor models in canine cancer. The primary takeaway lesson from this integrative approach is that while powerful for extending survivorship and quality of life, inducing sustained nutritional ketosis via a ketogenic diet and the consistent application of HBOT does not constitute a cure-all. Additional observations are needed to determine and optimize how these adjuvant therapies help various tumor types. Addressing cancer successfully requires early detection, a multi-modality approach to intervention, and the meticulous care of a veterinary oncologist in partnership with passionate pet parents.

Notably, some standard of care diagnostics (PET/CT) and adjuvant therapies (HBOT) that KPS utilized are not commonly feasible in a veterinary clinical setting, nor particularly reproducible in the home. Despite these limitations, the central pillars of a metabolic approach to addressing cancer, including caloric and macronutrient control and metabolic conditioning (rigorous exercise), are highly accessible, should pet parents and medical practitioners be excited about committing to them.

The KetoPet team of veterinary oncologists and research scientists gained unprecedented insights from addressing cancer as a disease of metabolism. Incorporating this approach with standard of care offers a new potential for dogs to live long vibrant lives.

Acknowledgements

The authors of this paper want to acknowledge the veterinarians, veterinarian oncologists, veterinarian technicians and workers who spent tireless hours making sure the dogs had the best quality of life at KPS. In memory of the canines that have passed, thank you for letting us be a part of your story. This open registry was supported by the Epigenix Foundation.

Reference

Drake, A. “Should my dog with cancer still exercise?” Dog Cancer Blog. 2018. Available at dogcancerblog.com/articles/full-spectrum-cancer-care/brain-chemistry/dog-with-cancer-exercise/.