OSA: Curative Intent Conventional Treatment for Canine Osteosarcoma

This exclusive article is part of the Veterinary Professional Blog Series

This article is the property of Dr. Erin Bannink, November 2020.

Do not distribute without written permission.

*Photo Credit: This is Sheeba Lu. She was one of my patients and her parents had the most amazing photo blog of her story. This is one of her running, as was her usual, through the park with her buddy. Sheeba survived 24 happy and adventure-filled months after her diagnosis of Osteosarcoma. She received an integrative protocol in cooperation with her local oncologist and local TCM veterinarian.

IN THIS ARTICLE

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Amputation alone:

Amputation and Chemotherapy:

Stereotactic radiation and chemotherapy:

Amputation and herbal therapies without chemotherapy (8 patients):

Amputation, chemotherapy and herbal therapies (7 patients)

Western Biomedical Perspective

Canine appendicular osteosarcoma (OSA) is a uniformly aggressively disease with a high metastatic rate and grave prognosis despite treatment with surgery and chemotherapy. At the time of diagnosis 90% of patients with osteosarcoma will have microscopic metastasis. Negative prognostic factors include large tumor size, high tumor histological grade, a persistently elevated ALP post-surgery, visible metastatic disease, young age (<5 years), and location (tumors of the rib, and scapula have a poorer prognosis). Additionally, evidence of tumor vascular embolization, high level of tumor necrosis and parathyroid hormone receptor-1 (PTH-1) expression in tumor tissue are poor prognostic factors.

Fibroblastic subtype is associated with a more favorable prognosis of 18 months compared to osteoblastic and chondroblastic subtypes. Location in the digital, metacarpal and metatarsal bones is associated with a significantly increased median survival time of 23 months compared to other appendicular sites.

CURATIVE INTENT CONVENTIONAL TREATMENT OPTIONS

Amputation followed by standard chemotherapy +/- metronomic chemotherapy

A recent study evaluated 470 dogs with osteosarcoma that were treated with amputation followed by a number of different chemotherapy protocols. Post surgically, this study compared the median disease-free interval and overall survival times using the following chemotherapy protocols: single agent carboplatin, alternating doxorubicin and carboplatin, and single agent doxorubicin. For all dogs, the overall survival time was 9.5 months. In this study, the proportion of dogs surviving one year, two year and three years after amputation and chemotherapy were 30-44%, 13-20%, and 3-10% respectively. The choice of chemotherapy protocol did not result in significant differences in survival times overall, although single agent carboplatin resulted in less adverse effects compared to alternating carboplatin and doxorubicin. Since that study was published, an accelerated carboplatin/doxorubicin protocol after amputation was evaluated for improved efficacy. Survival results were similar to other chemotherapy protocols with MST of 317 days (10.5 months) and 1- and 2-year survival rates of 43% and 13.9% respectively. For these reasons, single agent carboplatin administered every 3 weeks is the current chemotherapy protocol recommended for dogs with osteosarcoma at my practice.

Limb spare surgery

Dogs with osteosarcoma affecting the distal radius, tumor affecting less than 50% of the bone, and no evidence of disease elsewhere in the body, may be candidates for limb spare surgery. In limb spare surgery, the portion of bone affected by the tumor is removed and replaced with a piece of bone from the ulna. A long bone plate is then placed across the wrist joint and the length of the radius. This fuses the wrist joint. This procedure allows local removal of the tumor without limb amputation and can be a good option for dogs who are not good candidates for amputation, or where amputation is not desired. Complications arising from this procedure include, but are not limited to, local regrowth of the cancer in the bone or muscles around the tumor site, infection and complications with the implant. Infection can usually be controlled with antibiotics. In rare cases of severe complications, amputation of the limb may ultimately be required. If limb spare procedure is being considered, a thorough consultation with the surgeon performing the surgery is recommended to discuss the procedure, complications, and post-operative recovery.

There has been no significant difference in survival time between dogs treated with amputation and chemotherapy versus those treated with limb-spare and chemotherapy, although some dogs who developed severe infection at the surgery site have experienced longer survival times, presumably due to immune stimulation at the tumor site. Overall, 80% of dogs have good to excellent limb function after limb-spare surgery and fusion of the wrist joint. Average survival times are around one year with combination therapy, with some patients experiencing longer term survival and some developing disease sooner than average.

Ulnectomy:

Dogs with osteosarcoma affecting the mid-distal ulna, tumor affecting less than 50% of the bone, and no evidence of disease elsewhere in the body may be candidates for partial ulnectomy. In this limb spare surgery the portion of bone affected by the tumor is removed. Limb function afterwards is excellent. Risk associated with this procedure is a higher possibility of local tumor regrowth in the muscle surrounding the tumor site if there is extension of tumor into the tissues surrounding the bone. Tumors that are located at the distal end of the ulna are less ideal candidates for this procedure because the styloid process which is at the end of the ulna is the attachment point of the lateral collateral ligament which provides stability to the carpal joint. Removal of the styloid process results in elimination of this ligament and risk of carpal instability after this procedure is significant. Carpal braces are available and may be able to provide the stability needed in the carpus for good limb function, but the risk for less than optimal limb function when removal of the distal ulna is required is high and additional costs for post-operative management or carpal stabilization should be expected. If good limb function is not achieved, then amputation may ultimately be recommended to improve quality of life.

Stereotactic Radiation Followed by Chemotherapy

Stereotactic radiation is a very precise delivery of high dose radiation to the bone tumor. Depending on location, 1-3 consecutive doses of stereotactic radiation are given and general anesthesia is required for each treatment. Acute side effects associated with stereotactic radiation include localized hair loss and mild skin irritation. The most concerning risk with stereotactic radiation is a 20-40% incidence of pathologic fracture in the affected bone within 6 months following treatment. If a pathological fracture develops, amputation is recommended. The first dose of carboplatin is given at the first radiation treatment to increase the effectiveness of radiation. Three to four additional carboplatin treatments are recommended after radiation at three-week intervals. The goal of stereotactic radiation is marked improvement of lameness and return to function without amputation, although some dogs may require continued pain management. Zoledronate may be given 24 hours after radiation in order to improve the analgesic effects of both treatments.

Studies have shown that dogs treated with stereotactic radiation followed by chemotherapy have similar survival times compared to dogs with treated with amputation and chemotherapy. In a recent study, stereotactic radiation and chemotherapy resulted in a median survival time of 11.6 months, compared to 4.9 months in dogs receiving conventionally planned and delivered hypofractionated palliative radiation.

Which patients may benefit most from chemotherapy?

Interestingly, two recent studies of a large patient population (794 dogs) evaluated a model to predict 5-month and 1-year mortality risk for canine patients with OSA. These studies concluded that dogs with a high 5-month mortality risk had questionable benefit from the addition of chemotherapy and those with a low 5-month mortality risk (less than 0.43) benefited from chemotherapy treatment. The papers provide an excel spreadsheet to calculate this risk, which is based on a number of variables including breed, tumor location, ALP, gender, age and weight. This information could be very helpful for clients who are debating the benefits versus risks/costs impact of chemotherapy after amputation. This study suggests that dogs with aggressive disease and a high risk of early death may not benefit as much from chemotherapy. Palliative care may, therefore, be a more attractive option for some clients with dogs in this high risk category and be one way to further assist clients in decision making regarding aggressiveness of therapy.

Antiangiogenic/Metronomic chemotherapy

Metronomic chemotherapy involves chronic administration of low doses of oral chemotherapy agents or other drugs which target endothelial cells involved in the process of angiogenesis. The goal of this type of therapy is to inhibit blood vessel formation to the growing tumor mass in order to stunt continued growth. Benefits of this type of therapy include relatively low incidence of toxicity, circumvention of inherent or acquired chemotherapy resistance of the genetically unstable tumor cells, and possibility for a long term maintenance therapy for ongoing disease control in cancers where cure is not achieved with high dose chemotherapy protocols. Metronomic therapy appears to also inhibit regulatory T cells, which are recruited by tumor cells to evade immune surveillance.

Because it targets the angiogenic process required for growth and metastasis of cancer in general, metronomic therapy is not a tumor specific therapy. The most commonly used metronomic therapies include cyclophosphamide with or without a non-steroidal anti-inflammatory drug. This protocol is associated with a risk of sterile hemorrhagic cystitis, especially with high cumulative doses (two-fold increase with each 750mg/m2 dose increase). For this reason, metronomic chlorambucil is coming into favor as an alternative drug option. The most common long-term side effect with metronomic chlorambucil is thrombocytopenia.

Metronomic treatment protocols are usually started after standard chemotherapy has finished, although can be given with maximum-tolerated dose chemotherapy. These treatment are well-tolerated but published studies have not yet been able to prove prolonged survival with the additional of metronomic chemotherapy. A study published in April 2015 evaluating disease free interval and 1-year survival rates in dogs treated with Piroxicam and Cytoxan metronomic chemotherapy with or without Toceranib (Palladia) therapy after carboplatin chemotherapy did not show improved survival rates or disease free intervals over treatment with carboplatin alone.

Auranofin: An Investigational Repurposed Drug

A phase I/II pilot study evaluating Auranofin in combination with amputation and carboplatin chemotherapy was recently published in the Veterinary Comparative Oncology Journal. The study recruited 40 dogs and used a historical control group who received amputation followed by carboplatin (n = 26). The results showed a statistically significant improvement in overall survival time in the male cohort of the study group and, therefore, supported potential benefit of Auranofin in combination with amputation and chemotherapy in male dogs and justified a larger multicenter phase II trial.

Interestingly, improvement in survival was seen only in male dogs, not female dogs. The treatment did not negatively impact survival in female dogs. In the male cohort, survival in the Auranofin-treated group increased from 240 days in the control group to 474 days in the experimental treatment group. The treatment combination was well-tolerated with no dogs experiencing side effects outside that typically expected from Carboplatin and no dogs experiencing greater than grade I adverse effects.

The dose of Auranofin used in this study was 6mg every 3 days for dogs <15kg and 9mg every 3 days for dogs >15kg.

Auranofin is an orally available gold compound originally developed for treatment of Rheumatoid arthritis and immunomodulatory agent. The drug inhibits thioredoxin reductase activity. In cancer cells, this results in increased oxidative stress and induces apoptosis. A number of previous studies have proposed this drug as a potential candidate for repurposing as a cancer therapy. Auranofin has undergone laboratory investigation for potential use in treatment of canine lymphoid malignancies as well, although has not been evaluated in a clinical setting for that disease yet.

Chronic diarrhea has been reported as a side effect to Auranofin and was shown to increase gastric emptying time in lab beagles but did not affect large bowel transit times. Primates in this same study showed diarrhea, so risk of this side effect may not be the same for canine patients as it is in primates. Metabolism pathways are not completely understood.

A 1982 pharmakokinetic study on Auranofin in animals showed Gold terminal half life was 19.5 days (measured for 42 days) compared to 1.2-1.8 days in rats. Excretion of gold (rat and dog) was via feces (84 and 81%) urine (10 and 16%) and bile (3% of dose). Rat tissue levels of gold were highest in the kidney. As such, monitoring of renal parameters would be prudent, although no renal toxicity was noted in the above referenced osteosarcoma study in dogs.

RECENT AND ONGOING CLINICAL TRIALS

Immunotherapy: Autologous activated T-cell therapy

(This is not currently available in Michigan due to lack of accessible apheresis center in the midwest.)

A preliminary study was performed on 15 dogs with osteosarcoma treated with autologous T-cells. Ten dogs completed that study and experienced a median disease free interval of 7.1 months.

Elias Animal Health recently published results of a clinical trial evaluating 14 dogs with osteosarcoma treated with amputation and an intradermal autologous cancer cell vaccine followed by apheresis to harvest the patients own T cells. These were then infused back into the patients. The day after intravenous T-cell infusion, patients received recombinant human IL‐2 every 48 hours for five treatments by injection. The study resulted in a median disease-free interval of 7.7 months. Median survival time was 13.8 months. Five dogs survived more than 24 months. Side effects were minimal and self-limiting.

Elias Animal Health is currently enrolling patients for a similar study at seven centers across the US: Illinois, California, New Mexico, Pennsylvania, Texas, Virginia and Washington D.C. Information can be found at Elias Animal Health. Their study involves harvesting tumor cells from the patient's own tumor and creating a vaccine. The vaccine is administered and 2 weeks later the patient undergoes apheresis to harvest their own cancer-specific T cells which have, hopefully, been generated from the vaccine. These cells are then specially processed and re-infused into the patient.

Rapamycin: Targeting the mTOR pathway

Tumor growth, progression and development of chemoresistance has been associated with signaling through the mTOR pathway in a number of tumor types.

A dose escalation study of rapamycin was performed in 22 dogs with appendicular osteosarcoma and a safe and effective dose was identified to be 0.08mg/kg (2.5mg/30kg dog) given via intramuscular injection. Modulation of mTOR pathway targets was seen in doses as low as 0.01mg/kg. Side effects were self-limiting and included grade I or II vomiting, diarrhea, anorexia and thrombocytopenia. Results of a follow-up multi-institutional clinical trial evaluating orally administered rapamycin in an adjuvant setting after amputation and chemotherapy have not yet been published.

CONCLUSION

Osteosarcoma is an aggressive disease which shares many similarities between dogs and humans. This makes it an attractive focus for translational research. New developments in treatment of osteosarcoma for our veterinary patients may help improve treatments for childhood and adult osteosarcoma in people. Immunotherapy is a popular research focus, with extensive research into the immunology of osteosarcoma. The immunologic mechanisms involved in osteosarcoma are becoming better understood and are a promising new horizon. It is interesting to consider how natural interventions and epigenetic factors influenced by diet and herbal supplements may play into the mounting of a successful immune response. Additionally, a number of herbal compounds have been shown to inhibit the mTOR pathway. We will visit these topics in later blog articles.

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Conventional Oncology Treatments

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Auranofin

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Recent Clinical Trials

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Mason NJ, Gnanandarajah JS, Engiles JB, et al. Immunotherapy with a HER2-targeting listeria induces HER2-specific immunity and demonstrates potential therapeutic effects in a phase I trial in canine osteosarcoma. Clin Cancer Res 2016;22:4380–4390.

Paoloni MC, Mazcko C, Fox E, et al. Rapamycin pharmacokinetic and pharmacodynamic relationships in osteosarcoma: A comparative oncology study in dogs. PLoS One 2010;5:e11013.

epigenetics and herbal compounds

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mTOR inhibition and herbal compounds

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