Use of Palladia® for Metastatic Sarcoma: Two Inspiring Cases

Case #1 

Onyx, a 6-year-old spayed female Rottweiler, was evaluated by her primary care vet for a two-week history of left forelimb lameness. Upon evaluation, a firm swelling was noted along her distal left forelimb and radiographs identified an aggressive osteolytic lesion of the distal radius. She was referred to Hope Veterinary Specialists Medical Oncology service for further care. Upon consultation, three-view thoracic radiographs were free of measurable pulmonary metastatic disease and CBC/Chemistry was unremarkable. Therapeutic options were discussed and she subsequently underwent a left forequarter amputation; histopathology confirmed osteosarcoma of the distal radius with no evidence of lymph node metastasis. After healing, Onyx received a 6 cycle course of carboplatin (300 mg/m2 IV q3 weeks) and tolerated it well. Recheck thoracic radiographs at the time of the 4th carboplatin cycle remained free of metastatic disease. At a routine follow up visit 8 weeks post-completion of chemotherapy, thoracic radiographs identified a pulmonary nodule in the right cranial lung field, best seen on the left lateral view (Figure 1).

Figure 1. Pulmonary lesion (arrows) in a 6-year-old spayed female Rottweiler with left distal radius osteosarcoma that was excised via amputation 7 months prior.

This lesion was presumed to be osteosarcoma metastasis and the poor prognosis associated with this syndrome was discussed with the owner. Given her otherwise excellent health at the time and the desire to provide her with as much additional good quality time as possible, Onyx was started on rescue therapy with Palladia® (toceranib phosphate; 2.65 mg/kg PO on Mondays, Wednesdays, and Fridays). Thoracic radiographs 8 weeks later showed slight progression in size and density of the nodule, but no new nodules (Figure 2).

Figure 2. Follow up radiographs 8 weeks after Palladia® initiation for presumed osteosarcoma metastasis. The lesion (arrows) has progressed slightly in size (now 2.3 cm longest diameter, previously 1.9 cm) and radiodensity.

Given the finding of just borderline disease progression (21% increase in longest diameter of the lesion), Palladia® was continued and Rimadyl® (carprofen; 2.15 mg/kg PO q12) was added on non-Palladia® days (Tuesdays, Thursdays, Saturdays, and Sundays). Surprisingly, subsequent thoracic radiographs 8 weeks later (4 months after Palladia® initiation) showed complete resolution of the pulmonary nodule (Figure 3). Serial thoracic radiographs performed every 10-12 weeks have remained clear and Onyx is now 21 months from initial osteosarcoma diagnosis and 15 months post-discovery of metastasis, without disease recurrence and with a continued outstanding quality of life.

Figure 3. Follow up radiographs 16 weeks after Palladia initiation for presumed osteosarcoma metastasis. The previous lesion has completely disappeared.

 

Case #2

Baloo, an 11 month old castrated male Labrador retriever, developed a rapidly growing soft tissue mass in the musculature around the left stifle. The mass was surgically debulked by his primary care vet and histopathology confirmed an incompletely excised grade II/intermediate grade soft tissue sarcoma with mitotic index >20. He was referred to HopeVS oncology and upon initial consultation, three-view thoracic radiographs and CBC/Chemistry were normal. Abdominal ultrasound showed mild left iliac lymphadenopathy but fine needle aspirate cytology confirmed reactive lymphoid hyperplasia only. Baloo underwent left hind limb amputation and histopathology confirmed a grade II fibrosarcoma with mitotic index of 12 and 10% necrosis. Immunohistochemistry (IHC) for CD18 (cell surface marker of histiocytic sarcoma) was negative. Based upon biopsy and IHC results confirming an intermediate grade fibrosarcoma and the lack of measurable metastasis, no further therapy was recommended and monitoring with q3-4 month thoracic radiographs and abdominal ultrasound was planned for a period of 2 years. Baloo’s early serial restaging exams were all clear, but at 14-month mark post-diagnosis, a pulmonary lesion was noted in the right middle lung lobe, best seen on the left lateral view (Figure 4).

Figure 4. Pulmonary lesion (arrows) in a young Labrador retriever with a grade II fibrosarcoma that was excised via left hind limb amputation 14 months prior. 

Given the time frame and rapid growth, this lesion was presumed to be metastasis from the previously excised fibrosarcoma. Therapeutic approaches discussed included doxorubicin (30 mg/m2 IV q2-3 weeks) or Palladia® (2.6 mg/kg PO EOD) and the latter option was elected. Recheck thoracic radiographs after 8 weeks of Palladia® showed notable radiolucency within the center of the lesion, irregularity of the nodule’s margins, and 23% reduction in longest diameter (Figure 5).

Figure 5. Follow up radiographs 8 weeks after Palladia® initiation for presumed fibrosarcoma metastasis. The lesion now has a central area of radiolucency (arrow) consistent with cavitation. The outer margins of the tumor have also become irregular and it has reduced in size (now 3.6 cm longest diameter, previously 4.7 cm).

The changes to the lesion were thought due to Palladia®-induced tumor necrosis and thus were interpreted as a positive response to therapy, which was continued. Thoracic radiographs were reassessed another 8 weeks later and these showed continued regression of the lesion by almost 50% and even more pronounced cavitation (Figure 6). Baloo has been maintained on Palladia® and continues to enjoy a fantastic quality of life, now 19 months from initial sarcoma diagnosis and over 4 months from the discovery of pulmonary metastasis.

Figure 6. Follow up radiographs 16 weeks after Palladia® initiation for presumed fibrosarcoma metastasis. The radiolucency within the lesion (arrows) has progressed and it has further reduced in size (now 2.4 cm longest diameter, initially 4.7 cm).

Discussion

There is no question that pulmonary metastasis remains the most difficult and life-threatening problem associated with canine sarcomas. The risk of pulmonary metastasis from canine osteosarcoma is extremely high (estimated 90%), while the risk for soft tissue sarcomas is rather modest to moderate (7-33% for intermediate grade sarcomas, 22-44% for high-grade sarcomas). The benefit of adjuvant chemotherapy in preventing (or at least delaying) osteosarcoma metastasis is well documented across several veterinary studies. Specifically, the sum of available data shows a significant improvement in the 1-year and 2-year survival rates for dogs receiving carboplatin-based protocols following amputation, as compared to those of dogs undergoing amputation alone. The benefit of adjuvant chemotherapy for dogs with high-grade soft tissue sarcomas has not yet been confirmed statistically, although principles of cancer therapy suggest that there is likely utility behind adjuvant chemotherapy for this histology as well. Furthermore, effective therapies for gross metastatic disease of either subtype of sarcoma remain elusive. Historically, the prognosis for dogs with pulmonary metastatic disease from osteosarcoma is grave, with a reported median survival time of approximately 2 months. Recently, surgical metastatectomy has been shown to provide a survival advantage (median survival time 232 days after metastatectomy vs. 49 days without surgery) for these osteosarcoma patients, although criteria for recommending such intervention is stringent and many owners choose not to pursue an invasive surgery again when faced with a definitively terminal diagnosis. The survival impact that pulmonary metastasis from a soft tissue sarcoma my have on patients is unclear, but likely not as imminently life-threatening as with osteosarcoma.

As far as systemic therapy approaches for measurable and metastatic sarcomas, the response rates of canine sarcomas to conventional chemotherapy agents are generally low, although a few studies have documented remissions for dogs receiving cisplatin and doxorubicin. Results of preliminary investigations using immunotherapy for canine sarcomas have been promising, but the evolution of such therapy for dogs is still largely in its infancy. Clearly, more effective strategies are needed for managing aggressive and advancing canine sarcomas.

There has also been interest in the application of molecularly targeted therapies for metastatic sarcomas in dogs. In a 2011 study evaluating the use of Palladia®, a receptor tyrosine kinase inhibitor that was FDA approved for treatment of aggressive canine mast cell tumors in 2009,

in dogs with solid (non-mast cell) tumors, 23 dogs received the drug for pulmonary metastasis from osteosarcoma. Of those patients, 1 dog (4.3%) experienced a partial response (PR; at least 30% decrease in the longest diameter of target lesions) and 10 dogs (43.5%) experienced stable disease (SD; decrease in target lesions of less than 30% or increase of target lesions less than 20%). Thus, in sum, almost 50% of dogs derived some clinical benefit from Palladia, for a median duration of almost 6 months. Interestingly and conversely, there was minimal benefit noted in another more recent study evaluating dogs receiving Palladia® for metastatic osteosarcoma. Specifically, 20 dogs with pulmonary metastasis from appendicular osteosarcoma were treated with Palladia® and only 17.6% experienced stable disease for a median duration of less than 4 months.  Furthermore, the use of Palladia® in combination with metronomic cyclophosphamide and piroxicam in the microscopic disease setting following amputation and carboplatin chemotherapy provided no survival advantage when compared to dogs receiving the same adjuvant regimen without Palladia®. Comparable data regarding Palladia® use in the microscopic and macroscopic disease settings for dogs with metastatic soft tissue sarcoma is not available.

The outcomes of the two patients described above illustrate dramatic positive responses of sarcoma metastasis to Palladia®. These particular results are no doubt encouraging but do likely represent the exception – that minority of patients that is fortunate enough to experience measurable and durable remissions of their advanced sarcomas with systemic therapy. Nevertheless, their stories are inspiring and memorable. For now, “the jury is still out” on whether or not Palladia® is the most effective systemic therapy currently available for metastatic sarcomas, not only because the results of the aforementioned studies were so divergent and the number of our clinical successes remains modest, but also because results of ongoing clinical trials evaluating potentially promising immunotherapies for aggressive sarcomas are still forthcoming.

Submitted by Christine Mullin, VMD, Diplomate ACVIM (Oncology)

References

Boston S, Ehrhart N, Dernell W, et al. Evaluation of survival time in dogs with stage III osteosarcoma that undergo treatment: 90 cases (1985-2004). JAVMA 2006; 228:1905-1908. https://www.ncbi.nlm.nih.gov/pubmed/16784383

Dennis MM, McSporran KD, Bacon NJ, et al. Prognostic Factors for Cutaneous and Subcutaneous Soft Tissue Sarcomas in Dogs. Vet Pathol 2011;48: 73-84.

https://www.ncbi.nlm.nih.gov/pubmed/21139143

Laver T, London CA, Vail DM, et al. Prospective evaluation of toceranib phosphate in metastatic canine osteosarcoma. Vet Comp Oncol 2018;16(1):E23-E29.

https://onlinelibrary.wiley.com/doi/abs/10.1111/vco.12328

London C, Mathie T, Stingle N, et al.  Preliminary evidence for biologic activity of toceranib phosphate (Palladia®) in solid tumours. Vet Comp Oncol 2011;10:194-205.

mailto:https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1476-5829.2011.00275.x

London CA, Gardner HL, Mathie T, Stingle N, Portela R, Pennell ML, et al. Impact of Toceranib/Piroxicam/Cyclophosphamide Maintenance Therapy on Outcome of Dogs with Appendicular Osteosarcoma following Amputation and Carboplatin Chemotherapy: A Multi-Institutional Study. PLoS ONE 2015;10(4):e0124889.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414350/

Selting KA, Powers BE, Thompson LJ, et al. Outcome of dogs with high-grade
soft tissue sarcomas treated with and without adjuvant doxorubicin chemotherapy:
39 cases (1996–2004). J Am Vet Med Assoc 2005;227:1442–1448. https://www.ncbi.nlm.nih.gov/pubmed/16279389

Turner J, Seguin B, Worley DR, et al. Prognosis for dogs with stage III osteosarcoma following treatment with amputation and chemotherapy with and without metastasectomy. J Am Vet Med Assoc. 2017;251(11):1293-1305.

https://avmajournals.avma.org/doi/abs/10.2460/javma.251.11.1293?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed

 

 

 

 

 

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