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Published on: May 3, 2021
Adjuvant Sirolimus Does Not Improve Outcome in Pet Dogs Receiving Standard-of-Care Therapy for Appendicular
Amy K LeBlanc1, Christina N Mazcko2, Aswini Cherukuri2
1Comparative Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. amy.leblanc@nih.gov t-fan@illinois.edu.
Purpose:
The mTOR pathway has been identified as a key nutrient signaling hub that participates in metastatic progression of high-grade osteosarcoma. Inhibition of mTOR signaling is biologically achievable with sirolimus, and might slow the outgrowth of distant metastases. In this study, pet dogs with appendicular osteosarcoma were leveraged as high-value biologic models for pediatric osteosarcoma, to assess mTOR inhibition as a therapeutic strategy for attenuating metastatic disease progression.
Patients And Methods:
A total of 324 pet dogs diagnosed with treatment-naïve appendicular osteosarcoma were randomized into a two-arm, multicenter, parallel superiority trial whereby dogs received amputation of the affected limb, followed by adjuvant carboplatin chemotherapy ± oral sirolimus therapy. The primary outcome measure was disease-free interval (DFI), as assessed by serial physical and radiologic detection of emergent macroscopic metastases; secondary outcomes included overall 1- and 2-year survival rates, and sirolimus pharmacokinetic variables and their correlative relationship to adverse events and clinical outcomes.
Results:
There was no significant difference in the median DFI or overall survival between the two arms of this trial; the median DFI and survival for standard-of-care (SOC; defined as amputation and carboplatin therapy) dogs was 180 days [95% confidence interval (CI), 144-237] and 282 days (95% CI, 224-383) and for SOC + sirolimus dogs, it was 204 days (95% CI, 157-217) and 280 days (95% CI, 252-332), respectively.
Conclusions:
In a population of pet dogs nongenomically segmented for predicted mTOR inhibition response, sequentially administered adjuvant sirolimus, although well tolerated when added to a backbone of therapy, did not extend DFI or survival in dogs with appendicular osteosarcoma.
Insights
Sirolimus, an mTOR inhibitor, did not improve disease-free interval or survival in pet dogs with osteosarcoma. This study suggests adjuvant sirolimus therapy is not effective for this cancer in dogs.
Area of Science:
- Oncology
- Pharmacology
- Veterinary Medicine
Background:
- The mechanistic target of rapamycin (mTOR) pathway is crucial in signaling nutrient availability and is implicated in osteosarcoma metastasis.
- Sirolimus is an FDA-approved drug that inhibits mTOR signaling.
- Pet dogs with appendicular osteosarcoma serve as valuable models for human pediatric osteosarcoma.
Purpose of the Study:
- To evaluate the efficacy of mTOR inhibition with sirolimus in preventing or delaying metastatic progression in dogs with appendicular osteosarcoma.
- To assess the impact of adjuvant sirolimus on disease-free interval (DFI) and overall survival in canine osteosarcoma patients.
Main Methods:
- A multicenter, randomized superiority trial involving 324 pet dogs with treatment-naïve appendicular osteosarcoma.
- Dogs underwent limb amputation followed by adjuvant carboplatin chemotherapy, with or without oral sirolimus.
- Primary endpoint was DFI; secondary endpoints included survival rates and sirolimus pharmacokinetics.
Main Results:
- No significant difference in median DFI or overall survival was observed between the standard-of-care (amputation and carboplatin) and the standard-of-care plus sirolimus groups.
- Median DFI was 180 days for SOC and 204 days for SOC + sirolimus.
- Median overall survival was 282 days for SOC and 280 days for SOC + sirolimus.
Conclusions:
- Adjuvant sirolimus, when added to standard therapy for appendicular osteosarcoma in pet dogs, did not extend disease-free interval or survival.
- Sirolimus was well-tolerated in this canine population.
- These findings suggest that mTOR inhibition may not be an effective therapeutic strategy for attenuating metastatic disease progression in this osteosarcoma model.
