TY - JOUR
T1 - Adjuvant sirolimus does not improve outcome in pet dogs receiving standard-of-care therapy for appendicular osteosarcoma
T2 - A prospective, randomized trial of 324 dogs
AU - LeBlanc, Amy K.
AU - Mazcko, Christina N.
AU - Cherukuri, Aswini
AU - Berger, Erika P.
AU - Kisseberth, William C.
AU - Brown, Megan E.
AU - Lana, Susan E.
AU - Weishaar, Kristen
AU - Flesner, Brian K.
AU - Bryan, Jeffrey N.
AU - Vail, David M.
AU - Burton, Jenna H.
AU - Willcox, Jennifer L.
AU - Mutsaers, Anthony J.
AU - Woods, J. Paul
AU - Northrup, Nicole C.
AU - Saba, Corey
AU - Curran, Kaitlin M.
AU - Leeper, Haley
AU - Wilson-Robles, Heather
AU - Wustefeld-Janssens, Brandan G.
AU - Lindley, Stephanie
AU - Smith, Annette N.
AU - Dervisis, Nikolaos
AU - Klahn, Shawna
AU - Higginbotham, Mary Lynn
AU - Wouda, Raelene M.
AU - Krick, Erika
AU - Mahoney, Jennifer A.
AU - London, Cheryl A.
AU - Barber, Lisa G.
AU - Balkman, Cheryl E.
AU - McCleary-Wheeler, Angela L.
AU - Suter, Steven E.
AU - Martin, Olya
AU - Borgatti, Antonella
AU - Burgess, Kristine
AU - Childress, Michael O.
AU - Fidel, Janean L.
AU - Allstadt, Sara D.
AU - Gustafson, Daniel L.
AU - Selmic, Laura E.
AU - Khanna, Chand
AU - Fan, Timothy M.
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/6/1
Y1 - 2021/6/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-21-0315
DO - 10.1158/1078-0432.CCR-21-0315
M3 - Article
C2 - 33753454
AN - SCOPUS:85107009936
SN - 1078-0432
VL - 27
SP - 3005
EP - 3016
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 11
ER -
