Jeerawan Klangjorhor1, Areerak Phanphaisarn2, Pimpisa Teeyakasem1, Parunya Chaiyawat1, Phichayut Phinyo3, Jongkolnee Settakorn1,4, Nipon Theera-Umpon5,6, Dumnoensun Pruksakorn7,8,9. 1. Musculoskeletal Science and Translational Research Center, Chiang Mai University, Chiang Mai, 50200, Thailand. 2. Department of Orthopedics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. 3. Center for Clinical Epidemiology and Clinical Statistics, Faculty of Medicine, Ching Mai University, Chiang Mai, Thailand. 4. Department of Pathology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. 5. Biomedical Engineering Institute, Chiang Mai University, Chiang Mai, Thailand. 6. Department of Electrical Engineering, Faculty of Engineering, Chiang Mai University, Chiang Mai, Thailand. 7. Musculoskeletal Science and Translational Research Center, Chiang Mai University, Chiang Mai, 50200, Thailand. dumnoensun.p@cmu.ac.th. 8. Department of Orthopedics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. dumnoensun.p@cmu.ac.th. 9. Biomedical Engineering Institute, Chiang Mai University, Chiang Mai, Thailand. dumnoensun.p@cmu.ac.th.
Abstract
PURPOSE: Early prediction of clinical response to conventional chemotherapy is a significant factor in determining an overall treatment strategy for osteosarcoma. METHODS: Cells were extracted from treatment-naïve biopsies from 16 osteosarcoma patients who received a doxorubicin and cisplatin-based neoadjuvant chemotherapy regimen and their sensitivities to doxorubicin and cisplatin were measured as IC50 values. Associations of in vitro drug sensitivity (IDS) levels and clinical outcomes were examined. RESULTS: Primary osteosarcoma cells responded to doxorubicin and cisplatin with IC50 values of 0.088 ± 0.032 µM and 16.7 ± 8.5 µM, respectively. The patients with a non-metastatic phenotype and surviving patients showed significantly lower IC50 values for both drugs. ROC analysis defined the optimal IC50 cut-off values for doxorubicin (IDSdox) and cisplatin (IDScpt) as 0.05 µM (AUC 0.82) and 14 µM (AUC 0.87), respectively. Survival analysis found significantly longer disease-free survival (DFS, n = 14) and overall survival (OS, n = 16) times in the patients with low IDSdox (p = 0.0064 for DFS and p = 0.0102 for OS) and low IDScpt (p = 0.0204 for DFS and p = 0.0021 for OS). Interestingly, when the patients with low IDScpt and those with low IDSdox were combined (Group 1), significant associations with prolonged DFS (p = 0.0042, C-statistic 0.78) and OS (p = 0.0010, C-statistic 0.79) were found. In this cohort, histological response to neoadjuvant chemotherapy could predict only OS. CONCLUSIONS: This study indicates that IDS analysis could potentially be a practical, rapid, and reliable technique for predicting clinical outcomes. It could also be used to identify patients for whom conventional chemotherapy is most appropriate and, in the future, help advance personalized therapy.
PURPOSE: Early prediction of clinical response to conventional chemotherapy is a significant factor in determining an overall treatment strategy for osteosarcoma. METHODS: Cells were extracted from treatment-naïve biopsies from 16 osteosarcomapatients who received a doxorubicin and cisplatin-based neoadjuvant chemotherapy regimen and their sensitivities to doxorubicin and cisplatin were measured as IC50 values. Associations of in vitro drug sensitivity (IDS) levels and clinical outcomes were examined. RESULTS:Primary osteosarcoma cells responded to doxorubicin and cisplatin with IC50 values of 0.088 ± 0.032 µM and 16.7 ± 8.5 µM, respectively. The patients with a non-metastatic phenotype and surviving patients showed significantly lower IC50 values for both drugs. ROC analysis defined the optimal IC50 cut-off values for doxorubicin (IDSdox) and cisplatin (IDScpt) as 0.05 µM (AUC 0.82) and 14 µM (AUC 0.87), respectively. Survival analysis found significantly longer disease-free survival (DFS, n = 14) and overall survival (OS, n = 16) times in the patients with low IDSdox (p = 0.0064 for DFS and p = 0.0102 for OS) and low IDScpt (p = 0.0204 for DFS and p = 0.0021 for OS). Interestingly, when the patients with low IDScpt and those with low IDSdox were combined (Group 1), significant associations with prolonged DFS (p = 0.0042, C-statistic 0.78) and OS (p = 0.0010, C-statistic 0.79) were found. In this cohort, histological response to neoadjuvant chemotherapy could predict only OS. CONCLUSIONS: This study indicates that IDS analysis could potentially be a practical, rapid, and reliable technique for predicting clinical outcomes. It could also be used to identify patients for whom conventional chemotherapy is most appropriate and, in the future, help advance personalized therapy.
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