Sandro Pasquali1, Emanuela Palmerini2, Vittorio Quagliuolo3, Javier Martin-Broto4,5, Antonio Lopez-Pousa6, Giovanni Grignani7, Antonella Brunello8, Jean-Yves Blay9,10, Oscar Tendero11, Robert Diaz-Beveridge12, Virginia Ferraresi13, Iwona Lugowska14, Gabriele Infante15, Luca Braglia16, Domenico Franco Merlo16, Valeria Fontana17, Emanuela Marchesi18, Davide Maria Donati19, Elena Palassini20, Giuseppe Bianchi19, Andrea Marrari21, Carlo Morosi22, Silvia Stacchiotti20, Silvia Bagué23, Jean Michel Coindre24, Angelo Paolo Dei Tos25,26, Piero Picci27, Paolo Bruzzi17, Rosalba Miceli15, Paolo Giovanni Casali19,28, Alessandro Gronchi1. 1. Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 2. Osteoncology, Bone and Soft Tissue Sarcomas, and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy. 3. Department of Surgery, IRCCS Humanitas Research Hospital, Rozzano, Italy. 4. Medical Oncology Department, University Hospital Virgen del Rocio, Seville, Spain. 5. Institute of Biomedicine of Seville, University of Seville, Seville, Spain. 6. Department of Cancer Medicine, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 7. Department of Cancer Medicine, Fondazione del Piemonte per l'Oncologia IRCCS Candiolo, Turin, Italy. 8. Department of Oncology, Medical Oncology 1 Unit, Istituto Oncologico Veneto, IRCCS, Padua, Italy. 9. Department of Cancer Medicine, Léon Bérard Cancer Center, Lyon, France. 10. Université Claude Bernard Lyon I, Lyon, France. 11. Department of Surgery, Hospital Universitari Son Espases, Palma de Mallorca, Spain. 12. Department of Cancer Medicine, Hospital Universitari i Politècnic La Fe, Valencia, Spain. 13. Department of Cancer Medicine, Istituto Regina Elena, Rome, Italy. 14. Department of Soft Tissue/Bone Sarcoma and Melanoma, Centrum Onkologii Instytut im Marii Skłodowskiej Curie, Warsaw, Poland. 15. Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 16. Research and Statistics Infrastructure, Azienda Unità Sanitaria Locale-IRCCS, Reggio Emilia, Italy. 17. Clinical Trial Center and Department of Epidemiology, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy. 18. Clinical Trial Center, Italian Sarcoma Group, Bologna, Italy. 19. Department of Orthopedic Oncology, Istituto Ortopedico Rizzoli, Bologna, Italy. 20. Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 21. Department of Cancer Medicine, Istituto Clinico Humanitas, Rozzano, Italy. 22. Department of Radiology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 23. Department of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 24. Department of Pathology, Institut Bergonié, Bordeaux, France. 25. Department of Pathology, Treviso General Hospital, Padua, Italy. 26. University of Padua, Padua, Italy. 27. Laboratory of Oncologic Research, Istituto Ortopedico Rizzoli, Bologna, Italy. 28. Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
Abstract
BACKGROUND: The value of neoadjuvant chemotherapy in soft tissue sarcoma (STS) is not completely understood. This study investigated the benefit of neoadjuvant chemotherapy according to prognostic stratification based on the Sarculator nomogram for STS. METHODS: This study analyzed data from ISG-STS 1001, a randomized study that tested 3 cycles of neoadjuvant anthracycline plus ifosfamide (AI) or histology-tailored (HT) chemotherapy in adult patients with STS. The 10-year predicted overall survival (pr-OS) was estimated with the Sarculator and was stratified into higher (10-year pr-OS < 60%) and lower risk subgroups (10-year pr-OS ≥ 60%). RESULTS: The median pr-OS was 0.63 (interquartile range [IQR], 0.51-0.72) for the entire study population, 0.62 (IQR, 0.51-0.70) for the AI arm, and 0.64 (IQR, 0.51-0.73) for the HT arm. Three- and 5-year overall survival (OS) were 0.86 (95% confidence interval [CI], 0.82-0.93) and 0.81 (95% CI, 0.71-0.86) in lower risk patients and 0.69 (95% CI, 0.70-0.85) and 0.59 (95% CI, 0.51-0.72) in the higher risk patients (log-rank test, P = .004). In higher risk patients, the 3- and 5-year Sarculator-predicted and study-observed OS rates were 0.68 and 0.58, respectively, and 0.85 and 0.66, respectively, in the AI arm (P = .04); the corresponding figures in the HT arm were 0.69 and 0.60, respectively, and 0.69 and 0.55, respectively (P > .99). In lower risk patients, the 3- and 5-year Sarculator-predicted and study-observed OS rates were 0.85 and 0.80, respectively, and 0.89 and 0.82, respectively, in the AI arm (P = .507); the corresponding figures in the HT arm were 0.87 and 0.81, respectively, and 0.86 and 0.74, respectively (P = .105). CONCLUSIONS: High-risk patients treated with AI performed better than predicted, and this adds to the evidence for the efficacy of neoadjuvant AI in STS. LAY SUMMARY: People affected by soft tissue sarcomas of the extremities and trunk wall are at some risk of developing metastasis after surgery. Preoperative or postoperative chemotherapy has been tested in clinical trials to reduce the chances of distant metastasis. However, study findings have not been conclusive. This study stratified the risk of metastasis for people affected by sarcomas who were included in a clinical trial testing neoadjuvant chemotherapy. Exploiting the prognostic nomogram Sarculator, it found a benefit for chemotherapy when the predicted risk, based on patient and tumor characteristics, was high.
BACKGROUND: The value of neoadjuvant chemotherapy in soft tissue sarcoma (STS) is not completely understood. This study investigated the benefit of neoadjuvant chemotherapy according to prognostic stratification based on the Sarculator nomogram for STS. METHODS: This study analyzed data from ISG-STS 1001, a randomized study that tested 3 cycles of neoadjuvant anthracycline plus ifosfamide (AI) or histology-tailored (HT) chemotherapy in adult patients with STS. The 10-year predicted overall survival (pr-OS) was estimated with the Sarculator and was stratified into higher (10-year pr-OS < 60%) and lower risk subgroups (10-year pr-OS ≥ 60%). RESULTS: The median pr-OS was 0.63 (interquartile range [IQR], 0.51-0.72) for the entire study population, 0.62 (IQR, 0.51-0.70) for the AI arm, and 0.64 (IQR, 0.51-0.73) for the HT arm. Three- and 5-year overall survival (OS) were 0.86 (95% confidence interval [CI], 0.82-0.93) and 0.81 (95% CI, 0.71-0.86) in lower risk patients and 0.69 (95% CI, 0.70-0.85) and 0.59 (95% CI, 0.51-0.72) in the higher risk patients (log-rank test, P = .004). In higher risk patients, the 3- and 5-year Sarculator-predicted and study-observed OS rates were 0.68 and 0.58, respectively, and 0.85 and 0.66, respectively, in the AI arm (P = .04); the corresponding figures in the HT arm were 0.69 and 0.60, respectively, and 0.69 and 0.55, respectively (P > .99). In lower risk patients, the 3- and 5-year Sarculator-predicted and study-observed OS rates were 0.85 and 0.80, respectively, and 0.89 and 0.82, respectively, in the AI arm (P = .507); the corresponding figures in the HT arm were 0.87 and 0.81, respectively, and 0.86 and 0.74, respectively (P = .105). CONCLUSIONS: High-risk patients treated with AI performed better than predicted, and this adds to the evidence for the efficacy of neoadjuvant AI in STS. LAY SUMMARY: People affected by soft tissue sarcomas of the extremities and trunk wall are at some risk of developing metastasis after surgery. Preoperative or postoperative chemotherapy has been tested in clinical trials to reduce the chances of distant metastasis. However, study findings have not been conclusive. This study stratified the risk of metastasis for people affected by sarcomas who were included in a clinical trial testing neoadjuvant chemotherapy. Exploiting the prognostic nomogram Sarculator, it found a benefit for chemotherapy when the predicted risk, based on patient and tumor characteristics, was high.