Abstract
BackgroundThe value of chemotherapy in soft tissue sarcoma (STS) remains controversial. Several expert teams consider that chemotherapy provides a survival advantage and should be proposed in high-risk (HR) patients. However, the lack of accuracy in identifying HR patients with conventional risk factors (large, deep, FNCLCC grade 3, extremity STS) is an issue that cannot be neglected. For example, while the FNCLCC grading system is a powerful tool, it has several limitations. CINSARC, a 67-gene signature, has proved to be an additional independent factor for predicting metastatic spread and outperforms histological grade. Regardless of FNCLCC grade, CINSARC stratifies patients into two separate prognostic groups: one with an excellent prognosis (low-risk (LR) CINSARC) and the other with a worse outcome (HR-CINSARC) in terms of metastatic relapse. Here we evaluate the role of chemotherapy in grade 1–2 STS patients with HR-CINSARC and assess the prognostic value of CINSARC in patients treated with standard of care.MethodsCHIC is a parallel, randomized, open-label, multicenter study evaluating the effect on metastasis-free survival of adding perioperative chemotherapy to standard of care in patients with grade ½ STS sarcoma defined as HR by CINSARC. In this target selection design, 600 patients will be screened with CINSARC to randomize 250 HR-CINSARC patients between standard of care and standard of care plus chemotherapy (4 cycles of 3 weeks of intravenous chemotherapy with doxorubicin in combination with dacarbazine or ifosfamide according to histologic subtype). LR-CINSARC patients will be treated by standard of care according to the investigator. The primary endpoint is metastasis-free survival. Secondary endpoints include overall survival, disease-free survival and safety. Furthermore, the prognostic value of CINSARC will be evaluated by comparing LR-CINSARC patients to HR-CINSARC patients randomized in standard of care.DiscussionCHIC is a prospective randomized phase III trial designed to comprehensively evaluate the benefit of chemotherapy in HR-CINSARC patients and to prospectively validate the prognostic value of CINSARC in grade ½ STS sarcoma patients.Trial registrationClinicalTrials.gov identifier: NCT04307277 Date of registration: 13 March 2020
Highlights
The value of chemotherapy in soft tissue sarcoma (STS) remains controversial
Trial objectives Primary objective The primary objective of this study is to demonstrate whether adding four cycles of perioperative doxorubicinbased chemotherapy improves metastasis-free survival (MFS) as compared with standard management in patients with resectable FNCLCC grade 1/2 (G1/2) STS, considered as HR according to Complexity Index in SARComas (CINSARC)
Quality control of samples will be assessed by the investigational site pathologist and samples with less than 50% of tumor cells will be considered as non-eligible for CINSARC analysis
Summary
The value of chemotherapy in soft tissue sarcoma (STS) remains controversial. Several expert teams consider that chemotherapy provides a survival advantage and should be proposed in high-risk (HR) patients. Based on previous published studies, many expert teams currently consider that chemotherapy provides a survival advantage and should be proposed in HR patients [4] This HR subgroup includes patients with large, deep, high FNCLCC grade, and extremity STS [5]. The debate concerning the value of chemotherapy in localized STS is currently in deadlock, mirroring the difficulty of accurately identifying HR patients by using conventional factors, and the FNCLCC grade. This grading system, which splits STS into three grades (1, 2 or 3), remains the best predictor of metastatic relapse available in localized sarcoma [5, 7]. The CINSARC signature, which is especially informative in patients with intermediate-grade tumors, could be a way out of this “never-ending story”
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