Randomized phase III trial of neo-adjuvant and adjuvant chemotherapy vs adjuvant chemotherapy alone for localized soft tissue sarcoma (NACLESS, JCOG2102).

TPS11589 Background: Soft-tissue sarcomas (STS) are a rare malignant tumor. Adjuvant perioperative chemotherapy has been investigated for high-risk patients due to the poor overall survival (OS) for surgery. A meta-analysis revealed that adjuvant chemotherapy (AC) with doxorubicin plus ifosfamide (AI) significantly prolonged OS with an absolute risk reduction of 11%. However, the optimal timing for surgery and number of courses of chemotherapy are still controversial. In Europe, Italian sarcoma group and the Spanish sarcoma group reported on the non-inferiority of three courses of neoadjuvant chemotherapy (NAC) + surgery without AC, compared to three courses of NAC + surgery + two courses of AC. On the other hand, even in the same Europe, the latest report on perioperative chemotherapy with AI from Germany was a trial of surgery + AC. Furthermore, adjuvant chemotherapy itself remains skeptical in other countries such as the US, UK, and Canada. No investigation has been made into whether chemotherapy/surgery are better to initiate treatment with. In Japan, the standard treatment is three courses of NAC with AI, surgery, and two of AC with AI. However, in JCOG1306, NAC was discontinued in 12 of 70 (17.1%) patients due to high toxicity. Only one patient (1.4%) became partial response after NAC, whereas six patients (8.6%) had disease progression during NAC. Of the 65 patients eligible for limb-sparing surgery at enrollment, three (4.6%) underwent limb amputation. Upfront surgery followed by three courses of AC was considered the most promising treatment, it avoided extended surgery and reduced toxicity while maintaining an OS equivalent to the standard treatment. The aim of this trial is to optimize the balance between the survival benefit of perioperative chemotherapy, reduce toxicities, and risks of extended surgery. Methods: This is a multicenter two-arm open-label randomized phase III trial. Patients are randomly assigned to standard (three courses of NAC, surgery, and two of AC) or experimental (surgery and three courses of AC) arms with AI comprising doxorubicin (30 mg/m 2 , days 1, 2) and ifosfamide (2 g/m 2 , days 1–5). Major inclusion criteria were (1) spindle cell STS; (2) T2-4N0M0 (UICC/AJCC 8th edition) and deeply located; (3) resectable tumors in the extremities or trunk; (4) age, 16–70 years; (5) ECOG performance status of 0–1; (6) no history of chemotherapy/radiotherapy; and (7) sufficient bone marrow function. To evaluates the non-inferiority in OS (margin: hazard ratio of 1.61) with power of 70% and one-sided alpha of 10%, 224 patients will be enrolled from 39 institutions in Japan. We began this study on November 16, 2022, and 27 of 224 patients have been enrolled as of January 7, 2024. Clinical trial information: jRCTs031220446 .