Redefining radiologic responses (RR) in solid tumors: Shall we brace ourselves for a post-RECIST era? Results from a randomized clinical trial (RCT) on neoadjuvant chemotherapy in high-risk soft-tissue sarcomas (HR-STS) of the trunk or extremities.

11553 Background: ISG-STS 1001, a RCT comparing anthracycline + ifosfamide (AI) vs. histology-tailored (HT) neoadjuvant chemotherapy (N) in primary localized HR-STS (G3; d >5 cm; deeply seated) showed superiority of AI, especially in the higher risk group. We report the results of the planned secondary analysis of RR. Methods: Patients (pts) with undifferentiated pleomorphic sarcoma (UPS), leiomyosarcoma (LMS), malignant peripheral nerve sheath tumor (MPNST), synovial sarcoma (SS) or myxoid liposarcoma (MLPS) were randomized, whereas pts with myxofibrosarcoma (MFS), pleomorphic liposarcoma (PLPS), pleomorphic rhabdomyosarcoma (PRMS) or unclassified sarcoma (US) were included in the observational arm (O). Pts with UPS, LMS or MLPS needing concurrent preoperative radiotherapy (RT) were included in O. Primary endpoint was Disease Free Survival (DFS). Planned secondary endpoints included Overall Survival (OS) and centrally reviewed RR per RECIST 1.1. Associations between DFS/OS and RR (per RECIST and as percent dimensional variation (D), dichotomized and continuous), DFS/OS and histology, and RR and histology were evaluated via Cox regression models. Results: 435 pts were included: 287 were randomized and 148 included in O. This analysis comprised all 236 pts with measurable disease and centrally reviewed RR. RECIST best responses were: 28 (11.9%) partial response (PR), 195 (82.6%) stable disease (SD), 13 (5.5%) progressive disease (PD). RR per RECIST significantly correlated with both DFS (PD vs PR: HR 8.2, 95% CI 3-22.6; SD vs PR: HR 3.0, 95% CI 1.3-6.8) and OS (PD vs PR: HR 12.6, 95% CI 3.4-46.8; SD vs PR: HR 4.2, 95% CI 1.3-13.5). A concordant yet not statistically significant trend for DFS was observed in pts who received N (AI or HT) without RT (157 pts; PD + SD vs PR: HR 2.2, 95% CI 0.8-6.1) and those who received AI without RT (93 pts; PD + SD vs PR: HR 2.4, 95% CI 0.8-7.9). To rule out confounding factors, we proved no significant correlation existed between histology and RR per RECIST. We computed the median value of D (-1.6%) and demonstrated that pts with D > -1.6% had worse clinical outcomes than those with D < -1.6% (DFS: HR 1.7, 95% CI 1.2-2.5; OS: HR 1.9, 95% CI 1.2-2.9), and that D in continuous scale significantly correlated with both DFS (HR 1.5, 95% CI 1.3-1.9) and OS (HR 1.8, 95% CI 1.4-2.3). This suggests any D proportionally impacted DFS/OS Conclusions: These results confirm the independent prognostic value of RR both per RECIST and D in selected HR-STS treated with N, and hint that arbitrary thresholds may be divested, as any change in size allows to infer the proportional efficacy of treatment. The greater the dimensional reduction, the stronger the positive influence on clinical outcome; the greater the increase in size, the stronger the corresponding detrimental effect Clinical trial information: NCT01710176 .