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Clinical Trial
. 2025 Mar;10(3):104299.
doi: 10.1016/j.esmoop.2025.104299. Epub 2025 Mar 7.

Redefining radiologic responses in high-risk soft-tissue sarcomas treated with neoadjuvant chemotherapy: final results of ISG-STS 1001, a randomized clinical trial

A Vanzulli  1 , R Vigorito  2 , C Buonomenna  2 , E Palmerini  3 , V Quagliuolo  4 , J M Broto  5 , A Lopez Pousa  6 , G Grignani  7 , A Brunello  8 , J-Y Blay  9 , R Diaz Beveridge  10 , V Ferraresi  11 , I Lugowska  12 , S Pizzamiglio  13 , P Verderio  13 , V Duroni  13 , V Fontana  14 , D M Donati  15 , E Palassini  16 , G Bianchi  15 , A Bertuzzi  17 , A Buonadonna  18 , S Pasquali  19 , A P Dei Tos  20 , P G Casali  21 , C Morosi  2 , S Stacchiotti  16 , A Gronchi  22
Affiliations
Clinical Trial

Redefining radiologic responses in high-risk soft-tissue sarcomas treated with neoadjuvant chemotherapy: final results of ISG-STS 1001, a randomized clinical trial

A Vanzulli et al. ESMO Open. 2025 Mar.

Abstract

Background: We report the results of the pre-planned secondary analysis of radiologic responses (RRs) of ISG-STS 1001, a randomized trial comparing anthracycline + ifosfamide (AI) versus histology-tailored (HT) neoadjuvant chemotherapy for primary localized high-risk soft-tissue sarcomas of the extremities and trunk wall.

Patients and methods: Patients with undifferentiated pleomorphic sarcoma (UPS), leiomyosarcoma (LMS), malignant peripheral nerve sheath tumor, synovial sarcoma or myxoid liposarcoma (MLPS) were randomized, whereas patients with myxofibrosarcoma, pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma or unclassified sarcoma were included in the observational arm (O) and treated with AI. Patients with UPS, LMS or MLPS needing concurrent preoperative radiotherapy were included in O. We evaluated associations between: disease-free survival (DFS)/overall survival (OS) and centrally reviewed RR, assessed with RECIST 1.1 and as percent dimensional variation (D; both dichotomized and continuous); DFS/OS and histology; RR and histology.

Results: Four hundred and thirty-five patients were included (287 randomized, 148 observed). The analysis of RRs comprised 236 patients (154 randomized, 82 observed) with measurable disease and available for central review. RECIST best responses were: 28 (11.9%) partial response (PR), 195 (82.6%) stable disease (SD), 13 (5.5%) progressive disease (PD). RECIST significantly correlated with DFS [PD versus PR: hazard ratio (HR) 8.18, 95% confidence interval (CI) 2.96-22.58; SD versus PR: HR 2.96, 95% CI 1.30-6.75] and OS (PD versus PR: HR 12.61, 95% CI 3.40-46.84; SD versus PR: HR 4.24, 95% CI 1.34-13.47). The median value of D was -1.6%. Patients with D >-1.6% had worse clinical outcomes than those with D <-1.6% (DFS: HR 1.73, 95% CI 1.19-2.50; OS: HR 1.86, 95% CI 1.21-2.86). D in continuous scale inversely correlated with DFS (HR 1.53, 95% CI 1.25-1.87) and OS (HR 1.78, 95% CI 1.41-2.25).

Conclusions: These results confirm the prognostic value of RRs as per RECIST and D and demonstrate that any variation in size predicts the proportional efficacy of treatment.

Keywords: RECIST; neoadjuvant chemotherapy; prognosis; randomized clinical trial; sarcoma; tumor response.

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Figures

Figure 1
Figure 1
CONSORT diagram detailing study design and treatment arms.aRandomized patients: 65/93 in arm A and 63/64 in arm B (1 patient was randomized as UPS, but histological central review concluded for MFS, non-randomizable histology as per study protocol; the patient was excluded from our analyses). AI, anthracycline + ifosfamide; CONSORT, Consolidated Standards of Reporting Trials; HT, histology-tailored chemotherapy; MFS, myxofibrosarcoma; RT, radiotherapy; UPS, undifferentiated pleomorphic sarcoma.
Figure 2
Figure 2
Disease-free and overall survival probabilities according to RECIST 1.1. (A) Disease-free survival and (B) overall survival probabilities of RECIST 1.1 (n = 236). (C) Disease-free survival and (D) overall survival probabilities of dichotomized percent dimensional variation after the third cycle of neoadjuvant chemotherapy (n = 236). (E) Disease-free survival and (F) overall survival probabilities of different histologies on the overall series of patients with measurable disease (n = 366). LMS, leiomyosarcoma; MFS, myxofibrosarcoma; MLPS, myxoid liposarcoma; MPNST, malignant peripheral nerve sheath tumor; SYNOV, synovial sarcoma; UPS, undifferentiated pleomorphic sarcoma.
Figure 2
Figure 2
Disease-free and overall survival probabilities according to RECIST 1.1. (A) Disease-free survival and (B) overall survival probabilities of RECIST 1.1 (n = 236). (C) Disease-free survival and (D) overall survival probabilities of dichotomized percent dimensional variation after the third cycle of neoadjuvant chemotherapy (n = 236). (E) Disease-free survival and (F) overall survival probabilities of different histologies on the overall series of patients with measurable disease (n = 366). LMS, leiomyosarcoma; MFS, myxofibrosarcoma; MLPS, myxoid liposarcoma; MPNST, malignant peripheral nerve sheath tumor; SYNOV, synovial sarcoma; UPS, undifferentiated pleomorphic sarcoma.
Figure 3
Figure 3
Disease-free and overall survival probabilites according to dichotomized percent dimensional variation after the third cycle of neoadjuvant chemotherapy. (A) Disease-free survival and (B) overall survival probabilities of percent dimensional variation after the third cycle of neoadjuvant chemotherapy in continuous scale at median follow-up (n = 236).
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