Pathological Response Does Not Reliably Predict Survival in Sarcoma

Pathological response after neoadjuvant chemotherapy, radiotherapy, or chemoradiotherapy did not consistently predict survival in patients with soft tissue sarcoma (STS), according to a systematic review of 27 studies published in Cancer Treatment Reviews.¹

Low levels of residual viable tumor (RVT) were significantly associated with improved survival in 9 of 25 studies (36%) that assessed them, and high necrosis was associated with decreased survival in 6 of 8 studies (75%). Findings for fibrosis/hyalinization were mixed, with 3 of 7 studies (43%) reporting a significant favorable association and 2 of 7 (29%) reporting a significant unfavorable one.

The authors concluded that current evidence is insufficient to support pathological response as a reliable prognostic predictor and proposed a framework to standardize how it is assessed and reported.

Pathological Response as a Surrogate Marker in Soft Tissue Sarcoma

STS accounts for approximately 1% of newly diagnosed cancers, and high-risk localized disease is often treated with surgery plus neoadjuvant radiotherapy, chemotherapy, or both. Even with multimodal treatment, about 15% of patients develop local recurrence and 30% or more develop distant metastases. Trials of neoadjuvant strategies have increasingly used pathological response as a surrogate marker of treatment efficacy—an approach established in breast and urothelial carcinomas and osteosarcoma but not yet validated in STS, the authors noted.

The researchers searched MEDLINE, Scopus, and Embase through January 27, 2026, for clinical trials, observational studies, and retrospective studies of at least 50 patients that linked RVT, necrosis, or fibrosis/hyalinization to a survival outcome. The 27 included studies enrolled 3961 patients (median, 112; range, 50-496) and were published between 2001 and 2025. Nine studies evaluated chemotherapy, 11 radiotherapy, and 7 chemoradiotherapy. Definitions, regimens, and outcomes varied too widely for a meta-analysis, so the study results were synthesized narratively. The authors noted that 60% of studies had a serious risk of bias, primarily from confounding and selection bias.

Residual Viable Tumor and Necrosis Outcomes by Treatment Modality

Of the 27 studies, 16 (59%) reported a significant association between their own pathological response classification and at least 1 survival end point. Cutoffs for favorable response ranged from 0% to 25% RVT, and reported rates of favorable pathological response ranged from 5% to 47% after chemotherapy, 0% to 22% after radiotherapy, and 14% to 44% after chemoradiotherapy.

Some of the largest studies supported a prognostic role for RVT. In a chemoradiotherapy cohort of 496 patients, 5% or less RVT was independently associated with improved local control and overall survival, and in a radiotherapy-focused cohort of 330 patients, the same threshold independently predicted local control and overall survival. However, the largest chemotherapy study, a secondary analysis of 388 patients from the ISG-STS 1001 trial (NCT01710176), found no association between 0% RVT and disease-free survival.^1,2 Histologic subtype also appeared to shape response, as 1 cohort reported rates of 5% or less RVT of 62% in undifferentiated pleomorphic sarcoma and 56% in myxoid liposarcoma compared with 0% in synovial sarcoma.¹

The term “necrosis” was used inconsistently, sometimes describing all nonviable tissue and sometimes a distinct component, so the authors reclassified 13 studies that used the broader definition as RVT-based assessments. When assessed as a distinct component, necrosis was mostly linked to worse outcomes.

“Rather than representing a favorable [pathological response], high levels of necrosis likely reflect higher histological grade and intrinsic tumor aggressiveness, as suggested by inverse correlations with survival in several studies,” the authors wrote.

Study Limitations and the CHIRE Framework for Standardized Reporting

The review was limited by substantial heterogeneity across studies and by missing or differently conducted central pathology review and specimen workup across studies. Most included analyses were not adjusted for confounders such as tumor grade, histologic subtype, and resection margin, and adjuvant therapies given after neoadjuvant treatment that may have influenced survival outcomes, the authors noted.

The authors also cautioned that favorable pathological response is unlikely to substantially alter overall treatment strategy, though it could support patient counseling and, if validated, serve as a surrogate end point in clinical trials. They recommended prioritizing RVT as the primary marker and proposed the CHIRE framework, which standardizes reporting of patient characteristics, histology, intervention, response, and events.

“This variability largely stems from the lack of standardized methods for assessing treatment response in STS, including differences in the histological parameters evaluated, their definitions, cut-off values, and the terminology used to classify response categories. Harmonized assessment methods, definitions, and study reporting practices are needed to clarify the prognostic role of [pathological response],” the authors concluded.

References

1. van Riet BHG, van der Burg SJC, van der Klaauw T, et al. The prognostic value of pathological response in soft tissue sarcoma: a systematic review. Cancer Treat Rev. 2026;151:103219. doi:10.1016/j.ctrv.2026.103219

2. Pasquali S, Collini P, Romagosa C, et al. Histopathological response after neoadjuvant chemotherapy for high-risk soft-tissue sarcomas: a secondary analysis of a randomized clinical trial. JAMA Netw Open. 2025;8(11):e2540177. doi:10.1001/jamanetworkopen.2025.40177