A group of investigators led by Dr. Dian Wang of the Rush University Medical Center in Chicago, IL, US sought to determine the prognostic significance of treatment-induced histologic response in soft tissue sarcoma (STS) in a large homogeneous group of patients receiving neoadjuvant radiotherapy and/or chemotherapy. Patients enrolled in previous Radiation Therapy Oncology Group (RTOG) sarcoma 9514 and 0630 studies received a relatively uniform preoperative treatment regimen with primary endpoints reported. Long-term outcomes of the RTOG 9514 study have been reported, and long-term outcomes of the RTOG 0630 study are updated in the article published on 30 March 2023 in the JAMA Oncology.
The long-term update of disease outcomes from the RTOG 0630 multi-institutional preoperative image-guided radiotherapy study has further suggested that the target volumes used in this study are appropriate for preoperative image-guided radiotherapy. Furthermore, the ancillary analysis of RTOG 9514 and 0630 studies has demonstrated that pathologic complete response (pCR) was associated with improved survival outcomes in patients with STS who received preoperative therapy. To this end, pCR should be considered a prognostic factor for clinical outcomes in future STS clinical trials.
The authors wrote in the background that neoadjuvant radiotherapy and/or chemotherapy have been commonly used to treat STS of extremity and trunk. The most objective reliable measure of sensitivity to neoadjuvant treatment is the extent of pathologic response. Treatment-induced pathologic necrosis has been shown to be an independent prognostic factor in patients with osteosarcoma and Ewing sarcoma, although not all studies have conclusively demonstrated the correlation of histologic response with treatment and survival. However, in patients with extremity or truncal STS, the prognostic effect of histologic response is much less clear, with only a few published studies offering conflicting results. These studies were limited by either their relatively small study populations or by the heterogeneity of the treatment regimens.
In their article published in the JAMA Oncology, the investigators sought to determine the prognostic significance of pCR on survival outcomes in STS for patients receiving neoadjuvant chemoradiotherapy in RTOG 9514 or preoperative image-guided radiotherapy alone in RTOG 0630 and provide a long-term update of RTOG 0630. RTOG has completed 2 multi-institutional, non-randomised phase II studies for patients with localised STS. A total, 143 eligible patients (79 from RTOG 0630 and 64 from RTOG 9514) were included in the ancillary analysis of pCR and patients from RTOG 0630 were also evaluated for long-term outcomes. Overall survival (OS) and disease-free survival (DFS) rates were estimated by the Kaplan-Meier method. Hazard ratios (HRs) and p values were estimated by multivariable Cox model stratified by study, where possible; otherwise, p values were calculated by stratified log-rank test.
Overall, there were 42 men (53.2%); 68 (86.1%) were white; with a mean age of 59.6 years. For RTOG 0630, at median follow-up of 6.0 years, there was 1 new in-field recurrence and 1 new distant failure since the initial report. From both studies, 123 patients were evaluable for pCR and 14 of 51 (27.5%) in RTOG 9514 and 14 of 72 (19.4%) in RTOG 0630 had pCR.
Five-year OS was 100% for patients with pCR versus 76.5% (95% confidence interval [CI] 62.3%-90.8%) and 56.4% (95% CI 43.3%-69.5%) for patients with less than pCR in RTOG 9514 and 0630. Overall, pCR was associated with improved OS (p = 0.01) and DFS (HR 4.91; 95% CI 1.51-15.93; p = 0.008) relative to less than pCR. Five-year local failure rate was 0% in patients with pCR versus 11.7% (95% CI 3.6%-25.1%) and 9.1% (95% CI 3.3%-18.5%) for patients with less than pCR in RTOG 9514 and 0630. Histologic types other than leiomyosarcoma, liposarcoma, and myxofibrosarcoma were associated with worse OS (HR 2.24; 95% CI 1.12-4.45).
The authors commented that this is the first report of the prognostic significance of pathologic response in patients with STS who received preoperative treatment with chemotherapy and/or radiotherapy from RTOG 9514 and 0630 studies. However, this was an ancillary analysis of a small number of patients rather than a prespecified endpoint. Correlation of hyalinisation/fibrosis to oncologic outcomes could have further strengthened the study. Assessment of imaging and pathologic response in relation to disease outcomes was not performed and would provide valuable and potentially prognostic biomarker information. Further clarity is required on which histologic types may benefit from treatment intensification.
This work was supported by grants from the US National Cancer Institute.
Reference
Wang D, Harris J, Kraybill WG, et al. Pathologic Complete Response and Clinical Outcomes in Patients With Localized Soft Tissue Sarcoma Treated With Neoadjuvant Chemoradiotherapy or Radiotherapy The NRG/RTOG 9514 and 0630 Nonrandomized Clinical Trials. JAMA Oncology; Published online 30 March 2023. doi:10.1001/jamaoncol.2023.0042