Concurrent And Adjuvant Cyclophosphamide And Etoposide With Preoperative Radiotherapy For High-Risk Extremity Soft Tissue Sarcoma: A Matched-Pair Analysis With 20-Year Follow-Up

To assess the efficacy and toxicity of preoperative RT with concurrent and adjuvant chemotherapy in patients with high-risk extremity soft tissue sarcoma (STS). Fifteen patients received 2 cycles of concurrent and 4 cycles of adjuvant chemotherapy with cyclophosphamide and etoposide as part of a novel preoperative chemoradiotherapy limb-conservation regimen for high-risk extremity STS. All tumors were high-grade (AJCC G3 - 4) with a median size of 13 cm (range, 3 - 35 cm). A 2:1 matched-pair analysis was conducted with 30 control patients treated identically but without chemotherapy. Control patients were matched by size, location, grade, and T stage. Unmatched features of each group were similar with the exception of younger age in the chemotherapy group (p = 0.0497). Ten-year local control (LC), local control and amputation-free survival (LC+AFS), distant metastasis-free survival (DMFS), cause-specific survival (CSS), overall survival (OS), and toxicity were compared between the two groups. Median follow-up for living patients was 20 years. OS was higher in chemotherapy patients (10-year OS: 67% versus 43%, p = 0.009) with a similar trend towards improved CSS (10-year CSS: 73% versus 55%, p = 0.12). However, the 10-year LC, LC+AFS, and DMFS rates (100% versus 91%, p = 0.29; 93% versus 85%, p = 0.49; and 53% versus 50%, p = 0.78, respectively) were similar between the chemotherapy and control groups. A greater proportion of patients in the chemotherapy group (3/7 versus 0/15) who developed metastatic disease were cured by surgical salvage. With the exception of hematologic toxicity in the chemotherapy cohort, the rate of grade 3+ complications was similar between the groups. This prospective pilot study in patients with high-risk extremity STS reveals that a novel regimen of cyclophosphamide and etoposide-based chemoradiotherapy is feasible and results in excellent long-term LC and limb preservation without increasing local complications. On matched-pair analysis, chemotherapy did not result in a DMFS benefit. The higher cure rate observed in surgically salvaged patients with metastases who received chemotherapy requires further validation.