Radiation Therapy for Extremity Soft Tissue Sarcoma: In the Absence of a Clear Survival Benefit, Why Do We Give It?

Abstract

Due in large part to several sentinel contributions from the National Cancer Institute (NCI), the local management of extremity soft tissue sarcoma (ESTS) today typically results in excellent local control and very good limb function. In 1982, Rosenberg et al. 1 showed equivalent 5-year survival rates for limb-sparing surgery (LSS) plus radiation therapy (RT) compared with amputation and an acceptable 15 % local recurrence (LR) rate for LSS plus RT. Following publication of this landmark trial, amputation rates appropriately plummeted. In 1998, Yang et al. reported results from a second NCI randomized trial that compared LSS plus RT with LSS alone and showed a clear significant local control benefit for RT for both high-and low-grade ESTS. A randomized trial from Memorial Sloan-Kettering Cancer Center (MSKCC) in 1996 affirmed the local control advantage for RT (in the form of brachytherapy) in addition to LSS.3 Several nonrandomized series have reported LR rates\15 % for LSS alone without RT, but others have shown unacceptably high rates of LR with this approach. [4][5][6][7][8] Given the conflicting results for surgery alone from nonrandomized reports, and the clear local control advantage with RT demonstrated by randomized trials, the standard of care for most high-grade ESTS is LSS plus RT.The main and undisputed benefit of adjuvant RT is improved local control, and local control rates for LSS plus RT are \15 % in modern series.9-12 However, the effect of RT on overall survival is ambiguous. The aforementioned randomized trials as well as the 20-year update of the NCI trial reported by Beane et al. that accompanies this editorial, fail to show a statistically significant difference in survival with the addition of RT. 1-3,13Since RT has its own treatment-related toxicities and is not associated with an improvement in overall survival, should we stop using RT in conjunction with LSS? The report by Beane et al. shows a trend toward higher 20-year survival rates for LSS plus RT compared with LSS alone (71 vs. 64 %, p = 0.22). As the authors point out, this study was only powered to detect a 21 % survival difference. On the other hand, a review of 6,960 patients with high-grade ESTS showed a statistically significant improved 3-year survival rate of 73 % for LSS plus RT compared with 63 % for LSS alone (p \ 0.001).14 It is quite possible that adjuvant RT for ESTS does in fact confer a statistically significant survival advantage, but due to small patient numbers in most series, such a benefit has not been reliably demonstrated. This was the case for breast cancer. Most individual trials failed to show a significant association between local control and survival. 15,16 Nevertheless, patients with breast cancer were still treated with RT because of the local control advantage it conferred. Ultimately, a meta-analysis of 42,000 patients demonstrated a clear link between improved local control and superior survival. 17Another potential benefit of adjuvant RT relates to the consequences of a LR. The development of a L...

The Use of Radiation Therapy in Localized High-Grade Soft Tissue Sarcoma and Potential Impact on Survival

“…8 These conflicting data have raised questions of whether the benefit of treating patients with high-grade STS with radiation therapy is simply to reduce the risk of LR or whether it also may increase the likelihood of long-term survival. 9 Moreover, given the potential complications associated with radiation therapy, if radiation therapy does not improve survival, then it perhaps it should be omitted in select sarcoma patients. Indeed, several studies have shown that, in selected patients, appropriate surgery alone can achieve adequate local control and survival, while avoiding the morbidity of radiation therapy.…”

Neoadjuvant radiation improves margin‐negative resection rates in extremity sarcoma but not survival

“…Margin‐negative resection for extremity sarcoma has been demonstrated to be an important prognostic factor from this disease 20‐22 in addition to size 23 histology, and grade 24,25 . The addition of radiation has been previously shown to improve the likelihood of margin‐negative resection this has not consistently translated to a survival benefit 8,14,26 . NAR improved margin‐negative resection however this did not translate to improved survival over AR or surgery alone.…”

“…Key studies have demonstrated that the addition of RT improves margin‐negative resection rates and local control for this disease 5,7,12 . Although these improvements have not translated to a survival benefit in most studies, the benefit of radiation in the treatment of extremity sarcomas is well‐established 13,14 . The timing of delivery remains a significant area of study.…”

“…Additionally, it has been associated with the improved ability to achieve negative margins at surgery, 16,17 which is critical for local control. Overall, most studies have been unable to demonstrate a survival benefit for radiation 5,18,14 . One prospective trial evaluating the timing of radiation from the National Cancer Institute of Canada (SR2 trial) initially reported a slight benefit in OS for NAR versus adjuvant radiotherapy (AR) but the benefit was lost at 5‐year follow‐up.…”

Brazilian consensus on the diagnosis and treatment of extremities soft tissue sarcomas

“…No randomized study has specifically defined the subgroup of patients with high‐grade tumors who do not require RT. Given the conflicting outcomes of nonrandomized trials and the clear benefit in local control that is offered by adjuvant RT in randomized trials, the standard treatment for most high‐grade lesions remains limb preservation surgery that is followed by RT 64 …”