Preoperative radiotherapy for retroperitoneal sarcoma: Where do we go from here?

The role of radiation therapy (RT) in the management of retroperitoneal sarcomas has been a longstanding topic of debate among physicians, and institutional and individual preferences have led to significant variability and inconsistencies in its use.¹ The presumed benefit of RT in the management of retroperitoneal sarcomas has been inferred from its local control benefit in extremity sarcomas.^2,3

In October 2020, Bonvalet and colleagues published EORTC-62092 (STRASS), the first completed, randomized clinical trial assessing the efficacy of neoadjuvant RT in retroperitoneal sarcomas.⁴

Study design

EORTC-62092 (STRASS) was a phase 3 randomized control trial conducted at 31 centers across Europe, Canada, and the U.S., which enrolled patients from 2012 to 2017. Patients with resectable, nonmetastatic soft-tissue sarcomas of the retroperitoneum suitable for RT were randomized 1:1 to undergo curative-intent radical resection alone or neoadjuvant RT followed by curative-intent radical resection. Patients were stratified based on institution and performance status but not histologic subtype. In the RT plus surgery arm, 50.4Gy RT was delivered by three-dimensional conformal radiotherapy or intensity-modulated radiotherapy depending on institutional preference. Surgical resection was performed four to eight weeks following completion of RT. Surveillance computed tomography or magnetic resonance imaging scans were performed every 12 weeks for the first year and then every six months until recurrence or death.

The primary endpoint of the trial was abdominal recurrence-free survival (ARFS) beginning from date of randomization and was defined using a composite endpoint, including the following:

• Local or distant progression during RT
• Change to inoperable status based on performance status or superior mesenteric artery, aortic, or bony involvement
• Peritoneal disease detection during surgery
• Incomplete (R2) resection
• Intra-abdominal relapse after complete resection

Patients with distant recurrence were followed until local failure was detected. The study was powered to detect a 20 percent difference in ARFS at five years.

Trial outcomes

Of the 266 patients enrolled in the trial, 124 in the surgery-alone cohort and 115 patients in the RT plus surgery cohort completed their designated treatment and were evaluable at follow-up. Liposarcoma was the most common histologic subtype in both groups (75 percent), and most tumors were either low- or intermediate-grade (65 percent). Complete macroscopic resection was achieved in 95 percent of patients, with a reoperation rate of 11 percent in both cohorts.

FIGURE 1. ABDOMINAL RECURRENCE-FREE SURVIVAL IN ALL PATIENTS

At a median follow-up of 43.1 months, no difference was detected in three-year ARFS (58.7 versus 60.4 percent; HR 1.01; 95 percent CI 0.71–1.44; p = 0.95) (see Figure 1). However, at the time of the current analysis, more local relapses were observed following complete resection in the surgery-alone group (n = 39) compared with the RT plus surgery group (n = 17), but whether these data hold over time remains to be seen.

Fifteen of the 19 patients who progressed or became inoperable based on performance status while undergoing RT were able to undergo complete surgical resection. Therefore, the data safety monitoring board recommended additional sensitivity analyses to exclude these patients. Although excluding patients who underwent complete resection despite progression on RT did not affect the primary outcome (HR 0.78, 95 percent CI 0.53–1.16), a post hoc sensitivity analysis of liposarcoma patients suggested an improvement in three-year ARFS in the RT plus surgery group (75.7 percent) compared with the surgery-alone group (65.2 percent; HR 0.62, 95 percent CI 0.38–1.02) (see Figure 2).

Discussion

The intent of STRASS was to validate the use of RT in the management of retroperitoneal sarcomas. Based on the primary endpoint of ARFS, the STRASS trial was a negative trial. One criticism of the trial is the use of a broad definition of abdominal recurrence as described above. The intent of incorporating the composite endpoint was to account for scenarios that could render patients unresectable following RT, which was a concern at the time of trial design. One argument in support of incorporating RT is that inclusion of these endpoints could undermine the true local control benefit of preoperative RT on final analysis. However, the sensitivity analyses and exclusion of these factors did not change the final results for the entire cohort.

FIGURE 2. SECOND SENSITIVITY ANALYSIS OF ABDOMINAL RECURRENCE-FREESURVIVAL IN THE LIPOSCARCOMA SUBGROUP

Despite failing to demonstrate efficacy based on the primary endpoint, several important observations and limitations were evident. The trial was not specific to tumor grade or histologic subtype; all patients with retroperitoneal sarcomas were included. Since the time of the study design, differences in histiotype-specific outcomes have become increasingly recognized and should help guide future trials.

As liposarcoma was the most prevalent subtype and has a high incidence of local relapse, this cohort was selected for subgroup analysis. This post-hoc analysis suggested that preoperative RT may be beneficial in the management of well-differentiated liposarcomas; however, the endpoint was not predefined, and this subgroup analysis was ultimately underpowered. As a result, these data are hypothesis-generating, and the incorporation of RT into evidence-based clinical practice is evolving.

Nonetheless, the potential benefit of RT for patients with retroperitoneal liposarcomas does suggest that further studies are warranted, as RT may still improve outcomes in this group. Other investigators have proposed that delivering higher doses of RT along high-risk margins, referred to as “dose painting,” may decrease local recurrence rates in patients with retroperitoneal sarcomas.^5,6

The STRASS investigators should be applauded because this research highlights the challenges in the management of patients with retroperitoneal sarcomas. Although negative, the trial underscores the importance of future trials in the management of these rare cancers.

References

1. Chouliaras K, Senehi R, Ethus CG, et al. Role of radiation therapy for retroperitoneal sarcomas: An eight-institution study from the US Sarcoma Collaborative. J Surg Oncol. 2019;120(7):1227-1234.
2. Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol. 1998;16(1):197-203.
3. O’Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: A randomised trial. Lancet. 2002;359(9325):2235-2241.
4. Bonvalot S, Gronchi A, Le Pechoux C, et al. Preoperative radiotherapy plus surgery versus surgery alone for patients with primary retroperitoneal sarcoma (EORTC-62092: STRASS): A multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020;21(10):1366-1377.
5. Baldani EH, Bosch W, Kane JM, et al. Retroperitoneal sarcoma (RPS) high risk gross tumor volume boost (HR GTV boost) contour delineation agreement among NRG sarcoma radiation and surgical oncologists. Ann Surg Oncol. 2015;22(9):2846-2852.
6. DeLaney TF, Chen YL, Bladini EH, et al. Phase 1 trial of preoperative image guided intensity modulated proton radiation therapy with simultaneously integrated boost to the high risk margin for retroperitoneal sarcomas. Adv Radiat Oncol. 2017;2(1):85-93.