|LETTER TO THE EDITOR
|Ahead of print publication
STRASS trial: Preoperative radiotherapy in retroperitoneal sarcoma: A commentary
Sorun Shishak1, Sameer Rastogi2, Kaushal Kalra2, Manasa Parisa2
1 Department of Radiation Oncology, AIIMS, New Delhi, India
2 Department of Medical Oncology, AIIMS, New Delhi, India
|Date of Submission||06-Aug-2019|
|Date of Acceptance||12-Sep-2019|
|Date of Web Publication||13-Oct-2020|
Department of Medical Oncology, AIIMS, New Delhi
Source of Support: None, Conflict of Interest: None
Surgical resection is the standard of care for localized operable retroperitoneal sarcoma (RPS). Unlike extremity soft-tissue sarcoma, the role of preoperative radiotherapy (RT) in RPS has remained largely unanswered. As local recurrence is the major cause of death in most of the RPS cases, there is increasing interest in the role of preoperative RT. The advantages of preoperative RT over postoperative RT are smaller treatment volumes, easier tumor volume delineation, radiobiologically superior normal vasculature/oxygenation, and lesser toxicities to normal organs such as bowel. However, patient recruitment into clinical trials for RPS has historically been limited by the rarity of this disease. The only randomized multicentric trial conducted in the USA (ACOSOG Z9031) which attempted to answer the role of preoperative RT in RPSs was closed due to slow patient accrual.
In 2016, a propensity score-matched analysis of a nationwide clinical database published in the Lancet Oncology by Nussbaum et al. included over 9000 patients. This database study showed that RT was associated with improved overall survival (OS) compared with surgery alone when delivered either preoperatively or in postoperative setting. However, a propensity matched analysis is not a replacement for a properly conducted randomized trial.
This year, A trial looking at radiotherapy and surgery for sarcoma (STRASS), a Phase III randomized study of preoperative RT plus surgery versus surgery alone for patients with RPS, European Organisation for Research and Treatment of Cancer protocol (62092-22092), was presented at the American Society of Clinical Oncology2019. This is the first trial with transatlantic collaboration that randomized 256 RPS patients to preoperative RT followed by surgery versus surgery alone, with the primary end point being abdominal recurrence-free survival (ARFS) which was defined by one of the following events:
- During or after surgery:
- Local relapse after macroscopically complete resection
- Peritoneal sarcomatosis found at laparotomy
- Macroscopic local disease left behind at laparotomy (R2).
- Before surgery:
- Development of distant metastases while on preoperative RT
- Local progression of primary tumor while on preoperative RT
- Becoming American Society of Anesthesiologist score = 3, involvement of superior mesenteric artery or aorta or bone.
In July 2017, the Independent Data Monitoring Committee (IDMC) recommended a sensitivity analysis in which local progression on RT was not regarded as a primary end point event for patients who subsequently achieve a complete surgical resection.
Majority of the patients (75%) had liposarcoma (LPS) (well-differentiated LPS: 33.1%, dedifferentiated LPS [DDLPS]: 39.5%, and other LPS: 1.9%), whereas leiomyosarcoma (LMS) constituted just 14.3% of the patient population. RT dose was 50.4 Gy/28#/5.5 weeks delivered by intensity-modulated radiation therapy in a majority of patients (n = 120, 95%) and three-dimensional conformal RT in 5% (n = 7) of patients. The only Grade 4 RT toxicity was lymphopenia in thirty patients (23%).
After a median follow-up of 43 months, the ARFS in preoperative RT was 60.4% versus 58.7% in surgery arm (P = 0.95). With the IDMC-recommended modification, there was ARFS benefit in the LPS subgroup only. High-grade sarcomas and LMS did not benefit from preoperative RT. There was no significant OS difference in both arms.
The failure of this study could be due to a multitude of reasons. First, RPS cases are an extremely heterogeneous population, with different biologic behavior depending on the histology, subtypes, and grade. In well-differentiated LPS, the local recurrence rate is about 4%–5% per year. Hence, the median follow-up of 43 months as shown in this study might be inadequate for this subgroup to have significant events. Grade 1–2 DDLPS cases have rapid local failures (20% at 2 years and 40% at 5 years) with distant metastasis rate at 5 years <10%, whereas Grade 3 DDLPS and LMS have 50% risk of distant metastasis. The benefit in ARFS in LPS subgroup unlike LMS could be due to the recurrence pattern of LPS which is commonly local versus LMS which recurs at distant sites, as shown in [Table 1].
Another flaw was that grades were not available for one-fourth of the patients, which is unexpected from a randomized controlled trial. Along with this, the statistical proposition to show an absolute increase of 20% in the 5-year ARFS rate seems too optimistic a hypothesis. Simultaneously, as it is a multicentric study, there needs to be centralized assessment of surgery as the expertise in different institutes might lead to different perception of resectable disease.
Despite all its inherent flaws and limitations, it is still a highly laudable effort in terms of transatlantic collaboration in a rare disease such as this. The study has widened our perspective and encourages the pursuance of future trials, with the hope of elucidating the role of preoperative RT in RPS.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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