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Factors associated with disease‐free and abdominal recurrence‐free survival in abdominopelvic and retroperitoneal sarcomas

Abstract Background and Objectives Retroperitoneal and abdominopelvic sarcomas are rare heterogeneous malignancies. The only therapy proven to improve disease‐free survival (DFS) is R0/R1 surgical resection. We sought to analyze whether additional factors such as radiation and systemic therapy were associated with DFS and abdominal recurrence‐free survival (RFS). Methods Retrospective review of adults (≥18) with resectable abdominopelvic and retroperitoneal sarcomas who underwent intent‐to‐cure surgery at a high‐volume tertiary referral center between 1998 and 2015. The main outcome measures were DFS and abdominal RFS. Results Overall, 159 patients met the criteria for inclusion. Median follow‐up was 4.8 years (range 0.1–18.9 years). The most common histology was liposarcoma (49%). Systemic therapy was administered to 48% of patients and was not associated with improved outcomes. The neoadjuvant radiotherapy group (11%) had improved adjusted DFS (5.46 years, 95% CI [3.68, 7.24] vs. 3.1 years, 95% CI [2.48, 3.73]) and abdominal RFS (6.14 years, 95% CI [4.38, 7.89] vs. 3.22 years, 95% CI [2.61, 3.84]). The adjuvant radiotherapy group (19%) had no improvement. Conclusions In a cohort of patients undergoing resection for retroperitoneal or abdominopelvic sarcoma, neoadjuvant radiation improved DFS and abdominal RFS. A follow‐up of over three years was needed to appreciate a difference in outcomes.


| INTRODUCTION
Retroperitoneal and abdominopelvic sarcomas represent a histologically heterogeneous group of tumors that carry a poor prognosis compared to the more prevalent extremity sarcomas. [1][2][3][4][5] To date, surgical excision with R0 or R1 margins remains the best chance for cure, reinforcing the importance of abdominal recurrence-free survival (RFS). [6][7][8][9] Recurrence after treatment is common even after resection with negative margins and is associated with decreased survival. 10 Pathologic margin status is difficult to determine conclusively on large tumors and it is possible that even "marginnegative" resections may leave microscopic tumor behind. Therapies that treat residual disease may, therefore, improve outcomes in recurrence and mortality.
Unfortunately, systemic chemotherapy and radiation therapy have not been shown to conclusively improve abdominal RFS, disease-free survival (DFS), or overall survival in retroperitoneal or abdominopelvic sarcomas; though radiotherapy has shown benefit in extremity sarcoma. 11,12 Additional information about the therapeutic value of radiotherapy in non-extremity sarcoma would be beneficial given the significant associated toxicities, especially in the postoperative setting. Large observational studies show radiotherapy is administered to 25%-45% of retroperitoneal sarcoma patients, with a trend towards increased use of neoadjuvant radiotherapy in recent years. [13][14][15][16][17] While results were mixed, some of these studies found modest improvements in overall survival. [13][14][15]17 Another observational study of the National Cancer Database (NCDB) that focused exclusively on neoadjuvant radiotherapy found an improved negative margin rate but no effect on overall survival as compared to surgical treatment alone. 18 Prospective and randomized controlled trials have been more limited, with the first trial studying neoadjuvant radiation therapy (ACOSOG Z9031) closing prematurely due to low participation. More recently, STRASS (EORTC 62092), an international randomized, controlled trial comparing neoadjuvant radiotherapy and surgery compared to surgery alone, was successfully completed and while the trial failed to demonstrate a survival or RFS benefit with a median follow up of 43.1 months, a subgroup analysis suggests that there may be a benefit in RFS for those with liposarcoma. 19 Data on systemic therapies are even more limited. 20 With the ambiguity of the current data, we sought to assess the use of neoadjuvant and adjuvant therapy for abdominopelvic and retroperitoneal sarcoma at a high-volume sarcoma center and regional referral hospital. Our aims were to investigate the association between tumor characteristics, neoadjuvant and adjuvant systemic and radiation therapies, with the two outcomes of DFS and local recurrence.

| MATERIALS AND METHODS
This is a retrospective cohort of all adults (diagnosed over 18 years old) with resectable abdominopelvic and retroperitoneal sarcomas who underwent surgery with intent-to-cure at a high-volume institution from January 1, 1998 to January 1, 2015. Patients were identified in the institutional cancer registry who had a diagnosis of any sarcoma subtype originating within the abdomen, retroperitoneum, and/or pelvis. Chart review of these patients confirmed the diagnoses. Patients were excluded if there was medical record evidence of unresectability based on tumor board or surgeon note, or metastatic disease at diagnosis. If medical record evidence suggested that sarcoma was resectable before the operation, but it was later found to be unresectable peri-operatively, it was included in the analysis (intent-to-cure). Gastrointestinal stromal tumors, visceral sarcomas, and abdominal wall sarcomas were excluded from this study. This study was approved by the institutional IRB (#HUM00068553).

| Tumor characteristics
Histologic subtype was based on the first surgical resection pathology specimen determined by a soft tissue sarcoma specialized pathologist. If FNCLCC number grading was not available, grade was coded according to the pathologic description as shown in Table 1.
Some patients underwent care, including their first resection, at an outside institution before presenting to our hospital. The study team reviewed all available information and any information not available was determined to be "unknown."

| Outcome measures
To determine overall DFS and local RFS, we calculated the time from surgical resection to recurrence, irrespective of radiation or systemic therapy timing. Abdominal RFS was defined as number of years without recurrence in the retroperitoneum or abdomen. Recurrence in the parenchyma of the liver was considered distant recurrence.

| Statistical analysis
All data were analyzed using Stata version 16

| Study population
One hundred fifty-nine patients met the criteria for inclusion. A summary of patient and tumor characteristics is available in Table 1 and a more detailed description of tumor histology by primary site and therapy type is available in Table A1 and A2, respectively. In this cohort, 77 (48%) were female and the mean ± SD age at diagnosis was 58 ± 14 years; median follow-up was 4.8 years (interquartile range 1.8-7.6 years, range 0.1-18.9 years). The most common histologic types were liposarcoma (n = 78, 49%) and leiomyosarcoma (n = 47, 30%). Liposarcomas were more likely to be low grade compared with leiomyosarcomas (43% vs. 4%, p < 0.001). The majority (87%) of tumors were retroperitoneal. Because our analysis was based on patients undergoing an intent-to-treat surgical resection, four (2.5%) patients were included who underwent curative-intent surgery but were found on inspection of the abdomen to be unresectable. With regard to treatment, more patients underwent systemic therapy (48%) compared to radiation therapy (30%) (  years median follow-up, which is shorter than our median followup of 4.8 years. 19 In addition, the trial did appear to identify some absolute treatment benefit in liposarcomas that was not statistically significant. In our study, the marginal benefit of neoadjuvant radiation was not detectable until after three years of follow-up and was primarily observed in the liposarcoma group. Our study therefore corroborates findings in STRASS (EORTC 62092) suggesting a differential treatment effect by histology, with liposarcomas receiving more therapeutic benefit after neoadjuvant radiation. Unlike STRASS (EORTC 62092) whose preoperative radiotherapy group included 35% well-differentiated liposarcomas, we were not able to perform any comparison by grade because no pure well-differentiated liposarcomas underwent neoadjuvant radiation in our study cohort. Additionally, some concerns with the STRASS trial include a high rate of protocol deviations as well as a very high neoadjuvant radiation toxicity rate, with >75% of patients having a grade ≧ 3 toxicity, which is in contrast to the low toxicity rate (3/17, 18%) in our study as well as other reported studies. 21,22 In addition to our findings on neoadjuvant radiation, our analysis demonstrated findings similar to prior studies in that improved DFS is notable in histologically favorable sarcomas. 5 With regard to trends in treatment utilization, the majority of patients with RP sarcoma at our institution did not receive radiation therapy. However, of the 30% of patients who did receive it, adjuvant radiation was more commonly used than neoadjuvant radiation. Potential reasons for these observations include patient/surgeon preference, symptoms requiring immediate surgery, fear of becoming unresectable during radiation therapy, and lack of supporting data.
Contrary to our hypothesis that adjuvant therapy would be used more often in patients with a positive margin, we did not find any association between margin status and receipt of adjuvant radiation.
Adjuvant radiation decision-making may instead take into account a "close margin," as defined by the operative surgeon but not found in the pathology report. Also, at our institution adjuvant radiation would be considered for a positive margin after resection of a high grade  Table 3 Table 4.