Sarcoma Guidelines

What is the role of radiation therapy in the management of primary retroperitoneal sarcomas?

  • Population – Adult patients with primary retroperitoneal sarcoma
  • Intervention – Surgical resection with neoadjuvant or adjuvant radiation therapy
  • Comparator – Surgical resection alone
  • Outcomes – abdominal recurrence free survival, recurrence free survival perioperative morbidity, overall survival

Authors: Anna Lawless, Deborah Zhou, Joshua McDonough, Helen Lo, Iain Ward, Joanna Connor, Stephen Thompson, David, Gyorki, Angela Hong and ANZSA Sarcoma Guidelines Working Party

Introduction

Retroperitoneal sarcoma (RPS) are rare malignancies that can be difficult to manage given their large size and involvement of critical retroperitoneal structures. While surgery is the mainstay of therapy, the role of radiation therapy (RT) remains controversial. Some centres recommend pre-operative RT if macroscopically complete (R0/R1) resection is not feasible, while others recommend for most patients, in particular those with low grade liposarcoma.

The aim of perioperative RT is to improve the local control. RT for RPS is technically challenging in target delineation and treatment planning due to large tumour size, invasion into critical surrounding retroperitoneal structures, and the difficulty of differentiating tumour from surrounding normal lipomatous tissue.

This clinical question aimed to examine the literature to define the role of RT in management of primary resectable RPS.

Abdominal recurrence free survival

Twenty four studies reported the local or abdominal recurrence endpoint for patients with localised retroperitoneal sarcoma undergoing surgery with or without RT. Most included all histologic subtypes of retroperitoneal sarcoma, but few reported subgroup analyses. Four studies focused specifically on liposarcoma (1-4). The size of the study cohorts ranged from 41 to 1097. Most studies included a mixture of pre-, post- and/or intra-operative RT. Across all trials around one third of patients received RT (median 31%, range 12.4-66%).

One randomised controlled trial (RCT) and 8 retrospective series found no difference in local/abdominal recurrence free survival (ARFS) with the addition of RT to surgery (1, 2, 5-10). 15 retrospective series found increased ARFS with addition of RT (3, 4, 11-21).

The phase 3 EORTC-STBSG-62092 (STRASS) trial (n=266) was the only randomised controlled trial reporting local/abdominal recurrence (5). This trial’s primary endpoint was a composite endpoint ARFS, defined as local (abdominal) or distant progressive disease during preoperative RT, tumour or patient becoming inoperable (defined as ASA score of 3 and higher, or involvement of the superior mesentery artery, aorta or bone), peritoneal metastasis found at surgery, macroscopic residual disease left in at surgery, or local relapse (after macroscopically complete resection). There was no difference in ARFS with the addition of pre-operative RT (50 Gy in 25 fractions) to surgery (4.5 years with preop RT compared to 5 years with surgery alone, HR 1.01, 95% CI 0.71-0.44, p=0.95). The 2nd sensitivity analysis of the STRASS trial modified the ARFS endpoint to exclude abdominal recurrence events if patients proceeded to macroscopic complete resection (mCR) despite tumour progression during RT or becoming medically unfit. By this definition of ARFS (which may be more clinically meaningful given the importance of mCR), addition of RT was not associated with difference in ARFS. However, in the post-hoc, exploratory analysis of the 198 patients with liposarcoma, pre-operative RT was associated with a 10% improvement in 3-year ARFS (3y ARFS 65.2% vs 75.7%, HR 0.62, 95% CI 0.38-1.02). Additional subgroup analyses suggested trend to improved ARFS for low grade tumours (HR 0.73, 95% CI 0.33-1.46) and well differentiated liposarcoma (HR 0.69, 95% CI 0.33-1.46). This trial was not powered to detect differences by histologic subtype or tumour grade. A subsequent analysis of the RT quality of the STRASS participants by Haas et al. found non-compliant RT plans in 29% of patients (22). Older age, dedifferentiated liposarcoma, tumours located on the right side, and in the iliac fossa were more likely to have non-compliant RT plans.  A non-compliant RT plan was associated with a higher local relapse rate (14.6% vs 5.6%), with worse 3-year ARFS (HR 2.32, 95% CI 1.25-4.32, p=0.008).

The STREXIT study retrospectively analysed a cohort of patients meeting inclusion criteria for the STRASS trial but treated off trial over the same period (13). Using propensity score matching (with age, sex, tumour size, tumour grade, multifocality, and histology as covariates) they also analysed a combined cohort of STRASS (n=266) and STREXIT (n=202) patients. Abdominal recurrence was defined as macroscopically incomplete resection or local recurrence without concomitant distant relapse (the same as the 2nd sensitivity analysis of STRASS). Pre-operative RT was associated with improved ARFS for all histological types in both STREXIT (HR 0.63, 95% CI 0.41-0.99) and the pooled cohort (HR 0.75, 95% CI 0.56-1.01). Subgroup analysis of well differentiated liposarcoma (WDLPS) and grades 2 dedifferentiated liposarcoma (DDLPS) (n=266) showed improved ARFS with addition of RT (HR 0.63, 95% CI 0.40-0.97). The 5-year ARFS was 65.8% (54.7-74.8%) in preoperative RT with surgery group and 56.0% (95% CI 44.1-66.4) in the surgery alone group. In the subgroup of patients with G3 DDLPS (n=29) and LMS (n=65) RT was not associated with improvement in ARFS (HR 0.68 (95% CI 0.22-2.16) for G3 DDLPS, HR 0.99 (95% CI 0.47-2.11) for LMS.

Although the only RCT reporting ARFS was not powered to detect differences by histologic subtype, combining the data from STRASS and STREXIT suggests pre-operative RT may decrease rates of local/abdominal recurrence for patients with well-differentiated or grades 1-2 dedifferentiated liposarcoma.

Of the 14 retrospective studies (excluding STREXIT) in this systematic review that found increased ARFS with the addition of RT to surgery, 12 used multivariate analysis, but the majority did not report subgroup differences for effect of RT by histologic type. Of those that reported subgroup differences, Bredbeck et al. (2022) found pre-operative but not post-operative RT was associated with improved ARFS in all comers, and on subgroup analysis this benefit was seen for liposarcoma, but not leiomyosarcoma (12). Toulmonde et al. (2014) demonstrated decreased locoregional recurrence with peri-operative RT for de-differentiated LPS, but not well-differentiated LPS, or for LMS (21). Four of 23 studies focused specifically on LPS. These all used multivariate analysis and found no difference in local recurrence rates at 3 years(2), 5 years (3, 4) or 8 years (1) with the addition of RT.

Haas et al. reported on 607 patients with liposarcoma (WDLPS and grades 1-3 DDLPS) who underwent surgical resection with or without RT at eight high volume sarcoma centres across the US, UK and Europe between 2002 and 2011 (1). They found no difference in 8 year local recurrence rates after inverse probability of treatment weighting to account for biases in non-random RT assignment (HR 0.54 95% CI 0.06-4.8, p=0.579 for surgery + RT vs surgery alone for WDLPS; HR 0.70, 95% CI 0.36-1.39, p=0.312 for G1-2 DDLPS; HR 0.34, 95% CI 0.07-1.58, p=0.170 for G3 DDLPS).

Choularis et al. reported on 425 patients from eight sarcoma centres in the US treated with surgery with or without RT for localised RPS between 2000 and 2016 (6). After propensity score matching there was no difference in local recurrence with neoadjuvant RT (local recurrence interval 59 months RT and surgery vs 35.1 months surgery, p=0.35) or adjuvant RT (local recurrence interval 71.1 months surgery vs 94.5 months surgery and RT, p=0.27). Similarly, in the multivariate analysis there was no difference in local recurrence with preoperative RT (HR 1.18, p=0.7) or postoperative RT (HR 0.47, p=0.07).

Recurrence free survival

One randomised controlled trial and 26 retrospective cohort studies reported on the recurrence free survival (RFS) endpoint. Most studies included all histologic subtypes of retroperitoneal sarcoma. Three studies reported specifically on liposarcoma (1-3). The number of study participants ranged from 34 to 1942. Most studies included a mixture of pre-, post- and/or intra-operative RT. Across all studies around one third of patients received RT (median 36%, range 12-66%).

The STRASS randomised trial and 11 of the 27 retrospective series reported specifically on distant recurrence (1, 3, 5, 9, 14, 19, 21, 23). STRASS found no difference in three-year metastasis free survival (MFS) with the addition of RT to surgery for all histologies (3y MFS 68.3% surgery and 68.3% RT, HR 0.89, 95% CI 0.58-1.36, p=0·59)(5). There was no difference in (underpowered) post-hoc analysis of patients with liposarcoma (3y MFS 78.3% surgery and 76.5% RT, HR 1.02, 95% CI 0.57-1.80). The STREXIT study similarly found no difference in distant metastatic free survival (DMFS) in the pooled STRASS and STREXIT cohort, overall (HR 0.82, 95% CI 0.73-1.38), nor in subgroup analyses of histologic types (LPS, WDLPS + G1-2 DDLPS, and LMS)(13). Of the remaining retrospective series (apart from STREXIT), eight of 10 found no difference in DMFS (1, 3, 6, 7, 9, 10, 14, 21). Eight studies used multivariate analysis and one used propensity score matching.

A retrospective series from the Transatlantic Retroperitoneal Sarcoma Working Group (TARPSWG) found no difference in rate of distant metastases with addition of RT to surgery after inverse probability of treatment weighting (1). This result was consistent on subgroup analysis of grade 1-2 dedifferentiated liposarcoma (8 year distant metastasis 9.6% with preop RT vs 8.1% with surgery alone, HR 1.04, 95% CI 0.15-7.35, p=0.966), G3 dedifferentiated liposarcoma (8 year distant metastases 35.1% vs 30.6%, HR 1.30, 95% CI 0.25-6.67, p=0.750). The liposarcoma subgroup was too small to analyse. Choularis et al. reported results from eight institutions of the US Sarcoma Collaborative and found no difference in RFS with use of neoadjuvant RT (HR 0.98, p=0.95) or adjuvant RT (HR = 0.7, p=0.15)(6).

The majority (11 of 16) of retrospective series reporting combined RFS (local and distant) found no difference with addition of RT to surgery for localised RPS (2, 8, 11, 24-31). 11 of 16 studies utilised multivariate analysis. Le Pechoux et al. found an association between RT and increased 5-year recurrence free survival (local and distant), but no difference for specifically distant metastases (10). Bredbeck et al. found that after adjusting for tumour grade and margin status, neoadjuvant RT improved disease-free survival for all histologic subtypes (5.46 vs 3.1 years, p=0.015), but adjuvant RT did not. On subgroup analysis by histologic subtype, neoadjuvant RT was associated with improved DFS for liposarcoma (8.86 vs 3.11 years, 95% CI 6.45-11.28, p<0.001), but not leiomyosarcoma (p=0.715). However, this study did not account for other potential confounding factors including tumour size, location, surgical margins, or patient characteristics.

Perioperative morbidity endpoint

Thirteen studies (one randomised trial and 12 retrospective series) reported on perioperative morbidity. Three of 14 studies focused specifically on liposarcoma (3, 27, 32). The number of patients ranged from institutional series of less than 100 patients (3, 4, 8, 31), to large US National Cancer Database studies with over 11 000 patients (33). Most studies utilised a mixture of pre-, post-, and intra-operative RT. Across the trials reporting on RT utilisation, less than one quarter of patients received RT (median 13%, range 6-50%). The studies reported a variety of endpoints regarding peri-operative morbidity, including operative duration, transfusion requirement, infection, hospital length of stay, and rates of re-operation and unplanned hospital readmission.

In the STRASS trial, receipt of neoadjuvant RT was associated with a higher rate of serious adverse events (24% vs 10%), most commonly grades 3-4 lymphopenia (77% vs 1%), anaemia (12% vs 8%), and hypoalbuminaemia (12% vs 4%)(5). The single treatment related death in the study was due to gastropleural fistula, in a patient who received RT. RT was associated with longer duration of surgery (300 vs 288 minutes) and intra-operative transfusion (29% vs 19%). However, rates of post-operative death (2% vs 2%) and re-operation (11% vs 12%) were similar between groups.

Ten retrospective studies found no association between receipt of RT and perioperative morbidity. Outcomes reported included 30 day morbidity (34), 30 and 90 day mortality (32-36), in hospital complication rate (6, 8, 35), length of stay (36, 37), major complication rate(35), re-operation rate (6), and readmission rate (6, 32, 33, 36, 38). 2 of 10 studies performed multivariate analysis with regard to perioperative morbidity outcome (34, 39). Bartlett et al. found body weight (overweight, obesity or underweight), prolonged operative time, clean-contaminated wound classification and increased blood transfusion requirement intra-operatively were all associated with increased 30-day morbidity and mortality, but RT was not (OR 0.5, 95% CI 0.2-1.4)(34). Tirotta et al. reported that comprehensive complication index, tumour size and organ weighted resection scores, were all associated with longer length of hospital stay, but RT was not (39).

Two retrospective studies found worse peri-operative morbidity with addition of RT (15, 40). Kelly et al. reported higher rate of complications within 30 days (41% vs 17%) for patients who received RT (94% had preoperative RT), but the same length of stay (7 days), and no operative or peri-operative deaths in either group (15). Multivariate analysis was not performed, and patients who received RT were more likely to have pelvic tumours. Leiting et al. reported statistically significant, but possibly not clinically significant increased unplanned readmission rate within 30 days (6.1% vs 5%) (40). Multivariate analysis was not performed, and RT was associated with younger age, treatment at non-academic facilities, use of chemotherapy, smaller and higher-grade tumours, leiomyosarcoma histology, and involved surgical margins.

Overall survival endpoint

Fifty seven studies reported survival outcomes for patients with localised RPS. Overall survival (OS) was reported in one randomised controlled trial and 47 retrospective studies. Disease specific survival (DSS) was reported in 12 retrospective studies. Three studies reported on both OS and DSS (41-43). Most studies were from the USA, or large multinational studies across the US, UK, and Europe. There was one Australian study (18). 9 studies utilised the US National Cancer Database (32, 33, 36, 38, 40, 44-47) and 8 studies utilised Surveillance, Epidemiology and End Results (SEER) database (41-43, 48-52). The number of patients ranged from small institutional series (n=27) to large database studies (n=11 324). Most studies reported a mixture of RT timing, including pre-, post-, and intra-operative RT. Across the trials reporting on RT utilisation, around one third of patients received RT (median 31%, range 6-73%).

The STRASS trial reported no difference in 5-year OS with the addition of neoadjuvant radiotherapy to surgery for localised RPS (80% vs 77%, HR 1.16, p=0.62)(5). Similarly, the STREXIT retrospective study which pooled the STRASS and STREXIT (off trial) cohorts found no difference in OS overall, nor in any histologic subgroups (13). Haas et al. demonstrated a trend towards worse OS in patients treated on the STRASS trial with non-compliant RT plans compared to those with RT-compliant plans (HR 2.42, 95% CI 0.84-6.95, p=0.100)(22).

Of the 47 retrospective studies reporting OS, 15 found improved OS (23, 32, 38, 40, 42, 44-48, 51-56) and 33 found no difference in OS (1, 2, 6, 8-11, 13, 14, 18-21, 24-26, 29, 30, 33, 36, 37, 41, 43, 50, 57-64) with the addition of RT to surgery for localised RPS. 37 studies performed multivariate analysis, four studies propensity score matching (13, 41, 46, 61), one performed inverse probability of treatment weighting(1), and 6 did not perform multivariate analysis (2, 14, 30, 58-60). Of the 12 studies reporting DSS, three found improved DSS (42, 49, 53) and nine found no difference in DSS (3, 4, 7, 15, 17, 27, 28, 41, 43) with addition of RT to surgery for localised RPS. Ten of 12 studies performed multivariate analysis and one performed propensity score matching.

Nussbaum et al. published two series utilising the NCDB, with very large patient numbers(33, 46). The first study with 11 324 patients treated for localised RPS between 1998-2011 found no difference in OS with the use of neoadjuvant RT either before or after propensity matching (5y OS 53.2% preop RT vs 54.2% surgery alone, p=0.695 after propensity matching). Exploratory analysis suggested improved survival in patients with higher grade tumours (5y OS 49.1% vs 46.2%, p=0.022)(33). The 2nd study with 9068 patients treated between 2003-2011 and excluding patients who had intra-operative RT or both pre- and post-operative RT, showed improved overall survival with pre-operative RT (median OS 110 months RT vs 66 months no RT, HR 0.70, p<0.0001) and post-operative RT (median OS 89 months vs 64 months, HR 0.78, p<0.0001). Post-hoc analysis showed the benefit of RT was not dependent on margin status (46).

Erstad et al. reported on patients in the US National Cancer Database with primary RPS treated with resection with or without RT (n=3911) between 2004 and 2017 (36). After propensity-matching adjusted analysis (n=208 WDLPS, n=290 DDLPS), there was no association between receipt of RT and OS for WDLPS (HR 1.01, p=0.052) or DDLPS (HR 1.02, p=0.889).

Haas et al. study of TARPSWG participants with liposarcoma utilised inverse probability of treatment weighting to account for biases due to non-random RT assignment. This study found no difference in OS by receipt of RT overall, nor in histologic subgroups (well-differentiated, grade 1-2 dedifferentiated, and grade 3 dedifferentiated liposarcoma)(1).

Evidence summary

Level of

evidence

References

The rate of local/abdominal recurrence after surgery may be reduced with the addition of pre-operative radiation therapy in patients with well-differentiated and grade 2 dedifferentiated liposarcoma based on preoperative biopsy and imaging. There is no benefit for radiation therapy in patients with grade 3 dedifferentiated liposarcoma, leiomyosarcoma or other histologic subtypes.

II, III

1-21, 23, 56, 57

There is no evidence to support improved recurrence free survival with the addition of radiation therapy to surgery for localised retroperitoneal sarcoma.

II, III

1-3, 5-14, 19, 21, 23-31, 53, 65, 66

Overall survival is not greater with the addition of radiation therapy to surgery for retroperitoneal sarcoma.

II, III

1, 2, 5, 6, 8, 9, 10, 11, 13, 14, 16, 18, 19, 20, 21, 23-26, 29, 30, 32, 33, 36, 37, 38, 40, 41, 43, 44-48, 50, 51, 52, 54-64

The rate of peri-operative complications may be increased with the use of preoperative radiation therapy.

 

II, III

3, 5, 6, 8, 15, 32-36, 38, 39, 40

Evidence-based recommendations

Grade of recommendation

Patients with localised well-differentiated and grade 1-2 dedifferentiated liposarcoma could be considered for pre-operative radiation therapy to improve local/abdominal recurrence free survival. Radiation therapy should not be recommended for other histologic subtypes.

C

Patients with localised retroperitoneal sarcoma should not routinely be recommended radiation therapy with the aim to improve recurrence free survival.

B

Patients with localised retroperitoneal sarcoma should not routinely be recommended radiation therapy with the aim to improve overall survival.

B

Patients with retroperitoneal sarcoma undergoing pre-operative radiation therapy should be informed of the increased risk of serious adverse events in the peri-operative period.

B

Practice Points

Patients with retroperitoneal sarcoma should be referred to specialist sarcoma centre for management.

The rationale and level of evidence for pre-operative radiation therapy for localised liposarcoma should be carefully discussed by the multidisciplinary sarcoma team with the patients.

Administration Report

Techncial Report

References

► Topic 2: Retroperitoneal Sarcoma