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What is the role of chemotherapy in primary retroperitoneal sarcoma?
- Population: Adult patients with primary retroperitoneal sarcomas
- Intervention: Surgical resection with neoadjuvant or adjuvant chemotherapy
- Comparator: Surgical resection without chemotherapy
- Outcomes: Recurrence free survival, overall survival, post-operative complication
Authors: Deborah Di-Xin Zhou, Elizabeth A Connolly, Peter S Grimison, Joanna Connor, David Gyorki, Angela Hong and ANZSA Sarcoma Guidelines Working Party
Current standard of care for patients presenting with localised retroperitoneal sarcoma (RPS) remains surgery alone, despite the high risk of relapse and mortality. The overall survival for these patients is poor, ranging from 39-70% at 5 years and 20-64% at 10 years (1-3). The role of adjuvant systemic therapy for RPS has been extrapolated from trials in extremity sarcoma, where adjuvant chemotherapy with anthracyclines and ifosfamide may increase cure rates. This clinical question addresses the impact of chemotherapy on survival outcomes and postoperative complication in patients with primary localised RPS.
Literature search identified 22 retrospective studies and one meta-analysis. No prospective or randomised studies were identified, nor any publications from Australia or New Zealand.
Of the 22 retrospective studies (4-25), five were retrospective cohort studies (10, 17-20) of which three included propensity matched cohorts (10, 17, 18), and study sample size varied significantly (range: 25-8653). The meta-analysis included six studies on the role of adjuvant chemotherapy for retroperitoneal sarcomas (26). Five studies utilised the United States National Cancer Database (NCDB) (10, 16, 17, 24) which captures >70% of all cancers reported in the United States. The NCDB captures the overall survival but not local recurrence or toxicity. Three studies presented data from the US Sarcoma Collaborative (USSC) database which captures data from eight tertiary institutions (8, 9, 22) and there may have some overlap with studies using the NCBD database. There were nine single centre studies (5, 6, 11-13, 15, 18, 21, 25) and two international series (7, 14).
The evidence presented must be considered carefully on account that most studies did not specifically examine the role of chemotherapy nor provide comprehensive details of chemotherapy used. Prognostic factors associated with outcomes were predominantly examined rather than the role of chemotherapy specifically. In most studies, patient selection was not well defined, baseline characteristics between the chemotherapy and non-chemotherapy groups were not described, and chemotherapy had been utilised only in a minority of all patients included. There is a high likelihood of selection bias which is supported by Bredback, Bremjit, Datta, Miura, Perez and Stahl et al. who demonstrated systemic therapy was administered in tumours of higher grade (5, 6, 10, 19), younger patients (5), with R1 resection (24) or macroscopic disease (19) and in ‘chemotherapy sensitive’ (19) or specific histologies. Only four studies (10, 14, 20, 22) discussed the impact of the chemotherapy on outcomes according to histology.
Recurrence free survival
Eleven studies reported recurrence free survival endpoints as local recurrence, metastasis free survival or disease free survival. Association of chemotherapy with improved recurrence free survival was not reported in any study.
Local recurrence
Six retrospective studies reported on the impact of chemotherapy on local recurrence (8, 12-14, 22, 25). Four studies demonstrated that the addition of chemotherapy was not associated with an improvement in local recurrence rates on multivariate analysis (8, 12-14). Chouliaris et al. (2019) multicentre study based on the USSC database specifically reported that neoadjuvant (HR 1.09, p=0.88) and adjuvant (HR 0.92, p=0.85) chemotherapy was not associated with improved local recurrence (8).
Schwartz et al. (2019) multi-centre case series from the United States Sarcoma Collaboration
database reported no difference in local recurrence in those who received neoadjuvant (n=89, 15.6% of cohort, p=0.35) or adjuvant chemotherapy (n=93, 16.3% of cohort, p=0.20) in univariate analysis (22). Zhuang et al. (2022) single centre Chinese case series, of 169 patients where 17 patients (10.1%) received chemotherapy, showed that chemotherapy was not associated with local recurrence on univariate analysis (HR 1.025, 95% CI 0.998-1.052, p=0.075) (25).
Metastases free survival
Three retrospective case series (12-14) reported on the impact of chemotherapy for retroperitoneal sarcomas on metastases free survival. In all studies, on multivariate analyses, the addition of chemotherapy to surgery was not associated with improved metastases free survival compared to surgery alone. The largest cohort was from Italy (13) with 331 patients included 288 patients report in their earlier publication (12). In the multivariate analysis, the addition of adjuvant chemotherapy did not improve the metastatic free survival (HR 0.66, 95% CI 0.36-1.2, p=0.169)
Disease free survival
Eight retrospective studies reported on the impact of chemotherapy in retroperitoneal sarcomas on disease free survival and none showed a benefit with the addition of chemotherapy (4-6, 8, 9, 11, 12, 22).
Four case series reported that the addition of neoadjuvant or adjuvant chemotherapy to surgery was not associated with improved disease free survival compared to surgery alone in multivariate analyses (6, 8, 12, 22). This was consistent in subgroup analyses with dedifferentiated liposarcoma and leiomyosarcoma (22). Furthermore, there was no difference in recurrence patterns (locoregional vs distance recurrence vs both) with the use of neoadjuvant (p=0.16) or adjuvant (p=0.64) chemotherapy on univariate analysis (22).
Two studies showed that chemotherapy was not associated with recurrence free survival in univariate analysis (4, 11) although in one Turkish study by Akagündüz et al. (2021), a numerical increase in median recurrence free survival was recorded with chemotherapy, or chemotherapy and radiotherapy, compared to surgery alone (35 and 50 months respectively vs 17 months, p=0.215) (4).
Bredbeck et al. (2022) single centre case series of 159 patients, where 48% received chemotherapy, stated “systemic therapy was not associated with improved disease free survival or abdominal recurrence free survival including the adjuvant and neoadjuvant subgroups and after adjusting for grade and resection margin” (5). The statistics supporting this statement, however, were not reported. Of note, in this study chemotherapy was more commonly utilised in younger patients (regression coefficient −0.048, p<0.001) and for higher grade tumours (64% of grade 2 and 3 vs. 0% of grade 1, p<0.001) (5). One retrospective case series described that of 31 patients who received neoadjuvant chemotherapy 74% (22/31) developed recurrence (9). Univariate analysis however was not performed.
Overall survival
Twenty retrospective studies reported the impact of chemotherapy for RPS on overall survival (4, 6-17, 19-25). Ten studies included over 100 patients who received chemotherapy and 14 studies included a minimum of 50 patients. No study showed evidence for the addition of chemotherapy in improving overall survival though notably 3 large retrospective cohort studies with propensity score matched analysis showed association of chemotherapy with inferior overall survival.
The three large retrospective cohort studies using the US National Cancer Database performed propensity score matched analyses with all demonstrating statistically significant worse overall survival with the addition of chemotherapy (10, 17, 19). Datta et al. (2017) identified 3892 sarcomas between 2004-2013 of whom 390 (10%) received chemotherapy (10). Propensity-score matched analysis of 767 patients showed that adjuvant chemotherapy was significant associated with worse overall survival (HR 1.3, 95% CI 1.05-1.61, p=0.017, median overall survival 47.8 vs 68.9 months) (10). Subgroup analyses demonstrated significantly worse survival with adjuvant chemotherapy in patients with well to moderately differentiated tumours, adjacent organ invasion and margin positive resection. There was no survival improvement with chemotherapy in females, males, non-Caucasians, any Charlson co-morbidity score, all tumour size and high-grade tumours. There was non-significant association with improved overall survival with spindle cell, giant cell and synovial sarcomas, but no improvement with other histologies. The second NCDB study of 8652 patients between 1998 and 2011 , where 1525 (18%) received chemotherapy (11% neoadjuvant, 32% adjuvant, 1% both, 56% unknown sequence), showed an inferior median overall survival with the addition of chemotherapy (40 vs 68.2 months with surgery alone, p<0.001) (19). Worse median overall survival with chemotherapy persisted in propensity matched analysis (40 vs 52.4 months with surgery alone, p 0.002, n=1525 in each group) (19). Chemotherapy was associated with worse overall survival in patients with tumour size equal to or greater than 10cm, but no association with survival for moderate to high grade tumours, or R1 and R2 resection (19). Patients with moderate and high-grade tumours, macroscopic disease, leiomyosarcoma and undifferentiated pleomorphic sarcoma histologies (compared to liposarcoma) were more likely to receive chemotherapy (19). The most recent study using the NCBD analysed the outcomes of 6814 patients between diagnosed between 2005-2015 (17). Only 193 patients (3%) received chemotherapy, and 186 patients were included in the propensity matched analysis (17). There was statistically significant worse overall survival with the addition of preoperative chemotherapy compared to surgery alone in both the unmatched and matched analysis (HR 1.55, 95% CI 1.27-1.88, p<0.01 and HR 1.44, 95% CI 1.07-1.94, p=0.02). The addition of preoperative chemotherapy was associated with lower overall survival in multivariate analysis (HR 0.88, 95% CI 0.77-0.99, p=0.03) (17).
Four other studies also demonstrated inferior survival with the addition of chemotherapy to surgery compared to surgery alone (7, 20, 22, 25) with worse overall survival demonstrated in multivariate analysis in three studies (7, 22, 25). Specifically, a large international series of 1942 patients from 10 sarcoma centres by demonstrated an inferior disease specific survival for chemotherapy on multivariate analyses (HR 1.33, 95% CIF 1.26-1.66, p=0.011) (7). The study by Perez et al. (2007) reported worse median survival in the chemotherapy group compared to surgery alone (53 vs 86 months in 38 and 84 patients respectively) (20).
Seven studies did not find any impact of chemotherapy on overall survival in multivariate analyses (8, 11-14, 16, 24), with one study examining the effect of both neoadjuvant and adjuvant chemotherapy (8), and five studies did not demonstrate a statistically significant survival advantage in univariate analysis (4, 6, 15, 21, 23). In the meta-analysis, where 6 studies were analysed, no significant difference in overall survival in the adjuvant chemotherapy group vs surgery alone group was found (HR 1.11, 95% CI 0.95-1.29, p=0.19) (26). The Singer et al. (1995) dual centre series , which included 83 retroperitoneal sarcomas, reported no survival advantage of neoadjuvant (HR1.52, p=0.48) or adjuvant chemotherapy (HR 1.09, p=0.01) and 12-year survival rates were reduced in those who received chemotherapy (surgery alone 76%, surgery with neoadjuvant chemotherapy or adjuvant chemotherapy; 40% and 38% respectively) (23) . In the study by Bremjit et al. (2014, the chemotherapy group had higher proportion of grade 3 tumours (57.7% vs 27.2%) whilst there were no major numerical differences in tumour histology and size (6) .
Klooster et al. (2016) study showed disparate results (16). Of 395 patients in whom 122 (30.9%) received chemotherapy, a significant association of chemotherapy with improved short term (<3 years) survival (HR 0.69, 95% CI 0.5-0.95, p=0.024) was seen however an adverse association with long term (>5 years) survival (HR 2.15, 95% CI 1.21-3.18, p=0.009) and no association with overall survival (HR 1.09, 95% CI 0.83-1.45, p=0.51) (16).
The impact of the chemotherapy on overall survival, in individual histological subtypes, also varied. Perez et al. (2007) described poorer survival in leiomyosarcoma (p=0.014), a trend towards to poorer survival with liposarcoma (p=0.075) though a trend towards improved survival in fibrosarcoma (p=0.091) on univariate analysis for combined truncal and retroperitoneal sarcomas (20). Schwartz et al. (2019) did not report any differences in overall survival in patients with dedifferentiated liposarcoma with neoadjuvant (p=0.10) or adjuvant (p=1.00) chemotherapy, however neoadjuvant chemotherapy was associated with increased overall survival in leiomyosarcoma on univariate analysis (p=0.04) (22). Datta et al (2017) assessed for the association of survival with chemotherapy in multiple histological subtypes but found no statistically significant associations (10). A retrospective case series of 1007 patients, of whom 183 (18%) received chemotherapy, demonstrated that receipt of chemotherapy varied significant in patients with leiomyosarcoma (p<0.0001) and concluded that the discrepancies in adjuvant systemic therapies did not impact on overall survival in these patients however the statistics were not reported (14).
Postoperative complication
The literature search identified only one retrospective single centre study reporting the impact of neoadjuvant chemotherapy on post-operative complications in 309 patients with soft tissue sarcomas including both extremity and primary retroperitoneal/visceral sarcoma (18). Of the 108 patients with retroperitoneal sarcomas, 34 (31%) received neoadjuvant chemotherapy. Univariate analysis of retroperitoneal sarcoma, and multivariate analysis of all sarcoma patients, both showed there no differences between neoadjuvant chemotherapy followed by surgery compared to surgery alone in the rate of surgical complications, readmissions, reoperations, and hospital stay greater than 7 days. In all sarcomas who received neoadjuvant chemotherapy (n=105 extremity and retroperitoneal/visceral), the complication rate was 20% (one of five patients), 13% (one of eight patients), 42% (eight of 19 patients) and 35% (23 of 66 patients) when the interval between the end of chemotherapy and surgery was within 6 days, 7 to 13 days, 14 to 30 days, and greater than 30 days respectively.
In summary, there is currently no evidence to support the benefit of neoadjuvant or adjuvant chemotherapy in improving local recurrence, disease free survival, or overall survival. There is some evidence, including three large propensity matched retrospective cohort studies, of an association of chemotherapy with worse overall survival. A single retrospective study did not show any evidence of neoadjuvant chemotherapy impacting post-operative complications. Evidence of the benefit of chemotherapy in individual histological subtypes is limited. It must be considered, however, that all evidence is retrospective in nature with a high likelihood of selection bias, and inclusion of only small numbers receiving chemotherapy in many series.
Evidence summary |
Level |
References |
|
The addition of chemotherapy to surgery was not associated with improvement in local recurrence rates, metastases free or disease free survival in primary localised retroperitoneal sarcomas. |
III-2 |
(4-6, 8, 9, 11-14, 22, 25) |
|
There is no evidence for the addition of chemotherapy to surgery in improving overall survival in primary localised retroperitoneal sarcomas. There is some evidence of an association of chemotherapy with worse overall survival. |
III-2 |
(4, 6-17, 19-25) |
|
Neoadjuvant chemotherapy followed by surgery was not associated with increased post-operative complications compared to surgery alone in primary localised retroperitoneal sarcomas. |
III-2 |
(18) |
Evidence Recommendations |
Grade of Recommendation |
|
|
The use of perioperative chemotherapy in primary localised retroperitoneal sarcoma is not the current standard of care. |
C |
|
Practice point |
||
|
Patients with primary localised retroperitoneal sarcoma should be managed by a specialised sarcoma centre. Patients may be considered for perioperative chemotherapy in a clinical trial setting. |
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