Perioperative radiotherapy versus surgery alone for retroperitoneal sarcomas: a systematic review and meta-analysis

Retroperitoneal soft tissue sarcomas (RPS) constitute a rare and quite heterogeneous group of mesenchymal neoplasms that are located in the retroperitoneum and count for less than 10–15% of all soft tissue sarcomas (STSs).1 With an incidence of approximately 0,5–1 case per 100000, these tumors are most often considered sporadic especially in the absence of a genetic syndrome (Li-Fraumeni syndrome, Gardner’s syndrome, familial adenomatous polyposis [FAP], Carney-Stratakis syndrome, Hereditary retinoblastoma, etc.).2 Histological subtypes are the well-differentiated liposarcoma (WDLPS), leiomyosarcoma dedifferentiated liposarcoma (DDLPS), undifferentiated pleomorphic sarcoma, solitary fibrous tumors, malignant peripheral nerve sheath tumors and synovial sarcoma.3

Until now surgery with curative intent (R0 resection) remains the gold standard treatment for most patients with resectable disease contributing to long-term disease-free survival (DFS).4,5 However, complete macroscopic surgical resection is achieved in about 70% of the patients reflecting the high incidence of local recurrence and disease progression.6,7 Thus, multimodality treatment involving RT and/or chemotherapy could favor the ability to obtain negative surgical margins with a subsequently better local control of the disease and longer survival.

Radiotherapy to the retroperitoneum is a quite complex procedure and can be administered pre-operatively, postoperatively, intraoperatively or even in a combined therapy setting. In the era of newer RT techniques as 3D-CRT and IMRT, the surrounding normal tissues can be protected and acute radiation induced adverse events can be reduced.5

While current literature is not clear on whether RT, either preoperatively or postoperatively, reflects on a beneficial result in patients with RPS, we aim to investigate if the combination of perioperative RT and surgical resection benefits the overall survival (OS) and the local control of the disease.

Notwithstanding all the accumulated experience and knowledge regarding the diagnosis and treatment of patients with RPS through the past years, still, those patients’ management remains challenging. Current literature evidence is quite insufficient on treatment strategies based mainly on retrospective single-center series, covering small patients’ numbers, and treated with various combinations of surgical approaches, with or without adjuvant treatment modalities.

Surgical resection is adequate only when R0 excision of the RPS is feasible. However, due to its late presentation and its tendency to grow in close proximity with vital abdominal structures, in many cases, multivisceral excisions are needed to achieve a good oncologic outcome making it quite difficult to avoid either macroscopic or microscopic residual disease. RPS is often diagnosed in advanced stage, as it is often asymptomatic, and it makes complete excision difficult. Even after aggressive surgical treatment, the median survival of affected patients is 74 months and 5-year all survival rate is 36-58% with recurrence rates often >50%1,2,4 dictating the need of better local control of the disease.

On this basis, RT could be a logical addition to the patient’s management. Only a few studies have tested in a prospective manner the efficacy of RT in patients with RPS either on a neoadjuvant or adjuvant setting. Pierie et al., studied prospectively 103 consecutive patients who were treated for primary RPS and concluded that the most important factor influencing OS and recurrence rate was the complete resection of the disease, and only in patients at high risk of recurrence (i.e. high-grade tumors, positive microscopic margins) the addition of RT (IORT plus EBRT) can improve OS and local control of the disease with acceptable level of complications.15

Stucky et al., after reviewing 63 consecutive RPS patients concluded that the combination of preoperative radiation plus surgical resection and intra-operative radiation results in excellent local disease control for RPS but not respectively improves overall survival.17 Moreover, postoperative RT improves the local control of the disease in combination with conservative surgery in patients with negative, marginal or minimally microscopically positive surgical margins. Stoeckle et al. stated that adjuvant RT represents the most important prognostic factor for local control of the disease since it is associated with significantly reduced local recurrence rates.7 High-grade tumors and margin positivity status are at higher risk for local failure and can be considered for intensification of therapy.15 The combination of surgery, Intraoperative RT (IORT) plus External Beam RT (EBRT) yields favorable local control and survival data.27 On the contrary, Pirayeshand et al., re-emphasized the poor outcome of patients with RPS and failed to find any connection between adjuvant RT or chemotherapy and a better outcome either on survival or local control of the disease.21

In our metanalysis, it was found that RT delivered either preoperatively or postoperatively, is associated with better median overall and median 5-year survival. In concordance with the results of other retrospective studies, perioperative RT also favors recurrence-free survival compared to surgery alone.12,13,16 Interestingly, RT did not affect the R0 resection rates as previously reported in the literature.12 Thus, patients with RPS should be assessed within a multidisciplinary sarcoma tumor board in order to consider RT in their treatment strategy.

Regardless of the timing chosen for RT, physicians should also try to limit the dose of radiation to the surrounding normal tissues. High attention is required in regards to the small bowel, especially in the setting of adjuvant treatment, that may fall into space previously occupied by the removed sarcoma mass and get exposed to high doses of irradiation resulting sometimes in serious complications even in perforation and peritonitis if incidental inclusion of the bowel occurs, especially during IORT.24 According to current experience, preoperative radiotherapy should be probably preferred. More specifically, the potential advantages of preoperative RT treatment are a) The decrease of residual microscopic local malignant cells. b) Radiosensitivity is higher due to better-oxygenated cells since postsurgical area represents a potentially more radio-resistant hypoxic region). A more radiosensitive target allows the delivery of lower doses of radiation, smaller field sizes and lower toxic adverse events from surrounding organs at risk.23, 24, 25 c) Postoperative adhesions can induce inhomogeneities in the radiotherapeutic treatment plan and suboptimal RT delivery. d) RT can lead to tumor down-sizing / staging. e) RT enables more limited surgery and reduces the amount of normal tissue that needs to be removed. f) RT decreases tumor seeding at the time of surgery. g) In some cases of marginally resectable locally advanced disease, RT can achieve resectability. h) RT may increase R0 resection rate as a result of pseudocapsule that forms around the tumor.26

In the modern era, the use of newer and more sophisticated RT techniques as 3D-CRT and IMRT and conformal treatment planning can facilitate surrounding normal organ sparing and avoid acute radiation-adverse events such as enteritis, anorexia, nausea/vomiting and late sequelae as peritonitis.28 CT simulation and four-dimensional CT (4D-CT) scan for the assessment of the respiratory movement, allow the minimization of the RT dose to the normal tissues, and reduce the incidence of toxicity with excellent local control of the disease.28, 29, 30

Given the rarity of the disease, proper treatment of RPS must be investigated and determined only after multi-institutional participation in large randomized control trials. STRASS trial is the first, phase III, randomized, multicenter, EORTC study trying to assess whether there is a difference in abdominal recurrence-free survival between RPS patients treated with preoperative RT followed by surgery compared to surgery alone.22 The results of STRASS trial were presented at the ASCO meeting in 2019 and failed to demonstrate a benefit of pre-operative RT for RPS showing no difference in RFS between neoadjuvant RT and surgery vs. surgery alone arms with the exception of liposarcomas in an unplanned subset analysis. There was also, no difference in OS between the two groups. However, in the propensity matched analysis, there was a trend towards improved RFS and LR in the RT arm.

After taking into consideration certain limitations, in our metanalysis perioperative RT is associated with improved OS and lower recurrence rates and should be offered selectively, to patients with RPS in the frame of a multidisciplinary team meeting. However, multicentered randomized trials are needed to confirm or revoke these results and assess which patients with RPS could have the greatest clinical and oncological benefit. If the results of these trials confirm the results of our meta-analysis, which until now comprise the best evidence available, RT along with radical surgery could be the standard of care in at least a subgroup of patients with RPS. This subgroup taking into consideration the STRASS trial’s results is probably the LPS subgroup, but this remains to be confirmed in future studies.