Preoperative chemo-radiation therapy for localised retroperitoneal sarcoma: A phase I–II study from the Italian Sarcoma Group

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Abstract

Background

To study feasibility, safety and activity of the combination of high-dose long-infusion ifosfamide (HLI) and radiotherapy (RT) as preoperative treatment for resectable localised retroperitoneal sarcoma (RPS).

Methods

Patients received three cycles of HLI (14 g/m2). RT was started in combination with second cycle and administered up to a total dose of 50.4 Gy. Surgery was scheduled 4–6 weeks after the end of RT. Primary end-point was 3-year relapse free survival (RFS). The trial is registered with ITASARC_∗II_2004_003.

Findings

Between December 2003 and 2010, 83 patients were recruited. Main histological subtypes were well differentiated liposarcoma (19/83, 23%), dedifferentiated liposarcoma (26/83, 31%), leiomyosarcoma (14/83, 17%). Median tumour size was 120 mm (interquartile (IQ) range = 82–160). The overall preoperative treatment was completed in 60 patients. Chemotherapy (CT) was completed in 65, while RT in 73. Four patients progressed before surgery and were not operated. 79 patients underwent surgery. At a median follow-up of 4.8 years (IQ range = 3–6.1), 23 and 15 patients developed local recurrence (LR) and distant metastases (DM); 30 patients died of disease. 3 and 5-year RFS and overall survival were 0.56 (90% confidence interval (CI): 0.45, 0.65) and 0.44 (90% CI: 0.27, 0.48), and 0.74 (90% CI: 0.62, 0.81) and 0.59 (90% CI: 0.33, 0.58). Crude cumulative incidence of LR and DM at 5 years were 0.37 (standard error (SE): 0.06) and 0.26 (SE: 0.06).

Interpretation

The combination of preoperative HLI and RT was feasible in two thirds of patients, while preoperative RT could be completed in most (73/83). Although a systemic coverage can be added to RT when this is felt to be appropriate, the ongoing international phase III trial is exploring the role of RT alone.

Funding

This is a pure academic trial. No funding sources contributed to it.

Introduction

Retroperitoneal soft tissue sarcoma (RPS) are rare tumours, accounting for 0.1% of all adult malignancies [1]. Surgery is the mainstay of therapy and primarily consists of resection of the tumour along with a cuff of surrounding healthy tissues [2]. This necessarily implies resection of adjacent viscera, even when they are not overtly involved [3], [4], [5], [6], [7], [8], [9].

In an effort to complement surgery, with its inherent limitations, the administration of other treatment modalities, such as radiation therapy (RT) and chemotherapy (CT), has been tried. RT proved to benefit local control in extremity soft tissue sarcoma (STS) [10], [11]. CT showed a potential impact on the outcome of high-risk extremity STS [12], [13], [14], [15].

On this basis, we decided to run a phase I–II prospective study on preoperative concomitant chemo-radiation therapy followed by surgery in localised RPS, to test whether the results of this combination were worth being further studied in a larger cohort of patients in a randomised fashion.

Section snippets

Patients

Patients were recruited from four sites in Italy. Eligibility criteria included age ⩾18 years, histologically proven localised adult-type soft tissue sarcoma (STS) located to the retroperitoneum or pelvis, primary or locally recurrent, largest diameter >5 cm, any histological grade of aggressiveness, no evidence of distant metastases, suitable for complete surgical resection and radiation. Paediatric-type sarcoma (extra-skeletal Ewing sarcoma/primitive peripheral neuroectodermal tumour,

Results

Between December 2003 and 2010, 86 patients were recruited (Fig. 1). Following central pathological review, available for 72 patients, three were found not to be eligible for the study (cellular schwannoma, aggressive angiomyxoma and non-Hodgkin lymphoma). All others were confirmed and are listed in Table 1. The clinical characteristics of the 83 eligible patients are also listed in Table 1. These patients were selected from a pool of 382 patients affected by RPS observed and treated in the

Discussion

In this multicentric phase I–II study on localised RPS, the combination of preoperative HLI and RT followed by complete surgical resection proved to be feasible in two thirds of patients selected to be eligible for the procedure. Preoperative RT could be completed in most (73/83). The observed 3-year RFS was better than expected in this patient population (56% versus 40%). Although the primary end-point of the study was met, toxicity prevented one third of patients from completing the

Conflict of interest statement

None declared.

References (32)

  • Soft tissue and visceral sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

    Ann Oncol

    (2012)
  • A. Gronchi et al.

    Aggressive surgical policies in a retrospectively reviewed single-institution case series of retroperitoneal soft tissue sarcoma patients

    J Clin Oncol

    (2009)
  • S. Bonvalot et al.

    Primary retroperitoneal sarcomas: a multivariate analysis of surgical factors associated with local control

    J Clin Oncol

    (2009)
  • S. Bonvalot et al.

    Technical considerations in surgery for retroperitoneal sarcomas: position paper from E-Surge, a master class in sarcoma surgery, and EORTC-STBSG

    Ann Surg Oncol

    (2012)
  • A. Gronchi et al.

    Status of surgical margins and prognosis in adult soft tissue sarcomas of the extremities: a series of patients treated at a single institution

    J Clin Oncol

    (2005)
  • A. Stojadinovic et al.

    Analysis of the prognostic significance of microscopic margins in 2084 localized primary adult soft tissue sarcomas

    Ann Surg

    (2002)
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      However, current evidence is not conclusive. Some authors report a benefit regarding LR rates [12,17–20], whereas others failed to detect beneficial effects of IORT [21,22]. The aim of this retrospective analysis was to investigate the impact of IORT on LR rates, and to elaborate on its significance in multimodal therapy for retroperitoneal STS.

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