What is the evidence that pre-operative radiotherapy is superior to post-operative radiotherapy in limb and extremity soft tissue sarcoma in terms of local recurrence, survival and limb salvage and morbidity?

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What is the evidence that pre-operative radiotherapy is superior to post-operative radiotherapy in limb and extremity soft tissue sarcoma in terms of local recurrence, survival and limb salvage and morbidity?

Introduction

The optimal sequencing of radiotherapy and limb-sparing surgery in extremity soft tissue sarcoma (ESTS) is unclear. Following the landmark randomised trial by Rosenberg,[1] surgery followed by post-operative radiotherapy (RT) became, a widely practiced approach in localised resectable ESTS.

Subsequent interest in utilising radiotherapy in the pre-operative setting has been reported in multiple retrospective series. To date, there has only been one randomised controlled trial comparing pre-operative and post-operative radiotherapy in ESTS, and one systematic review/meta-analysis including the above randomised and four retrospective cohort studies. These are briefly summarised below. The majority of literature, in fact, lies in single-institutional case series.

O’Sullivan et al[2] randomised 190 patients to pre-operative radiotherapy (50Gy) versus post-operative radiotherapy (66-70Gy), with major wound complications being the primary endpoint. Patients whom received pre-operative radiotherapy had a significantly higher rate of major wound complications compared with patients receiving post-operative radiotherapy (35% versus 17%; p=0.01), with the highest rates of complications seen in the thigh. At a median follow-up of 3.3 years, local control was similar in both groups (p=0.7119). A difference in overall survival, was demonstrated favouring the pre-operative arm (p=0.0481), however the study was not powered to detect a difference in this secondary endpoint.

An update to this trial at a median follow-up of 6.9 years was presented in abstract form and confirmed ongoing equivalence of local control between the two arms (93% versus 92%), and similar overall survival (73% versus 67%; p=0.48).

Longer term functional outcomes for this trial were reported at two years by Davis et al,[3] and included 73 and 56 patients in the pre-operative and post-operative arms, respectively. A greater proportion of patients in the post-operative arm had grade 2 or greater subcutaneous fibrosis, edema and joint stiffness, however these differences did not reach statistical significance.

A systematic review/meta-analysis, included a total of 1,098 patients and reported moderate heterogeneity between studies as well as likely publication bias. It concluded there may be lower risk of local recurrence with pre-operative radiotherapy, with no likely detriment in overall survival.

A retrospective analysis conducted using the National Oncology Database,[4] included a total of 821 patients from multiple institutions across the United States, reported a statistically improved overall survival (OS) and cause specific survival (CSS) in the pre-operative RT group compared with post–operative RT group (HR =0.72, 95% CI 0.56-0.91, p<0.01, and HR =0.64, 95% CI 0.46-0.88, p<0.01, respectively). Pre-operative RT was also associated with a significantly reduced risk of local and distant relapse compared with post-operaive RT, with a five year local failure-free survival of 93% and 87%, respectively (p<0.05) and five year distant metastases-free survival of 89% and 77%, respectively (p<0.001).

Of note, there are three retrospective studies that have compared the outcome of pre-operative RT versus post-operative RT and found no difference in local control or CSS.

Although the analysis by Sampath et al[4] is the largest retrospective analysis comparing the outcomes of pre-operative and post-operative RT, it is still subjected to all the inherent limitations of a retrospective database study. Nevertheless, it suggests the need for additional clinical trials to examine the impact of RT sequence on clinical outcomes.

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Evidence summary and recommendations

Evidence summary Level References
There is no significant difference in local control or survival between pre-operative and post-operative radiotherapy in localised resectable extremity soft tissue sarcoma (ESTS). II, III-2 [2], [5]
Pre-operative radiotherapy increases the rate of wound complications, following limb-sparing surgery for extremity soft tissue sarcoma (ESTS). II [2]
Post-operative radiotherapy may increase the rate of long-term radiation toxicity including subcutaneous fibrosis, edema and joint stiffness. II [6]
Evidence-based recommendationQuestion mark transparent.png Grade
The timing of radiotherapy needs to be individualised dependent upon resection and reconstructive considerations.
B


Practice pointQuestion mark transparent.png

Pre-operative radiotherapy may be the preferred approach in certain situations such as:

A tumour of borderline resectability, and pre-operative radiotherapy may render it resectable.
Radiosensitive histology (eg., myxoid liposarcoma), where tumour downstaging may be advantageous.
Where adjacent critical structures (eg., brachial plexus) may limit the total dose of post-operative radiotherapy.

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References

  1. Rosenberg LA, Esther RJ, Erfanian K, Green R, Kim HJ, Sweeting R, et al. Wound Complications in Preoperatively Irradiated Soft-Tissue Sarcomas of the Extremities. Int J Radiat Oncol Biol Phys 2012 Jun 5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22677371.
  2. 2.0 2.1 2.2 O'Sullivan B, Davis AM, Turcotte R, Bell R, Catton C, Chabot P, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet 2002 Jun 29;359(9325):2235-41 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12103287.
  3. Davis AM, O'Sullivan B, Bell RS, Turcotte R, Catton CN, Wunder JS, et al. Function and health status outcomes in a randomized trial comparing preoperative and postoperative radiotherapy in extremity soft tissue sarcoma. J Clin Oncol 2002 Nov 15;20(22):4472-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12431971.
  4. 4.0 4.1 Sampath S, Schultheiss TE, Hitchcock YJ, Randall RL, Shrieve DC, Wong JY. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma: multi-institutional analysis of 821 patients. Int J Radiat Oncol Biol Phys 2011 Oct 1;81(2):498-505 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20888702.
  5. Al-Absi E, Farrokhyar F, Sharma R, Whelan K, Corbett T, Patel M, et al. A systematic review and meta-analysis of oncologic outcomes of pre- versus postoperative radiation in localized resectable soft-tissue sarcoma. Ann Surg Oncol 2010 May;17(5):1367-74 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20217260.
  6. Davis AM, O'Sullivan B, Turcotte R, Bell R, Catton C, Chabot P, et al. Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol 2005 Apr;75(1):48-53 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15948265.

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Appendices

Further resources