What is the evidence for radiotherapy in limb and extremity soft tissue sarcoma in terms of local recurrence, survival and limb salvage?

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What is the evidence for radiotherapy in limb and extremity soft tissue sarcoma in terms of local recurrence, survival and limb salvage?

Introduction

Modern management of limb and extremity soft tissue sarcoma (STS) typically consists of a combination of limb preserving surgery and radiotherapy (RT). Pre-operative or post-operative RT, intraoperative or perioperative brachytherapy with or without external beam radiotherapy (EBRT) have been used and reported by investigators from various institutions.

Evidence of radiotherapy in terms of local recurrence

Post-operative RT improves local control in combination with limb preserving surgery in patients with high or low grade extremity STS who had negative or marginal margins.[1] A local control rate in excess of 90% has been reported.

In the cases of intralesional margin, post-operative RT has been shown to improve local control (5yr local control 28% vs. 62%). However, the control rate remains inferior to cases in which a wide margin can be achieved.[2]

One randomised trial and several retrospective reports comparing pre-operative RT and post-operative RT have reported similar local control.[3]

Post-operative brachytherapy has been shown to improve local control in high grade STS after complete resection in a randomised controlled trial.[4][5][6] Although the local control benefit was not shown in low grade STS, this subset analysis was limited to 22 and 23 patients in each arm.

A French retrospective study evaluating altered fractionation schedule in the post operative setting reported no improvement in local control compared to conventional fractionated radiotherapy of 1.8-2Gy fractions.[7]

There is no evidence that the addition of radiosensitizer to post-operative radiotherapy improves local control.[8]

A prospective trial by Pisters et al.[9] in 2007 of 88 patients with T1 STS showed that a policy of R0 surgery alone (reserving post-operative radiotherapy for positive margins only) resulted in 5- and 10-year local recurrence rates of 14% and 16.2% for the entire cohort. The corresponding rates in the R0 surgery alone arm was 7.9% and 10.6%.

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Evidence for radiotherapy in terms of survival

Randomised studies for post-operative radiotherapy or brachytherapy following limb sparing surgery did not demonstrate any survival benefit. However, it is unclear if the sample sizes in these earlier trials were adequately powered to detect a difference in survival outcomes.

There is, however, level III-2 evidence from a SEER analysis by Koshy et al, 2010[10] that a statistically significant improvement in overall survival (OS) in patients with high grade extremity STS who received radiotherapy (three year OS 73% versus 63%) was demonstrated.

This was confirmed in another SEER analysis by Schreiber et al, 2012[11] which reported an improved OS and disease specific survival (DSS) for patients with tumours >5cm who had post-operative radiotherapy after limb sparing surgery.

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Evidence for radiotherapy in terms of limb salvage

There is level II evidence that the DSS and OS were equivalent in patients with high grade extremity STS who had limb sparing surgery with post-operative radiotherapy compared with those managed with amputation.[12]

Majority of these patients has excellent local control and acceptable functional outcome.

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Evidence summary and recommendations

Evidence summary Level References
Adjuvant radiotherapy improves local control in combination with limb preserving surgery in patients with high or low-grade extremity STS who had negative or marginal margins. II [1]
Adjuvant radiotherapy improves local control in the cases of intralesional margin. However, the control rate remains inferior to cases in which a wide margin can be achieved. IV [2]
Local control was similar in both the pre-operative RT and post-operative RT group. II [3]
Radiotherapy demonstrated improvement in overall survival only in patients with high grade extremity STS. III-2 [10], [11]
Evidence-based recommendationQuestion mark transparent.png Grade
All patients with large, localised, high-grade extremity soft tissue tumours should be offered radiotherapy.
B


Evidence summary Level References
R0 surgery alone demonstrated acceptable local control and sarcoma specific survival rates in selected patients with T1 extremity STS. IV [9]
Evidence-based recommendationQuestion mark transparent.png Grade
Omission of radiotherapy may be considered in select patients with small, superficial, extremity soft tissue tumours.
D



Practice pointQuestion mark transparent.png

Radiotherapy does not compensate for inadequate surgery.

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References

  1. 1.0 1.1 Yang JC, Chang AE, Baker AR, Sindelar WF, Danforth DN, Topalian SL, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998 Jan;16(1):197-203 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9440743.
  2. 2.0 2.1 Jebsen NL, Trovik CS, Bauer HC, Rydholm A, Monge OR, Hall KS, et al. Radiotherapy to improve local control regardless of surgical margin and malignancy grade in extremity and trunk wall soft tissue sarcoma: a Scandinavian sarcoma group study. Int J Radiat Oncol Biol Phys 2008 Jul 15;71(4):1196-203 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18207661.
  3. 3.0 3.1 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.
  4. Pisters PW, Harrison LB, Leung DH, Woodruff JM, Casper ES, Brennan MF. Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 1996 Mar;14(3):859-68 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8622034.
  5. Harrison LB, Franzese F, Gaynor JJ, Brennan MF. Long-term results of a prospective randomized trial of adjuvant brachytherapy in the management of completely resected soft tissue sarcomas of the extremity and superficial trunk. Int J Radiat Oncol Biol Phys 1993 Sep 30;27(2):259-65 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8407399.
  6. Shiu MH, Hilaris BS, Harrison LB, Brennan MF. Brachytherapy and function-saving resection of soft tissue sarcoma arising in the limb. Int J Radiat Oncol Biol Phys 1991 Nov;21(6):1485-92 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/1938557.
  7. Le Péchoux C, Le Deley MC, Delaloge S, Lartigau E, Levy-Piedbois C, Bonvalot S, et al. Postoperative radiotherapy in the management of adult soft tissue sarcoma of the extremities: results with two different total dose, fractionation, and overall treatment time schedules. Int J Radiat Oncol Biol Phys 1999 Jul 1;44(4):879-86 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10386645.
  8. Rhomberg W, Hassenstein EO, Gefeller D. Radiotherapy vs. radiotherapy and razoxane in the treatment of soft tissue sarcomas: final results of a randomized study. Int J Radiat Oncol Biol Phys 1996 Dec 1;36(5):1077-84 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8985029.
  9. 9.0 9.1 Pisters PW, Pollock RE, Lewis VO, Yasko AW, Cormier JN, Respondek PM, et al. Long-term results of prospective trial of surgery alone with selective use of radiation for patients with T1 extremity and trunk soft tissue sarcomas. Ann Surg 2007 Oct;246(4):675-81; discussion 681-2 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17893504.
  10. 10.0 10.1 Koshy M, Rich SE, Mohiuddin MM. Improved survival with radiation therapy in high-grade soft tissue sarcomas of the extremities: a SEER analysis. Int J Radiat Oncol Biol Phys 2010 May 1;77(1):203-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19679403.
  11. 11.0 11.1 Schreiber D, Rineer J, Katsoulakis E, Sroufe RL, Lange CS, Nwokedi E, et al. Impact of Postoperative Radiation on Survival for High-grade Soft Tissue Sarcoma of the Extremities After Limb Sparing Radical Resection. Am J Clin Oncol 2011 Jan 26 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21278563.
  12. Rosenberg SA, Tepper J, Glatstein E, Costa J, Baker A, Brennan M, et al. The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 1982 Sep;196(3):305-15 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7114936.

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Appendices

Further resources