What is the evidence that radiotherapy, either pre-operative or post-operative, decreases local recurrence or improves survival in retroperitoneal sarcomas?

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What is the evidence that radiotherapy, either pre-operative or post-operative, decreases local recurrence or improves survival in retroperitoneal sarcomas?

Introduction

Retroperitoneal Sarcomas (RPS) are relatively uncommon, constituting 10-15% of all Soft Tissue Sarcomas (STS). Patients usually present in their fifties, although the age range can be broad. Both males and females are equally affected. The most common histologic types of RPS are liposarcomas, leiomyosarcomas and pleomorphic undifferentiated sarcomas. RPS typically produce few symptoms until they are large enough to compress or invade surrounding structures. Most cases come to attention as an incidentally discovered abdominal mass in an asymptomatic or minimally symptomatic patient. Most tumours are already large at presentation (median size 15cm).

Rationale for adding Radiotherapy

Surgical resection has traditionally been the only potentially curative treatment of localised RPS. However, in contrast to Extremity STS where the most common site of first recurrence is a distant site, the primary pattern of failure after resection of a RPS is local. Five year local recurrence rates after complete resection of a RPS is around 50% and local recurrence is the site of first failure in 90% of cases. These high relapse rates have prompted investigation of combined modality approaches such as radiation therapy.

Unfortunately, with RPS being an “Orphan Disease” there are no randomised trials of surgery with and without External beam radiation therapy (EBRT). There was one trial Z9031 initiated by the American College of Surgeons Oncology Group (ASCOG) randomising to preoperative radiotherapy (RT) vs Surgery alone. This closed prematurely due to slow patient accrual. At the time of writing, the European Organisation for Research and Treatment of Cancer (EORTC) protocol 62092 is preparing to accrue patients for a phase III randomised controlled trial comparing preoperative RT plus surgery vs surgery alone for patients with RPS. However, the results of this study will not be available for many years to come.

There are many retrospective studies, mainly institutional reports which have shown improved local control benefit. Two large studies [1][2] have shown that adjuvant RT improves local recurrence free survival significantly. Recent large population based multi-institutional studies such as SEER database analysis which have looked at overall survival benefit have however been conflicting. A smaller SEER analyisis[3] showed no survival benefit, where as an analysis with larger number showed a survival benefit.[4] Another SEER analysis[5] showed survival benefit in malignant fibrous histiocytoma (MFH) subgroup only.

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Pre-operative versus post-operative radiotherapy

Although the studies had a mix of pre-operative or post-operative RT, there are benefits with pre-operative RT versus post-operative radiotherapy such as:

  • The main advantage of pre-operative RT is that the gross tumour volume can be precisely defined for radiation treatment planning, allowing accurate targeting of the radiation volume around the tumour.
  • The tumour itself can act to displace small bowel from the high-dose radiation treatment volume, resulting in safer and less toxic treatment.
  • Higher RT doses can be delivered to the actual tumour field, since bowel adhesions to tumour are less likely compared to the post-operative setting.
  • The risk of intraperitoneal tumour dissemination at the time of the operation may be reduced by pre-operative RT.
  • Radiation is considered to be biologically more effective in the pre-operative setting.
  • It is possible that an initially unresectable tumour may be converted to one that is potentially resectable for cure.

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Newer Radiotherapy techniques

There is some evidence that newer RT techniques such as Intraoperative Electron beam therapy (IORT) may be beneficial, but this is usually confined to few centres worldwide and not available in Australia. There is some promise with the use of Intensity modulated radiation therapy (IMRT) in RPS, but still in early stages and may take some time for results to come.

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Evidence summary and recommendations

Evidence summary Level References
In patients presenting with non metastatic retroperitoneal sarcomas, improved local control and local recurrence free survival benefit is seen with pre-operative or post-operative radiotherapy.

Pre-operative radiotherapy is preferable. Post-operative radiotherapy (in the absence of spacing devices) is associated with significant toxicity.

III-2, IV [6], [2], [1]
Evidence regarding radiotherapy benefit in improving overall survival is not clear. III-2 [3], [4], [5]
Evidence-based recommendationQuestion mark transparent.png Grade
In patients with non-metastatic retroperitoneal sarcomas, adding radiotherapy to surgery is appropriate to further improve local control. When offered, pre-operative radiotherapy is preferable to post-operative radiotherapy.
C


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Issues requiring more clinical research study

A number of gaps in the evidence have been identified. These include:

• Randomised Controlled trial comparing pre-operative RT followed by surgery versus surgery alone in patients presenting with non-metastatic retroperitoneal sarcoma.

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References

  1. 1.0 1.1 Sampath S, Hitchcock YJ, Shrieve DC, Randall RL, Schultheiss TE, Wong JY. Radiotherapy and extent of surgical resection in retroperitoneal soft-tissue sarcoma: multi-institutional analysis of 261 patients. J Surg Oncol 2010 Apr 1;101(5):345-50 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20119974.
  2. 2.0 2.1 Stoeckle E, Coindre JM, Bonvalot S, Kantor G, Terrier P, Bonichon F, et al. Prognostic factors in retroperitoneal sarcoma: a multivariate analysis of a series of 165 patients of the French Cancer Center Federation Sarcoma Group. Cancer 2001 Jul 15;92(2):359-68 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11466691.
  3. 3.0 3.1 Choi AH, Barnholtz-Sloan JS, Kim JA. Effect of radiation therapy on survival in surgically resected retroperitoneal sarcoma: a propensity score-adjusted SEER analysis. Ann Oncol 2012 Sep;23(9):2449-57 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22323436.
  4. 4.0 4.1 Zhou Z, McDade TP, Simons JP, Ng SC, Lambert LA, Whalen GF, et al. Surgery and radiotherapy for retroperitoneal and abdominal sarcoma: both necessary and sufficient. Arch Surg 2010 May;145(5):426-31 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20479339.
  5. 5.0 5.1 Tseng WH, Martinez SR, Do L, Tamurian RM, Borys D, Canter RJ. Lack of survival benefit following adjuvant radiation in patients with retroperitoneal sarcoma: a SEER analysis. J Surg Res 2011 Jun 15;168(2):e173-80 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21470630.
  6. Le Péchoux C, Musat E, Baey C, Al Mokhles H, Terrier P, Domont J, et al. Should adjuvant radiotherapy be administered in addition to front-line aggressive surgery (FAS) in patients with primary retroperitoneal sarcoma? Ann Oncol 2012 Nov 2 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23123508.

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Appendices

Further resources