Skip to main content

Intraoperative Electron Radiation Therapy Combined with External Beam Radiation Therapy after Gross Total Resection in Extremity Soft Tissue Sarcoma: A European Pooled Analysis

Abstract

Introduction

We report a pooled analysis evaluating the combination of gross complete limb-sparing surgery, intraoperative electron radiation therapy (IOERT), and external beam radiation therapy (EBRT) in patients with extremity soft tissue sarcoma (STS).

Methods

Individual data of 259 patients (median follow-up 63 months) with extremity STS from three European expert centers were pooled. Median age was 55 years and median tumor size was 8 cm. Eighty percent of patients presented with primary disease, mainly located in the lower limb (81%). Union for International Cancer Control 7th edition stage at presentation was as follows: stage I: 9%; stage II: 47%; stage III: 39%; stage IV: 5%. Most patients showed high-grade lesions (91%), predominantly liposarcoma (31%). Median IOERT dose was 12 Gy, preceeded (17%) or followed (83%) by EBRT, with a median dose of 45 Gy.

Results

Surgery resulted in R0 resections in 71% of patients and R1 resections in 29% of patients. The 5-year local control (LC) rate was 86%, and significant factors in univariate analysis were disease status and resection margin. Only margin remained significant in multivariate analysis. The 5-year distant control rate was 69%, and significant factors in univariate analysis were histology, grading, resection margin, and metastases prior to/at IOERT. Only grading and metastases remained significant in multivariate analysis. Actuarial 5-year rates of freedom from treatment failure and OS were 61% and 78%, respectively. Significant factors for OS were grading and metastases prior to/at IOERT (univariate, multivariate). Limb preservation and good functional outcome were achieved in 95% and 81% of patients.

Conclusions

Our pooled analysis confirmed prior reports of encouraging LC and survival, with excellent rates of preserved limb function with this treatment approach. Resection margin remained the most important factor for LC, while grading and metastases prior to/at IOERT mainly predicted survival.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

References

  1. Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of soft-tissue sarcomas of the extremities. Ann Surg. 1982;196:305–14.

    CAS  Article  Google Scholar 

  2. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology—Soft Tissue Sarcoma V2.2017. http://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf. Accessed 10 Feb 2017.

  3. Jebsen NL, Trovik CS, Bauer HC, 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;71:1196–1203.

    Article  Google Scholar 

  4. Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcoma of the extremity. J Clin Oncol. 1998;16:197–203.

    CAS  Article  Google Scholar 

  5. Zagars GK, Ballo MT. Significance of dose in postoperative radiotherapy for soft tissue sarcoma. Int J Radiat Oncol Biol Phys. 2003;56:473–81.

    Article  Google Scholar 

  6. Davis AM, O´Sullivan B, Turcotte R, et al. Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol. 2005;75:48–53.

    Article  Google Scholar 

  7. Oertel S, Treiber M, Zahlten-Hinguranage A, et al. Intraoperative electron boost radiation followed by moderate doses of external beam radiotherapy in limb-sparing treatment of patients with extremity soft-tissue sarcoma. Int J Radiat Oncol Biol Phys 2006;64:1416–23.

    Article  Google Scholar 

  8. Roeder F, Lehner B, Saleh-Ebrahimi L, et al. Intraoperative electron radiation therapy combined with external beam radiation therapy and limb sparing surgery in extremity soft tissue sarcoma: a retrospective single center analysis of 183 cases. Radiother Oncol. 2016;119:22–9.

    Article  Google Scholar 

  9. Edmonson JH, Petersen IA, Shives TC, et al. Chemotherapy, irradiation, and surgery for function-preserving therapy of primary extremity soft-tissue sarcomas. Cancer 2002;94:786–92.

    CAS  Article  Google Scholar 

  10. Azinovic I, Martinez Monge R, Javier Aristu J et al. Intraoperative radiotherapy electron boost followed by moderate doses of external beam radiotherapy in resected soft-tissue sarcomas of the extremities. Radiother Oncol. 2003;67:331–7.

    Article  Google Scholar 

  11. Kretzler A, Molls M, Gradinger R, et al. Intraoperative radiotherapy of soft tissue sarcomas of the extremity. Strahlenther Onkol. 2004;180:365–70.

    Article  Google Scholar 

  12. Llacer C, Delannes M, Minsat M, et al. Low-dose intraoperative brachytherapy in soft tissue sarcomas involving neurovascular structure. Radiother Oncol. 2006;78:10–6.

    Article  Google Scholar 

  13. Roeder FF, Schulz-Ertner D, Nikoghosyan AV, et al. A clinical phase I/II trial to investigate preoperative dose-escalated intensity-modulated radiation therapy (IMRT) and intraoperative radiation therapy (IORT) in patients with retroperitoneal soft tissue sarcoma. BMC Cancer. 2012;12:287.

    CAS  Article  Google Scholar 

  14. Roeder FF, Timke C, Saleh-Ebrahimi L, et al. Clinical phase I/II trial to investigate neoadjuvant intensity-modulated short term radiation therapy (5 × 5 Gy) and intraoperative radiation therapy (15 gy) in patients with primarily resectable pancreatic cancer—NEOPANC. BMC Cancer. 2012;12:112.

    Article  Google Scholar 

  15. Roeder F, Ulrich A, Habl G, et al. Clinical phase I/II trial to investigate preoperative dose-escalated intensity-modulated radiation therapy (IMRT) and intraoperative radiation therapy (IORT) in patients with retroperitoneal soft tissue sarcoma: interim analysis. BMC Cancer. 2014;14:617.

    Article  Google Scholar 

  16. Roeder F, Timke C, Uhl M, et al. Aggressive local treatment containing intraoperative radiation therapy (IORT) for patients with isolated local recurrences of pancreatic cancer: a retrospective analysis. BMC Cancer. 2012;12:295.

    Article  Google Scholar 

  17. Roeder F, Goetz JM, Habl G, et al. Intraoperative electron radiation therapy (IOERT) in the management of locally recurrent rectal cancer. BMC Cancer. 2012;12:592.

    Article  Google Scholar 

  18. Roeder F, Timke C, Oertel S, et al. Intraoperative electron radiotherapy for the management of aggressive fibromatosis. Int J Radiat Oncol Biol Phys. 2010;76:1154–60.

    Article  Google Scholar 

  19. Roeder F, Krempien R. Intraoperative radiation therapy (IORT) in soft-tissue sarcoma. Radiat Oncol. 2017;12:20.

    Article  Google Scholar 

  20. Calvo FA, Sole CV, Polo A, et al. Limb-sparing management with surgical resection, external-beam and intraoperative electron-beam radiation therapy for boost for patients with primary soft tissue sarcoma of the extremity: a multicentric pooled analysis of long-term outcomes. Strahlenther Onkol. 2014;190:891–8.

    Article  Google Scholar 

  21. de Paoli A, Bertola G, Boz G, et al. Intraoperative radiation therapy for retroperitoneal soft tissue sarcomas. J Exp Clin Cancer Res. 2003;22 Suppl 4:157–61.

    PubMed  Google Scholar 

  22. De Paoli A, Bertola G, Boz G, et al. Radiation therapy and conservative surgery for soft tissue sarcomas of the extremities, torso and head and neck. Ann Oncol. 1992;3 Suppl 2:97–101.

    Article  Google Scholar 

  23. Roeder F, Lehner B, Schmitt T, et al. Excellent local control with IOERT and postoperative EBRT in high grade extremity sarcoma: results from a subgroup analysis of a prospective trial. BMC Cancer. 2014;14:350.

    Article  Google Scholar 

  24. Alvarez A, Calvo FA, Gonzales C, et al. IORT in soft tissue sarcomas involving extremities: toxicities and long-term functional results [abstract]. Revisiones en cancer. 2008;22:s55.

    Google Scholar 

  25. Zagars GK, Ballo MT, Pisters PW, et al. Prognostic factors for patients with localized soft-tissue sarcomas treated with conservation surgery and radiation therapy: an analysis of 1225 patients. Cancer. 2003;97:2530–43.

    Article  Google Scholar 

  26. Hui AC, Ngan SY, Wong K, Powell G, Choong PF. Preoperative radiotherapy for soft tissue sarcoma: the Peter MacCallum Cancer Centre Experience. Eur J Surg Oncol. 2006;32:1159–64.

    CAS  Article  Google Scholar 

  27. Dagan R, Indelicato DJ, McGee L, et al. The significance of a marginal excision after preoperative radiation therapy of soft tissue sarcoma of the extremity. Cancer. 2012;118:3199–207.

    Article  Google Scholar 

  28. Kraybill WG, Harris J, Spiro IJ, et al. Phase II Study of neoadjuvant chemotherapy and radiation therapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: radiation therapy oncology group trial 9514. J Clin Oncol. 2006;24:619–25.

    CAS  Article  Google Scholar 

  29. Felderhof JM, Creutzberg CL, Putter H, et al. Long term clinical outcome of patients with soft-tissue sarcomas treated with limb-sparing surgery and postoperative radiotherapy. Acta Oncologica. 2012;52:745–52.

    Article  Google Scholar 

  30. Alektiar KM, Brennan MF, Singer S. Local Control comparison of adjuvant brachytherapy to intensity-modulated radiotherapy in primary high-grade sarcoma of the extremity. Cancer. 2011;117:3229–34.

    Article  Google Scholar 

  31. Lee J, Park YJ, Yang DS, et al. Treatment outcome of conservative surgery plus postoperative radiotherapy for extremity soft tissue sarcoma. Radiat Oncol J. 2012;30:62–9.

    Article  Google Scholar 

  32. Folkert M, Singer S, Brennan MF, et al. Comparison of local recurrence with conventional and intensity-modulated radiation therapy for primary soft-tissue sarcomas of the extremity. J Clin Oncol. 2014:32:3236–41.

    Article  Google Scholar 

  33. Weitz J, Antonescu CR, Brennan MF. Localized extremity soft tissue sarcoma: improved knowledge with unchanged survival over time. J Clin Oncol. 2003;21:2719–25.

    Article  Google Scholar 

  34. Alamanda VK, Crosby SN, Archer KR, et al. Predictors and clinical significance of local recurrence in extremity soft tissue sarcoma. Acta Oncol. 2013;52:793–802.

    Article  Google Scholar 

  35. Pisters PW, Leung DH, Woodruff J, et al. Analysis of prognostic factors in 1041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol. 1996;14:1679–89.

    CAS  Article  Google Scholar 

  36. Biau DJ, Ferguson PC, Chung P, et al. Local recurrence of localized soft tissue sarcoma. Cancer. 2012;118:5867–77.

    Article  Google Scholar 

  37. Gronchi A, Miceli R, Colombo C, et al. Primary extremity soft tissue sarcomas: outcome improvement over time at a single institution. Ann Oncol. 2011;22:1675–81.

    CAS  Article  Google Scholar 

  38. Müller DA, Beltrami G, Scoccianti G, et al. Combining limb sparing surgery with radiation therapy in high-grade soft tissue sarcoma of extremities—is it effective? Eur J Surg Oncol. 2016;42:1057–1063.

    Article  Google Scholar 

  39. Eilber FC, Rosen G, Nelson SD, et al. High-grade extremity soft tissue sarcomas—factors predictive of local recurrence and its effect on morbidity and mortality. Ann Surg. 2003;237:218–26.

    PubMed  PubMed Central  Google Scholar 

  40. Delaney TF, Kepka L, Goldberg SI, et al. Radiation therapy for control of soft-tissue sarcomas resected with positive margins. Int J Radiat Oncol Biol Phys. 2007;67:1460–69.

    Article  Google Scholar 

  41. O’Sullivan B, Griffin AM, Dickie CL, et al. Phase 2 study of preoperative image-guided intensity-modulated radiation therapy to reduce wound and combined modality morbidities in lower extremity soft-tissue sarcoma. Cancer. 2013;119:1878–94.

    Article  Google Scholar 

  42. Al Yami A, Griffin AM, Ferguson PC, et al. Positive surgical margins in soft tissue sarcoma treated with preoperative radiation: is a postoperative boost necessary? Int J Radiat Oncol Biol Phys. 2010;4:1191–97.

    Article  Google Scholar 

  43. Stinson SF, DeLaney TF, Greenberg J, et al. Acute and long-term effects on limb function of combined modality limb sparing therapy for extremity soft tissue sarcoma. Int J Radiat Oncol Biol Phys. 1991;21:1493–99.

    CAS  Article  Google Scholar 

  44. Alektiar KM, Hong L, Brennan MF, Della-Biancia C, Singer S. Intensity modulated radiation therapy for primary soft tissue sarcoma of the extremity: preliminary results. Int J Radiat Oncol Biol Phys. 2007;68:458–64.

    Article  Google Scholar 

  45. Dickie CI, Parent AL, Chung PW, et al. Measuring interfractional and intrafractional motion with cone beam computed tomography and an optical localization sytem for lower extremity soft tissue sarcoma patients treated with intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys. 2010;78:1437–44.

    Article  Google Scholar 

  46. Wang D, Zhang Q, Eisenberg BL, et al. Significant reduction of late toxicities in patients with extremity sarcoma treated with image-guided radiation therapy to a reduced target volume: results of a radiation therapy oncology group RTOG-0630 trial. J Clin Oncol. 2015;33:2231–38.

    Article  Google Scholar 

  47. Alamanda VK, Song Y, Shinohara E, et al. Postoperative radiation boost does not improve local recurrence rates in extremity soft tissue sarcomas. J Med Imag Radiat Oncol. 2014;58:633–40.

    Article  Google Scholar 

  48. Brenner DJ. The linear-quadratic model is an appropriate methodology for determining isoeffective doses at large doses per fraction. Sem Radiat Oncol. 2008;18:234–39.

    Article  Google Scholar 

  49. Mallick S, Benson R, Julka PK, Rath GK. Shifting paradigm in the management of anal canal carcinomas. J Gastrointest Cancer. 2015;46:1–4.

    Article  Google Scholar 

  50. Callister MD, Beauchamp CP, Fitch TR, Gunderson LL. Preoperative radiation and IOERT for soft-tissue sarcomas of the extremities and trunk [abstract]. Revisiones en Cancer. 2008;22:54.

    Google Scholar 

Download references

Acknowledgment

The authors thank Alexandra Diwo and Christiane Boos for their assistance in data handling and database management. No writing assistance was involved.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Falk Roeder MD.

Ethics declarations

Conflict of interest

Falk Roeder, Antonino de Paoli, Ladan Saleh-Ebrahimi, Ingo Alldinger, Giulio Bertola, Giovanni Boz, Federico Navarria, Miguel Cuervo, Matthias Uhl, Ana Alvarez, Markus Buechler, Burkhard Lehner, Juergen Debus, Felipe A. Calvo, and Robert Krempien declare no conflicts of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Roeder, F., de Paoli, A., Saleh-Ebrahimi, L. et al. Intraoperative Electron Radiation Therapy Combined with External Beam Radiation Therapy after Gross Total Resection in Extremity Soft Tissue Sarcoma: A European Pooled Analysis. Ann Surg Oncol 25, 3833–3842 (2018). https://doi.org/10.1245/s10434-018-6787-9

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-018-6787-9

Keywords

  • Intraoperative Electron Radiation Therapy (IOERT)
  • External Beam Radiation Therapy (EBRT)
  • Extremity STS
  • Freedom From Treatment Failure (FFTF)
  • IOERT Dose