Abstract
Background
Preoperative radiation therapy following by limb-sparing or conservative surgery is a standard approach for limb and trunk STS. Data supporting hypofractionated radiotherapy schedules are scarce albeit biological sensitivity of STS to radiation would justify it. We sought to evaluate the impact of moderate hypofractionation on pathologic response and its influence on oncologic outcomes.
Material and methods
From October 2018 to January 2023, 18 patients with limb or trunk STS underwent preoperative radiotherapy at a median dose of 52.5 Gy (range 49.5–60 Gy) in 15 fractions of 3.5 Gy (3.3-4 Gy) with or without neoadjuvant chemotherapy. A favorable pathologic response (fPR) was considered as ≥ 90% tumor necrosis on specimen examination.
Results
All patients completed planned preoperative radiotherapy. Eleven patients (61.1%) achieved a fPR, and 7 patients (36.8%) a complete pathologic response with total disappearance of tumor cells. Nine patients (47%) developed grade 1–2 acute skin toxicity, and 7 patients (38.8%) had wound complications on follow-up. With a median follow-up of 14 months (range 1–40), no cases of local relapse were observed, and actuarial 3-year overall survival (OS) and distant metastases-free survival (DMFS) are 87% and 76.4%, respectively. In the univariate analysis, the presence of a favorable pathologic response (fPR) was associated with improved 3-year OS (100% vs. 56.03%, p = 0.058) and 3-year DMFS (86.91% vs. 31.46%, p = 0.002). Moreover, both complete or partial RECIST response and radiological stabilization of the tumor lesion showed a significant association with higher rates of 3-year distant metastasis-free survival (DMFS) (83% vs. 83% vs. 56%, p < 0.001) and 3-year overall survival (OS) (100% vs. 80% vs. 0, p = 0.002).
Conclusions
Preoperative moderate hypofractionated radiation treatment for STS is feasible and well tolerated and associates encouraging rates of pathologic response that could have a favorable impact on final outcomes.
Similar content being viewed by others
Availability of data and material
All data will be available at a reasonable request.
References
Haas RL, Delaney TF, O’Sullivan B, Keus RB, Le Pechoux C, Olmi P, et al. Radiotherapy for management of extremity soft tissue sarcomas: why, when, and where? Int J Radiat Oncol Biol Phys. 2012;84(3):572–80. https://doi.org/10.1016/j.ijrobp.2012.01.062.
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;359(9325):2235–41. https://doi.org/10.1016/S0140-6736(02)09292-9.
Haas RL, Gronchi A, van de Sande MAJ, Baldini EH, Gelderblom H, Messiou C, et al. Perioperative management of extremity soft tissue sarcomas. J Clin Oncol. 2018;36(2):118–24. https://doi.org/10.1200/JCO.2017.74.7527.
Fein DA, Lee WR, Lanciano RM, Corn BW, Herbert SH, Hanlon AL, et al. Management of extremity soft tissue sarcomas with limb-sparing surgery and postoperative irradiation: do total dose, overall treatment time, and the surgery-radiotherapy interval impact on local control? Int J Radiat Oncol Biol Phys. 1995;32(4):969–76.
Andrews SF, Anderson PR, Eisenberg BL, Hanlon AL, Pollack A. Soft tissue sarcomas treated with postoperative external beam radiotherapy with and without low-dose-rate brachytherapy. Int J Radiat Oncol Biol Phys. 2004;59(2):475–80. https://doi.org/10.1016/j.ijrobp.2003.10.048.
San Miguel I, San Julián M, Cambeiro M, Fernández Sanmamed M, Vázquez-García B, Pagola M, et al. Determinants of toxicity, patterns of failure, and outcome among adult patients with soft tissue sarcomas of the extremity and superficial trunk treated with greater than conventional doses of perioperative high-dose-rate brachytherapy and external beam radiotherapy. Int J Radiat Oncol Biol Phys. 2011;81(4):e529–39. https://doi.org/10.1016/j.ijrobp.2011.04.063.
Soyfer V, Corn BW, Kollender Y, Issakov J, Dadia S, Flusser G, Bickels J, Meller I, Merimsky O. Hypofractionated adjuvant radiation therapy of soft-tissue sarcoma achieves excellent results in elderly patients. Br J Radiol. 2013;86(1028):20130258. https://doi.org/10.1259/bjr.20130258.
Roohani S, Ehret F, Kobus M, Flörcken A, Märdian S, Striefler JK, Rau D, Öllinger R, Jarosch A, Budach V, Kaul D. Preoperative hypofractionated radiotherapy for soft tissue sarcomas: a systematic review. Radiat Oncol. 2022;17(1):159. https://doi.org/10.1186/s13014-022-02072-9.
Shah D, Borys D, Martinez SR, Li CS, Tamurian RM, Bold RJ, et al. Complete pathologic response to neoadjuvant radiotherapy is predictive of oncological outcome in patients with soft tissue sarcoma. Anticancer Res. 2012;32(9):3911–5.
Bonvalot S, Wunder J, Gronchi A, Broto JM, Turcotte R, Rastrelli M, et al. Complete pathological response to neoadjuvant treatment is associated with better survival outcomes in patients with soft tissue sarcoma: results of a retrospective multicenter study. Eur J Surg Oncol. 2021;47(8):2166–72. https://doi.org/10.1016/j.ejso.2021.02.024.
Seldon C, Shrivastava G, Fernandez M, Jarboe J, Conway S, Pretell J, et al. Pathologic response rates after neoadjuvant therapy for sarcoma: a single institution study. Cancers (Basel). 2021;13(5):1074. https://doi.org/10.3390/cancers13051074.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. https://doi.org/10.1016/j.ejca.2008.10.026.
Wardelmann E, Haas RL, Bovée JV, Terrier P, Lazar A, Messiou C, et al. Evaluation of response after neoadjuvant treatment in soft tissue sarcomas; the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) recommendations for pathological examination and reporting. Eur J Cancer. 2016;53:84–95. https://doi.org/10.1016/j.ejca.2015.09.021.
Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys. 1995;31(5):1341–6. https://doi.org/10.1016/0360-3016(95)00060-C.
Chen-Zhao X, Montero Á, de las Heras J, De la Casa M, Sánchez E, Hernando O, et al. Perioperative high-dose-rate brachytherapy (PoHDR) in the multidisciplinary management of adult soft tissue sarcomas: a realistic alternative for a moderate radiotherapy dose escalation. J Radiat Oncol. 2020;9:15–24.
Koseła-Paterczyk H, Szacht M, Morysiński T, Ługowska I, Dziewirski W, Falkowski S, et al. Preoperative hypofractionated radiotherapy in the treatment of localized soft tissue sarcomas. Eur J Surg Oncol. 2014;40(12):1641–7. https://doi.org/10.1016/j.ejso.2014.05.016.
Pennington JD, Eilber FC, Eilber FR, Singh AS, Reed JP, Chmielowski B, et al. Long-term outcomes with ifosfamide-based hypofractionated preoperative chemoradiotherapy for extremity soft tissue sarcomas. Am J Clin Oncol. 2018;41(12):1154–61. https://doi.org/10.1097/COC.0000000000000443.
Potkrajcic V, Traub F, Hermes B, Scharpf M, Kolbenschlag J, Zips D, et al. Hypofractionated preoperative radiotherapy for high-risk soft tissue sarcomas in a geriatric patient population. Radiol Oncol. 2021;55(4):459–66. https://doi.org/10.2478/raon-2021-0038.
Koseła-Paterczyk H, Teterycz P, Spałek MJ, Borkowska A, Zawadzka A, Wągrodzki M, et al. Efficacy and safety of hypofractionated preoperative radiotherapy for primary locally advanced soft tissue sarcomas of limbs or trunk wall. Cancers (Basel). 2021;13(12):2981. https://doi.org/10.3390/cancers13122981.
Salah S, Lewin J, Amir E, Abdul RA. Tumor necrosis and clinical outcomes following neoadjuvant therapy in soft tissue sarcoma: a systematic review and meta-analysis. Cancer Treat Rev. 2018;69:1–10. https://doi.org/10.1016/j.ctrv.2018.05.007.
Palm RF, Liveringhouse CL, Gonzalez RJ, Bui MM, Binitie O, Yang GQ, et al. Effect of favorable pathologic response after neoadjuvant radiation therapy alone in soft-tissue sarcoma. Adv Radiat Oncol. 2022;8(1):101086. https://doi.org/10.1016/j.adro.2022.101086.
Bonvalot S, Wunder J, Gronchi A, Broto JM, Turcotte R, Rastrelli M, et al. Complete pathological response to neoadjuvant treatment is associated with better survival outcomes in patients with soft tissue sarcoma: results of a retrospective multicenter study. Eur J Surg Oncol. 2021;47(8):2166–72. https://doi.org/10.1016/j.ejso.2021.02.024.
Wang D, Harris J, Kraybill WG, Eisenberg B, Kirsch D, Ettinger DS, et al. Pathologic complete response and clinical outcomes in patients with localized soft tissue sarcoma treated with neoadjuvant chemoradiotherapy or radiotherapy: the NRG/RTOG 9514 and 0630 nonrandomized clinical trials. JAMA Oncol. 2023. https://doi.org/10.1001/jamaoncol.2023.0042.
Gannon NP, Stemm MH, King DM, Bedi M. Pathologic necrosis following neoadjuvant radiotherapy or chemoradiotherapy is prognostic of poor survival in soft tissue sarcoma. J Cancer Res Clin Oncol. 2019;145(5):1321–30. https://doi.org/10.1007/s00432-019-02885-4.
Mullen JT, Hornicek FJ, Harmon DC, Raskin KA, Chen YL, Szymonifka J, et al. Prognostic significance of treatment-induced pathologic necrosis in extremity and truncal soft tissue sarcoma after neoadjuvant chemoradiotherapy. Cancer. 2014;120(23):3676–82. https://doi.org/10.1002/cncr.28945.
Eilber FC, Rosen G, Eckardt J, Forscher C, Nelson SD, Selch M, et al. Treatment-induced pathologic necrosis: a predictor of local recurrence and survival in patients receiving neoadjuvant therapy for high-grade extremity soft tissue sarcomas. J Clin Oncol. 2001;19(13):3203–9. https://doi.org/10.1200/JCO.2001.19.13.3203.
Ryan CW, Montag AG, Hosenpud JR, Samuels B, Hayden JB, Hung AY, et al. Histologic response of dose-intense chemotherapy with preoperative hypofractionated radiotherapy for patients with high-risk soft tissue sarcomas. Cancer. 2008;112(11):2432–9. https://doi.org/10.1002/cncr.23478.
MacDermed DM, Miller LL, Peabody TD, Simon MA, Luu HH, Haydon RC, et al. Primary tumor necrosis predicts distant control in locally advanced soft-tissue sarcomas after preoperative concurrent chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2010;76(4):1147–53. https://doi.org/10.1016/j.ijrobp.2009.03.015.
Lu E, Perlewitz KS, Hayden JB, Hung AY, Doung YC, Davis LE, et al. Epirubicin and ifosfamide with preoperative radiation for high-risk soft tissue sarcomas. Ann Surg Oncol. 2018;25(4):920–7. https://doi.org/10.1245/s10434-018-6346-4.
Spałek MJ, Koseła-Paterczyk H, Borkowska A, Wągrodzki M, Szumera-Ciećkiewicz A, Czarnecka AM, et al. Combined preoperative hypofractionated radiotherapy with doxorubicin-ifosfamide chemotherapy in marginally resectable soft tissue sarcomas: results of a phase 2 clinical trial. Int J Radiat Oncol Biol Phys. 2021;110(4):1053–63. https://doi.org/10.1016/j.ijrobp.2021.02.019.
Guadagnolo BA, Bassett RL, Mitra D, Farooqi A, Hempel C, Dorber C, et al. Hypofractionated, 3-week, preoperative radiotherapy for patients with soft tissue sarcomas (HYPORT-STS): a single-centre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2022;23(12):1547–57. https://doi.org/10.1016/S1470-2045(22)00638-6.
Bedi M, Singh R, Charlson JA, Kelly T, Johnstone C, Wooldridge A, et al. Is 5 the new 25? Long-term oncologic outcomes from a phase ii, prospective, 5-fraction preoperative radiation therapy trial in patients with localized soft tissue sarcoma. Adv Radiat Oncol. 2022;7(3):100850. https://doi.org/10.1016/j.adro.2021.100850.
Haas RLM, Miah AB, LePechoux C, DeLaney TF, Baldini EH, Alektiar K, et al. Preoperative radiotherapy for extremity soft tissue sarcoma; past, present and future perspectives on dose fractionation regimens and combined modality strategies. Radiother Oncol. 2016;119(1):14–21.
Yang G, Yuan Z, Ahmed K, Welsh EA, Fulp WJ, Gonzalez RJ, et al. Genomic identification of sarcoma radiosensitivity and the clinical implications for radiation dose personalization. Transl Oncol. 2021;14(10):101165. https://doi.org/10.1016/j.tranon.2021.101165.
Canter RJ, Martinez SR, Tamurian RM, Wilton M, Li CS, Ryu J, Mak W, Monsky WL, Borys D. Radiographic and histologic response to neoadjuvant radiotherapy in patients with soft tissue sarcoma. Ann Surg Oncol. 2010;17(10):2578–84. https://doi.org/10.1245/s10434-010-1156-3.
Schuetze SM. Imaging and response in soft tissue sarcomas. Hematol Oncol Clin N Am. 2005;19(3):471–87.
Funding
The authors declare no financial disclosures.
Author information
Authors and Affiliations
Contributions
AM and XCZ contributed to study design, data analysis and manuscript writing. All the authors contributed to manuscript writing, editing and reviewing, reviewed previous drafts and provided comments and contributed to the final draft.
Corresponding author
Ethics declarations
Conflict of interest
All the authors declare no conflict of interest.
Ethical approval and informed consent
All procedures performed were in accordance with the ethical standards of the institutional research committee and with the Helsinki declaration, and informed consent was obtained from all individuals participants included in this study.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Montero, A., Chen-Zhao, X., Ciérvide, R. et al. Moderate hypofractionated radiation therapy and pathologic response for soft tissue sarcomas (STS) of limbs and trunk: experience from a tertiary cancer center. Clin Transl Oncol 26, 204–213 (2024). https://doi.org/10.1007/s12094-023-03237-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12094-023-03237-y