Neoadjuvant irradiation of extremity soft tissue sarcoma with ions (Extrem-ion): study protocol for a randomized phase II pilot trial

D Brügemann, B Lehner, M Kieser, J Krisam, A Hommertgen, C Jaekel, S B Harrabi, K Herfarth, G Mechtesheimer, O Sedlaczek, G Egerer, A Geisbüsch, M Uhl, J Debus, K Seidensaal, D Brügemann, B Lehner, M Kieser, J Krisam, A Hommertgen, C Jaekel, S B Harrabi, K Herfarth, G Mechtesheimer, O Sedlaczek, G Egerer, A Geisbüsch, M Uhl, J Debus, K Seidensaal

Abstract

Background: The standard of care treatment for soft tissue sarcoma of the extremities is a wide resection in combination with pre- or postoperative radiotherapy with high local control rates, sparing patients the necessity of amputation without compromising on overall survival rates. The currently preferred timing of radiotherapy is under debate. Albeit having higher rates of acute wound complications, late side effects like fibrosis, joint stiffness or edema are less frequent in preoperative compared to postoperative radiotherapy. This can be explained in smaller treatment volumes and a lower dose in the preoperative setting. Particles allow better sparing of surrounding tissues at risk, and carbon ions additionally offer biologic advantages and are preferred in less radiosensitive tumors. Hypofractionation allows for a significantly shorter treatment duration.

Methods: Extrem-ion is a prospective, randomized, monocentric phase II trial. Patients with resectable or marginally resectable, histologically confirmed soft tissue sarcoma of the extremities will be randomized between neoadjuvant proton or neoadjuvant carbon ion radiotherapy in active scanning beam application technique (39 Gy [relative biological effectiveness, RBE] in 13 fractions [5-6 fractions per week] in each arm). The primary objective is the proportion of therapies without wound healing disorder the first 120 days after surgery or discontinuation of treatment for any reason related to the treatment. The secondary endpoints of the study consist of local control, local progression-free survival, disease-free survival, overall survival, and quality of life.

Discussion: The aim of this study is to confirm that hypofractionated, preoperative radiotherapy is safe and feasible. The potential for reduced toxicity by the utilization of particle therapy is the rational of this trial. A subsequent randomized phase III trial will compare the hypofractionated proton and carbon ion irradiation in regards to local control.

Trial registration: ClinicalTrials.gov Identifier: NCT04946357 ; Retrospectively registered June 30, 2021.

Keywords: Carbon ion therapy; Extremity soft tissue sarcoma; Heavy ion therapy; Hypofractionation; Irradiation; Proton therapy; Randomized trial.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Target volume delineation and treatment planning: A The gross target volume (GTV) is depicted in green and encompassed by the clinical target volume in orange (CTV) with a margin of 3-4 cm in the longitudinal and 1.5-2 cm in the lateral direction. B The metallic wire marking the planned surgical incision is delineated and encompassed by a 2 cm margin for skin sparing if possible. C Dose distribution using opposing beams, the area of beam entrance was chosen outside of the region destined for surgical incision, treatment was performed with carbon ions

References

    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30. doi: 10.3322/caac.21442.
    1. van Vliet M, et al. Soft tissue sarcomas at a glance: clinical, histological, and MR imaging features of malignant extremity soft tissue tumors. Eur Radiol. 2009;19(6):1499–1511. doi: 10.1007/s00330-008-1292-3.
    1. von Mehren M, et al. NCCN guidelines insights: soft tissue sarcoma, version 1.2021. J Natl Compr Cancer Netw. 2020;18(12):1604–1612. doi: 10.6004/jnccn.2020.0058.
    1. Yang JC, 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;16(1):197–203. doi: 10.1200/JCO.1998.16.1.197.
    1. Pisters PW, et al. Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol. 1996;14(3):859–868. doi: 10.1200/JCO.1996.14.3.859.
    1. Rosenberg SA, 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;196(3):305–315. doi: 10.1097/00000658-198209000-00009.
    1. Albertsmeier M, et al. External beam radiation therapy for Resectable soft tissue sarcoma: a systematic review and Meta-analysis. Ann Surg Oncol. 2018;25(3):754–767. doi: 10.1245/s10434-017-6081-2.
    1. Alamanda VK, et al. Predictors and clinical significance of local recurrence in extremity soft tissue sarcoma. Acta Oncol. 2013;52(4):793–802. doi: 10.3109/0284186X.2012.711953.
    1. Wilson AN, et al. Local control of soft tissue sarcoma of the extremity: the experience of a multidisciplinary sarcoma group with definitive surgery and radiotherapy. Eur J Cancer. 1994;30A(6):746–751. doi: 10.1016/0959-8049(94)90286-0.
    1. O'Sullivan B, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet. 2002;359(9325):2235–2241. doi: 10.1016/S0140-6736(02)09292-9.
    1. Alektiar KM, et al. Adjuvant radiotherapy for margin-positive high-grade soft tissue sarcoma of the extremity. Int J Radiat Oncol Biol Phys. 2000;48(4):1051–1058. doi: 10.1016/S0360-3016(00)00753-7.
    1. Jebsen NL, 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(4):1196–1203. doi: 10.1016/j.ijrobp.2007.11.023.
    1. Gingrich AA, et al. Neoadjuvant radiotherapy is associated with R0 resection and improved survival for patients with extremity soft tissue sarcoma undergoing surgery: a National Cancer Database Analysis. Ann Surg Oncol. 2017;24(11):3252–3263. doi: 10.1245/s10434-017-6019-8.
    1. Davis AM, et al. Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol. 2005;75(1):48–53. doi: 10.1016/j.radonc.2004.12.020.
    1. Uhl M, Herfarth K, Debus J. Comparing the use of protons and carbon ions for treatment. Cancer J. 2014;20(6):433–439. doi: 10.1097/PPO.0000000000000078.
    1. Weber U, Kraft G. Comparison of carbon ions versus protons. Cancer J. 2009;15(4):325–332. doi: 10.1097/PPO.0b013e3181b01935.
    1. Haberer T, et al. Magnetic scanning system for heavy ion therapy. Nucl Instrum Methods in Phys Res SectA: Accelerators, Spectrometers, Detectors and Associated Equipment. 1993;330(1):296–305. doi: 10.1016/0168-9002(93)91335-K.
    1. Combs SE, et al. Heidelberg ion therapy center (HIT): initial clinical experience in the first 80 patients. Acta Oncol. 2010;49(7):1132–1140. doi: 10.3109/0284186X.2010.498432.
    1. Kunzmann K, K.M, Optimal adaptive two-stage designs for single-arm trial with binary endpoint. 2016.
    1. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989;10:1–10. doi: 10.1016/0197-2456(89)90015-9.
    1. Kunzmann K, Benner L, Kieser M. Point estimation in adaptive enrichment designs. Stat Med. 2017;36(25):3935–3947. doi: 10.1002/sim.7412.
    1. Kunzmann K, Kieser M. Test-compatible confidence intervals for adaptive two-stage single-arm designs with binary endpoint. Biom J. 2018;60(1):196–206. doi: 10.1002/bimj.201700018.
    1. Seidensaal K, et al. Neoadjuvant irradiation of retroperitoneal soft tissue sarcoma with ions (retro-ion): study protocol for a randomized phase II pilot trial. Trials. 2021;22(1):134. doi: 10.1186/s13063-021-05069-z.
    1. Wang D, 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 radiation therapy oncology group RTOG-0630 trial. J Clin Oncol. 2015;33(20):2231–2238. doi: 10.1200/JCO.2014.58.5828.
    1. Imai R, et al. Clinical efficacy of carbon ion radiotherapy for Unresectable chondrosarcomas. Anticancer Res. 2017;37(12):6959–6964.
    1. Guttmann DM, et al. A prospective study of proton reirradiation for recurrent and secondary soft tissue sarcoma. Radiother Oncol. 2017;124(2):271–276. doi: 10.1016/j.radonc.2017.06.024.
    1. Laughlin B, et al. Early Experience Using Proton Beam Therapy for Extremity Soft Tissue Sarcoma: A Multi-Institution Study. Int J Radiation Oncol*Biol*Phys. 2021;111(3, Supplement):e317–e318. doi: 10.1016/j.ijrobp.2021.07.980.
    1. Koseła-Paterczyk H, et al. Preoperative hypofractionated radiotherapy in the treatment of localized soft tissue sarcomas. Eur J Surg Oncol. 2014;40(12):1641–1647. doi: 10.1016/j.ejso.2014.05.016.
    1. Pennington JD, et al. Long-term outcomes with Ifosfamide-based Hypofractionated preoperative Chemoradiotherapy for extremity soft tissue sarcomas. Am J Clin Oncol. 2018;41(12):1154–1161. doi: 10.1097/COC.0000000000000443.
    1. van Leeuwen CM, et al. The alfa and beta of tumours: a review of parameters of the linear-quadratic model, derived from clinical radiotherapy studies. Rad Oncol (London, England) 2018;13(1):96. doi: 10.1186/s13014-018-1040-z.

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