Surgical Timing After Preoperative Hypofractionated Radiotherapy for Localized Extremity and Trunk Soft Tissue Sarcoma

Official title

Surgical Timing After Preoperative Hypofractionated Radiotherapy for Patients With Primary Localized Soft Tissue Sarcoma of the Extremity and Trunk: a Randomized Phase 2 Clinical Trial

Overview

Phase II, national, multicentric, prospective, randomized (1:1) non-inferiority trial with two parallel groups, incorporating a concurrent observational cohort of eligible non-randomized patients, designed to address critical knowledge gaps by prospectively evaluating the safety, efficacy, and feasibility of preoperative ultra-hypofractionated radiotherapy (HFRT) in patients with soft tissue sarcomas (STS) of the extremities and trunk.

Detailed description

This study is designed to address critical knowledge gaps by prospectively evaluating the safety, efficacy, and feasibility of preoperative ultra-hypofractionated radiotherapy (HFRT) in patients with soft tissue sarcomas (STS) of the extremities and trunk. Eligible patients will be randomized to receive an ultra-hypofractionated RT regimen consisting of 30 Gy delivered in 5 fractions of 6 Gy, followed by surgical resection at one of two predefined intervals: either 1-2 weeks or 4-6 weeks after completion of radiotherapy. In parallel, a non-randomized observational cohort will be recorded, consisting of patients treated according to current standard practice - surgery alone or surgery preceded by nonventional RT (50 Gy in 25 fractions) - to provide a contemporaneous benchmark for comparison. The aim of this study is to gather high-quality clinical evidence on the impact of ultra-hypofractionated RT on oncologic outcomes, treatment-related toxicity, perioperative morbidity, and patient-reported quality of life. Evaluation of logistical and economic implications of treatment de-escalation, such as healthcare resource utilization and treatment burden are also an important point to be addressed.

By systematically assessing these endpoints, this study aims to inform future clinical guidelines and support the potential integration of ultra-hypofractionated RT into routine clinical practice for selected patients with localized STS.

Interventions

• Procedure hypofractionated radiotherapy (30Gy/5 fractions) and surgical resection at 1-2 weeks after treatment
  hypofractionated radiotherapy (30Gy/5 fractions) and surgical resection at 1-2 weeks after treatment
• Procedure hypofractionated radiotherapy (30Gy/5 fractions) and surgical resection at 4-6 weeks after treatment
  hypofractionated radiotherapy (30Gy/5 fractions) and surgical resection at 4-6 weeks after treatment

Primary outcome measures

• Determine the incidence of postoperative complications [Time frame: Day of surgery (DOS); 7-14-21-30-60-90 days post DOS; 4-8-12-16-20-24 months post DOS]

Secondary outcome measures (9)

• Quality of Life (QoL) [Time frame: At last available QoL assessment date for patients without confirmed deterioration]
• Overall Survival (OS) [Time frame: At the last date that patient was known to be alive]
• Disease-Free Survival (DFS) [Time frame: Months 4-8-12-16-20-24 post surgery]
• Cumulative Incidence of Local Recurrence (CCI-LR) [Time frame: Months 4-8-12-16-20-24 post surgery]
• Cumulative Incidence of Distant Metastasis (CCI-DM) [Time frame: Months 4-8-12-16-20-24 post surgery]
• Pathological response [Time frame: At any time during the study]
• Radiological response (RECIST 1.1 and CHOI) [Time frame: Months 4-8-12-16-20-24 post surgery]
• Treatment-related toxicity [Time frame: 7-14-21-30-60-90 days DOS, 4-8-12-16-20-24 months post DOS]
• Postoperative complications [Time frame: 7-14-21-30-60-90 days DOS, 4-8-12-16-20-24 months post DOS]

Eligibility criteria

Inclusion criteria

• Voluntary written informed consent, with the ability to fully understand and effectively communicate, before performance of any study-related procedure not part of normal medical practice, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
• Age > 18 years
• Proven diagnosis of primary, resectable extremity/trunk wall STS with low-medium risk (Sarculator© predicted 10y-OS > 60%)
• Measurable disease criteria (RECIST 1.1 and CHOI)
• ECOG: 0, 1 or 2 (if influenced by orthopedic condition and not by general status)
• No major contraindication to the planned radiotherapy or surgical treatment
• Active participation with adherence to requested treatment schedule and follow-up
• Female subject will undergo a negative pregnancy test
• Adequate bone marrow function (hemoglobin > 9g/dL, Leukocytes > 3000/mm³, platelets > 100,000/mm³). Patients with plasma creatinine ≤ 1.6 mg/dL, transaminase (AST-SGOT, ALT-SGPT) ≤ 2.5 times the UNL; total bilirubin ≤ 1.5 time the UNL; alkaline phosphatase ≤ 2.5 times the UNL are acceptable. CRP, LDH, total protein and albumin must also be recorded.
• HBV and HCV serologies must be performed prior to patient inclusion. If hepatitis B surface antigen (HBsAg) is positive, further evaluation is required to exclude active viral replication (i.e., testing for hepatitis B e antigen \[HBeAg\] and HBV DNA). If either of these markers is positive, study inclusion is not recommended. In such cases, prophylactic treatment with lamivudine may be considered at the investigator's discretion. If a potential participant tests positive for anti-HCV antibodies, active infection must be ruled out through a qualitative HCV PCR test. If PCR testing cannot be performed, or if it confirms active infection, the patient will not be eligible for the study. Patients must be HIV-seronegative, with a CD4+ T-cell count greater than 400/mm³. Individuals with clinically significant immunodeficiency-either congenital or acquired-are not eligible for enrollment

Exclusion criteria

• Age < 18y
• Soft tissue sarcomas (STS) originating at different sites (i.e., retroperitoneal, abdominal, pelvic, head and neck), gynecological sarcomas, as well as gastrointestinal stromal tumors (GISTs), desmoid-type fibromatosis and pediatric-type sarcomas (i.e., extraosseous Ewing sarcoma, embryonal/alveolar rhabdomyosarcoma, desmoplastic small round cell tumor) are excluded.
• Recurrent or metastatic condition or previous whoop-surgery for sarcoma (incisional biopsies are allowed if performed 6 months before referral).
• Unresectable tumors (with limb sparing surgery)
• Diagnosed oncological condition in the 5 years before enrollment (exceptions: Gleason <6 prostatic adenocarcinoma; In-situ cervical cancer and melanoma; basal cell skin carcinoma radically treated)
• Prior radiation treatment to the site designated for planned surgery or radiotherapy, regardless of indication
• Any medical condition that can impair and reduce life expectancy to less than 2 years including but not limited to significant systemic diseases grade 3 or higher on the CI-CTCAE v5.0 scale, that limit patient availability, or according to investigator judgment may contribute significantly to treatment toxicity
• Uncontrolled bacterial, fungal, or viral infections-either systemic or localized at the site of planned surgery or radiotherapy
• Severe psychiatric disorder, psychological, familial, social or geographic circumstances that limit the patient's ability to comply with the protocol or informed consent.
• Patients who had participated in another clinical trial and/or had received any other investigational product in the last 30 days prior to inclusion
• Patients who had received any other treatment for the disease under study including chemotherapy, radiotherapy, surgery or any other treatment with curative intent. incisional biopsies are allowed if performed 6 months before referral.
• Inability to comply with the requested follow-up
• Women who are pregnant or breast-feeding
• Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study
• BMI > 40 and BMI < 18

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Cury FL, Viani GA, Gouveia AG, Freire CVS, Grisi GA, Moraes FY. Meta-analysis of 5-day preoperative radiotherapy for soft tissue sarcoma (5D-PREORTS). Radiother Oncol. 2024 Jan;190:109935. doi: 10.1016/j.radonc.2023.109935. Epub 2023 Oct 25. PMID 37884194
• Guadagnolo BA, Baldini EH. Are We Ready for Life in the Fast Lane? A Critical Review of Preoperative Hypofractionated Radiotherapy for Localized Soft Tissue Sarcoma. Semin Radiat Oncol. 2024 Apr;34(2):180-194. doi: 10.1016/j.semradonc.2023.12.003. PMID 38508783
• Kosela-Paterczyk H, Teterycz P, Spalek MJ, Borkowska A, Zawadzka A, Wagrodzki M, Szumera-Cieckiewicz A, Morysinski T, Switaj T, Lugowska I, Castaneda-Wysocka P, Zdzienicki M, Goryn T, Rutkowski P. Efficacy and Safety of Hypofractionated Preoperative Radiotherapy for Primary Locally Advanced Soft Tissue Sarcomas of Limbs or Trunk Wall. Cancers (Basel). 2021 Jun 14;13(12):2981. doi: 10.3390/cancers1 PMID 34198676
• Bedi M, Singh R, Charlson JA, Kelly T, Johnstone C, Wooldridge A, Hackbarth DA, Moore N, Neilson JC, King DM. 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 Jan 25;7(3):100850. doi: 10.1016/j.adro.2021.100850. eCollection 2022 May-Jun. PMID 35647402
• Kalbasi A, Kamrava M, Chu FI, Telesca D, Van Dams R, Yang Y, Ruan D, Nelson SD, Dry SM, Hernandez J, Chmielowski B, Singh AS, Bukata SV, Bernthal NM, Steinberg ML, Weidhaas JB, Eilber FC. A Phase II Trial of 5-Day Neoadjuvant Radiotherapy for Patients with High-Risk Primary Soft Tissue Sarcoma. Clin Cancer Res. 2020 Apr 15;26(8):1829-1836. doi: 10.1158/1078-0432.CCR-19-3524. Epub 2020 Feb 13. PMID 32054730
• Guadagnolo BA, Bassett RL, Mitra D, Farooqi A, Hempel C, Dorber C, Willis T, Wang WL, Ratan R, Somaiah N, Benjamin RS, Torres KE, Hunt KK, Scally CP, Keung EZ, Satcher RL, Bird JE, Lin PP, Moon BS, Lewis VO, Roland CL, Bishop AJ. Hypofractionated, 3-week, preoperative radiotherapy for patients with soft tissue sarcomas (HYPORT-STS): a single-centre, open-label, single-arm, phase 2 trial. Lancet On PMID 36343656
• Bishop AJ, Mitra D, Farooqi A, Swanson DM, Hempel C, Willis T, Pearlnath C, Wang WL, Ratan R, Somaiah N, Benjamin RS, Torres KE, Hunt KK, Scally CP, Keung EZ, Satcher RL, Bird JE, Lin PP, Moon BS, Lewis VO, Roland CL, Guadagnolo BA. Moderately hypofractionated, preoperative radiotherapy in patients with soft tissue sarcomas (HYPORT-STS): Updated local control, late toxicities, and patient-reported PMID 39192597
• Ahmed SK, Xu-Welliver M, Dorr M, Steinert KO, Houdek MT, Rose PS, Karim SM, Ashman JB, Goulding KA, Siontis BL, Haddock MG, Petersen IA. Hypofractionated Preoperative Radiation Therapy for Extremity and Superficial Trunk Soft Tissue Sarcomas: Results of a Prospective, Phase 2 Trial. Int J Radiat Oncol Biol Phys. 2025 Nov 15;123(4):980-989. doi: 10.1016/j.ijrobp.2025.05.006. Epub 2025 May 17. PMID 40389098

Identifiers

NCT: NCT07265661 · STARS

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗