SCOPES-II: short course of preoperative radiotherapy in head and neck, trunk and extremity soft tissue sarcomas – study protocol for a second randomised phase II clinical trial

Abstract

Introduction

Soft tissue sarcomas (STS) are rare malignant tumours typically treated with surgery in combination with radiotherapy and/or chemotherapy. Conventional preoperative radiotherapy (25×2 Gy) prolongs treatment duration up to 3–5 months, which can substantially have an impact on the patient’s burden. Moderate hypofractionated schedules (14–15×2.85–3 Gy) have shown comparable oncological outcomes and toxicity profiles to conventional treatment. Data on ultra-hypofractionated regimens, such as 5×6 Gy, suggest comparable outcomes. The SCOPES-II trial is designed to evaluate and compare a moderately hypofractionated radiotherapy regimen (14×3 Gy) with an ultra-hypofractionated schedule (5×6 Gy) in adults diagnosed with STS of intermediate or high histological grade.

Methods and analysis

This international, multicentre, randomised phase II trial will include 150 adult patients with localised STS showing intermediate or high tumour grade, arising in the head and neck region, trunk, chest wall or limbs. Patients assigned to arm A will receive preoperative radiotherapy delivered as 14 fractions of 3 Gy, whereas those in arm B will undergo treatment consisting of 5 fractions of 6 Gy. In both treatment arms, surgical resection is planned approximately 6 to 8 weeks following completion of radiotherapy. The primary endpoint is the rate of postoperative wound-related complications occurring within 120 days after surgery. Secondary objectives comprise assessment of oncological efficacy, including local control and the development of distant disease, evaluation of late radiation-associated toxicities, patient-reported Health-Related Quality of Life (HRQoL) and an analysis of cost-effectiveness.

Ethics and dissemination

Ethical approval for this trial has been obtained from the relevant Medical Ethics Committees (METc) in both the Netherlands (Medisch-Ethische Toetsingscommissie NedMec NL009842) and Poland (43/2026). Written informed consent will be obtained from all participants before inclusion in the study. The findings of this trial will be shared through publication in international peer-reviewed journals.

Trial registration number

NCT07071727.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• This is the first randomised, international, multicentre phase II trial directly comparing moderate hypofractionated and ultra-hypofractionated preoperative radiotherapy schedules in soft tissue sarcoma.

• Standardised collection of clinical, patient-reported and health economic outcomes enables comprehensive assessment using predefined methodologies.

• Inclusion of multiple soft tissue sarcoma histotypes may introduce biological heterogeneity that could affect treatment outcome estimates.

Introduction

Soft tissue sarcomas (STS) constitute a heterogeneous group that are mostly treated with surgery combined with radiotherapy and/or chemotherapy. Treatment is influenced by a combination of tumour-related and patient-related factors, including histological grade, tumour dimensions, anatomical site and the presence of patient comorbidities. The combination of surgery and radiotherapy is associated with improved local control.¹

Preoperative radiotherapy consisting of 25 fractions of 2 Grey (Gy), followed by a waiting period of 6–8 weeks before surgery, results in an overall treatment duration of approximately 3–5 months. Shortening the treatment duration with the aim to maintain local control has the potential to lessen both the physical and emotional impact on patients.

Radiobiological evidence suggests that STS have a relatively low α/β ratio, potentially making them more sensitive to hypofractionation.² Evidence from the HYPORT-STS trial (NCT03819985), the Mayo Clinic confirmation trial (NCT04562480) and pandemic-driven moderate hypofractionated data (IRB approved W236704) indicate that preoperative radiotherapy delivered in 14–15 fractions of 2.85–3 Gy yields toxicity profiles and oncological outcomes comparable to those achieved with the conventional 25×2 Gy regimen.^3–6 Despite the substantial number of patients included, these investigations were conducted as single-arm studies, underscoring the need for randomised comparative trials to formally establish equivalence in safety and efficacy. Currently, both regimens are compared in the Short Course Of Preoperative Radiotherapy in Head and Neck-, Trunk- and Extremity Soft Tissue Sarcomas: a randomised phase II clinical trial (SCOPES, NCT04425967) trial).⁷ All patients have been included in the study, and the final results are awaited.

As previously stated by Baldini et al, some further research has been conducted into ultra-hypofractionation.⁸ These studies varied in regimens, patient populations and study designs and reported results ranging from local control rates of 81 to 100% with ≥grade 2 late toxicities ranging from 9 to 41%.^9–12 Of these studies, the 5×6 Gy regimen over 5 days has yielded the most promising results to date as it most closely resembles conventional and moderate hypofractionated schedules in terms of both EQD2 doses and toxicity profiles.¹³

The short course of preoperative radiotherapy in head and neck, trunk and extremity soft tissue sarcomas: a second randomised phase II clinical trial (SCOPES-II, NCT07071727) is an international, multicentre trial to compare a moderately hypofractionated preoperative radiotherapy approach with an ultra-hypofractionated schedule. By directly evaluating these treatment strategies, the trial aims to provide high-quality evidence regarding local control, acute and late treatment-related toxicities, health-related quality of life (HRQoL) and economic impact. These results may help refine current treatment strategies and enhance outcomes for patients with STS.

Methods and analysis

This study is designed as an international, multicentre, randomised, prospective phase II clinical trial with two parallel treatment groups. Participants will be assigned to one of two preoperative radiotherapy strategies. In the first group (arm A), patients will receive moderately hypofractionated radiotherapy delivered to a total dose of 42 Gy, administered as 14 fractions of 3 Gy given once daily over a period of approximately 3 weeks. In the second group (arm B), radiotherapy will be delivered using an ultra-hypofractionated approach, consisting of a total dose of 30 Gy in five daily fractions of 6 Gy, completed within 1 week. For both treatment arms, surgical resection is planned to take place within a window of 6–8 weeks following completion of radiotherapy. The primary aim of the trial is to evaluate and compare the rates of postoperative wound-related complications occurring within 120 days after surgery between the two treatment groups.

Postoperative wound complications will be classified using the criteria in the CAN-NCIC SR-2 trial.¹ Complications necessitating reoperation, including procedures such as surgical debridement or drainage, will be categorised as major. Events requiring additional wound management without the need for a secondary surgical intervention, such as invasive procedures not involving general or regional anaesthesia (except for a single seroma aspiration), hospital readmission for wound care, or prolonged deep wound packing, will be considered as moderate complications. Wound complications that resolve without intervention or require only non-invasive measures, including treatment with oral antibiotics, will be classified as minor complications.

In addition to the primary endpoint, the study will assess secondary outcomes related to disease control and safety. These include analysis of oncological outcomes, specifically the occurrence of local tumour recurrence and the development of distant metastatic disease, as well as the evaluation of late adverse treatment effects. Toxicities will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.¹⁴ Further exploratory analyses will focus on patient-centred and economic outcomes, including health-related quality of life (HRQoL) and cost-effectiveness. HRQoL will be evaluated through validated questionnaires administered at predefined intervals throughout the study trajectory: prior to the initiation of treatment, at completion of neo-adjuvant radiotherapy, in the preoperative period, 1 month following surgery, and subsequently during annual follow-up visits for a duration of 5 years.¹⁵

Participants will be identified and enrolled through the multidisciplinary sarcoma tumour boards of collaborating centres in the Netherlands and Poland (Supplementary File (online supplemental file 1)1). No incentives will be offered to participants for taking part in this study. The study population will consist of adult patients with a pathological diagnosis of STS of intermediate or high grade, arising in the head and neck area, trunk or chest wall, or the extremities, for whom neo-adjuvant radiotherapy followed by surgical resection represents the standard of care approach. Eligible participants must meet at least one of the following criteria: a deep anatomical location (deep to the superficial fascia), a maximum tumour diameter of 5 cm or greater, an expected risk of narrow surgical margins, or classification as grade two or three according to the FNCLCC grading system. Prior to study participation, all patients will be required to provide written informed consent.

Sample size estimation was based on the Simon’s randomised phase II design.^16–19 Assuming a complication rate of 30% in the treatment arm with the lowest complication rate and 40% in the treatment arm with the highest complication rate (an absolute difference of 10%), a total of 75 evaluable patients per arm is required to select the best treatment with 90% probability.

The aim is to identify a safe treatment (with a manageable number of postoperative wound complications) to further proceed with a phase III trial.

Statistics

Baseline characteristics of the study population, including tumour site, demographic variables (age and sex), comorbidity profile and any previous history of major wound-related complications after surgery, will be summarised using descriptive statistics. Numerical variables will be expressed as mean values accompanied by their SE; when distributions deviate from normality, results will instead be presented as medians with corresponding minimum and maximum values. Categorical data will be reported as proportions.

For each treatment group, the proportion of patients experiencing a postoperative wound complication within 120 days after surgery will be calculated and compared. Wound complications will be classified as major, moderate, or minor according to CAN-NCIC-SR2 criteria, and the rates of each category will be reported descriptively. According to the Simon’s randomised phase II design, the regimen with the lowest overall postoperative wound complication (combining moderate and major wound complications) rate will be considered the preferred strategy. Patients who do not undergo surgery will not be included in the postoperative wound complication analysis.

To estimate the cumulative incidence of local control from surgery, a competing risk model will be employed, with distant metastasis and death as competing events.²⁰ Differences in cumulative incidence between arms will be assessed using Grey’s test.²¹ A cause-specific hazard model will be estimated to study the effect of treatment on oncological outcome. As HRQoL is assessed repeatedly over time from all included patients, longitudinal analyses will be performed using linear mixed-effects models, incorporating patients as random effects.

Cost-effectiveness

An economic evaluation will be performed using a decision-analytic framework with a lifetime time horizon, comparing ultra-hypofractionated preoperative radiotherapy (5×6 Gy) with the moderately hypofractionated approach (14×3 Gy). Incremental cost-effectiveness ratios (ICERs) will be derived from the relative differences in both clinical outcomes and costs, considering short-term outcomes (based on trial observations up to 120 days post-surgery) as well as long-term outcomes (from follow-up data and literature including survival). Analyses will be conducted from both a societal and a hospital perspective within the Dutch healthcare setting, in accordance with established guidelines for health economic evaluations.²² Future costs and health outcomes will be discounted at annual rates of 3% and 1.5%, respectively, as recommended in national guidelines.²³

Patient and public involvement (PPI)

A representative (G.F.) of the Sarcoma Patients Advocacy Global Network (SPAGN) was involved in the development of the study protocol.

Data availability/sharing statement

Not applicable, as data collection and statistical analyses have not yet commenced. All study data will be pseudonymised and securely stored within an approved cloud-based data management system. Access to the data will be restricted to authorised members of the research team. Principal investigators will have access to the finalised dataset from their respective study site, while access to datasets from other sites may be granted on reasonable request and in accordance with data-sharing procedures. Study findings will be disseminated through scientific publications and presentations, irrespective of the direction or significance of the results.

Study accrual

Inclusion started in December 2025, with an anticipated primary completion date of 1 November 2028 and study completion expected by 1 November 2033. Participating centres are The Netherlands Cancer Institute (NKI-AvL), Leiden University Medical Center (LUMC), University Medical Center Groningen (UMCG), Radboud University Medical Center (RUMC), Amsterdam University Medical Center (AUMC), and Maastricht University Medical Centre (MAASTRO).

Ethics and dissemination

This study will be conducted in agreement with the latest version of the Declaration of Helsinki (75th WMA General Assembly, October 2024) and the laws and regulations of the participating countries, whichever provides the greatest protection of the patient. The protocol has been written, and the study will be conducted according to the ICH Harmonized Tripartite Guideline for Good Clinical Practice. The protocol has been approved by the Local, Regional, or National Ethics Committees (irb@nki.nl). The conduct of the study will conform to the Medical Research Involving Human Subjects Act (WMO) and all pertinent Dutch laws and regulations. All participants will provide written informed consent prior to enrolment. Study data will be pseudonymised and handled in compliance with national and international data protection regulations. The results of the trial will be disseminated through peer-reviewed publications, conference presentations, and communication with patient organisations.