Dose-escalated, Hypofractionated, Definitive Proton Radiotherapy for Patients With Inoperable Soft Tissue Sarcoma.

PROSARC-2. Dose-escalated, Hypofractionated, Definitive Proton Radiotherapy for Patients With Inoperable Soft Tissue Sarcoma. A Single-arm, Multicenter, Phase II Clinical Trial.

The purpose of the study is to study if dose escalated proton radiotherapy can improve local controll for patients with inoperable soft tissue sarcomas. The standard treatment is photon-based radiation. By using proton radiotherapy instead, the hypothesis is that the dose can be increased to enhance treatment effectiveness without increasing side effects.

The planned radiation dose is 56 Gy in 16 fractions (treatments) over 4 weeks (4 fractions per week), with a maximum dose escalation centrally in the tumor up to 80 Gy (5 Gy per fraction).

At the same time, the study will investigate biomarkers that can predict treatment response, including changes in the tumor's genetic material (DNA), measurements of various molecules in the bloodstream, and the tumor's appearance on MRI scans.

The primary endpoint is local control after 2 years, meaning that the treated tumor has not grown during this period. Secondary endpoints include overall survival, progression-free survival, radiological response rates, side effects, and quality of life.

The study will be conducted in Norway, with a planned inclusion of 40 patients.

The objective of the PROSARC-2 trial is to investigate whether dose-escalated hypofractionated, definitive, proton beam therapy (PBT) can result in better local control in soft tissue sarcoma (STS). PROSARC-2 is a single arm, open-label, multicenter phase II clinical trial initiated at the Department of Oncology, Oslo University Hospital (OUS). The main inclusion criterion is patients with inoperable soft tissue sarcoma. The primary endpoint is 2-year local progression-free survival (LPFS). We expect to include 40 patients over three years and all patients will be followed for up to five years. All the sarcoma centers in Norway participate in the study: OUS; Haukeland University Hospital (HUH); St Olavs Hospital (SOH) and University Hospital of North-Norway (UNN). The indication for definitive radiotherapy (RT) will be decided in the sarcoma multidisciplinary (MDT) meeting at each center. A weekly/biweekly national sarcoma RT meeting will make the decision whether hypofractionated, dose-escalated PBT will be feasible after a careful clinical evaluation. For included patients PBT will be given at OUS and HUH. The prescribed dose is 56 Gray (Gy) in 16 fractions over 4 weeks (14 Gy per week) with a maximum dose-escalation to the tumor core of 80 Gy (5 Gy per fraction).

The PROSARC-2 trial includes translational radiomic research, where we aim to elucidate underlying mechanisms related to RT effect. To facilitate future biomarker studies for personalized therapy we will collect excess tumor tissue, whole blood, plasma and serum.

Inclusion Criteria:

1. ≥ 18 years of age at the time of informed consent.
2. Histological diagnosis of soft tissue sarcoma including gastrointestinal stromal tumor (GIST).
3. Measurable disease according to RECIST v1.1.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
5. For patients with metastatic disease a life-expectancy greater than 2 years should be expected.
6. Before patient registration, written informed consent must be given according to national and local regulations.
7. Ability to fill in patient questionnaires and comply with study procedures, including travelling to Bergen or Oslo for Proton Beam radiotherapy.

Exclusion Criteria:

1. Patients with a prior or concurrent malignant disease whose natural history or treatment have the potential to interfere with the safety or efficacy assessment of this clinical trial are not eligible. Patients with a history of breast cancer, requiring continued hormonal treatment (e.g. anti-estrogen or an aromatase inhibitor) may be included. Patients with a history of prostate cancer, requiring continued support with luteinizing hormone releasing hormone (LHRH) agonists, with or without androgens, may be included.
2. Previous radiotherapy to the tumor site.
3. Patients with pacemakers and/or implanted defibrillators.
4. Patients not able to give an informed consent or comply with study regulations as deemed by study investigator.
5. Administration of systemic cancer therapy (i.e. chemotherapy, targeted therapy or immune therapy) within 14 days prior to the first fraction of radiotherapy.