The primary objective of this trial is the evaluation of safety and feasibility of neoadjuvant hypofractionated irradiation in patients with extremity sarcoma using ions (protons or carbon ions) in raster scan technique. The primary endpoint is defined as the rate of wound healing disorders from beginning of radiotherapy to maximum 120 days after the planned tumor resection or discontinuation for any reason related to the treatment.
Secondary objectives include the assessment of local control (LC), local progression-free survival (LPFS) and disease-free survival (DFS). Overall survival (OS) will be calculated from the start of treatment until death or censoring. Quality of life (QoL) will be assessed using the EORTC-QLQ30 questionnaire.
The study is a parallel-group, prospective, randomized clinical trial with an adaptive two-stage phase II trial design (including a sample size recalculation at the interim analysis) for patients with extremity soft tissue sarcoma, randomized to one of the two treatment arms (arm A: proton therapy, arm B: carbon ion therapy). The total dose of 39 Gy (RBE) in 13 fractions will be prescribed in both arms. The accrual period of this trial will take approximately 2 years with a follow-up time of 12 months for each patient. Patients meeting the eligibility criteria and willing to participate will give written informed consent and will be enrolled at Heidelberg University Hospital.
Histologically confirmed soft-tissue sarcoma of the extremities with an indication for perioperative radiation treatment
Resectable or marginally resectable
Karnofsky index of ≥70%
Age ≥ 18 years
Carried out patient education and written consent
Patient is capable to give informed consent
Stage IV (distant metastases)
Lymph node metastasis
Metal implants that influence treatment planning with ions
Previous radiotherapy in the treatment area
Simultaneous participation in another clinical trial that could influence the results of the study.
Active medical implants for which no ion beam irradiation permit exists at the time of treatment (e.g., cardiac pacemaker, defibrillator)
Treatment planning and target volume delineation
Examinations for treatment planning consist of a CT scan (3-mm slice thickness) in treatment position and an MRI for 3D image correlation. The delineation of the extremity soft tissue sarcoma requires a T1-weighted post-gadolinium sequence.
Before performing the planning CT the prospective location of incision for the surgery is marked by the surgeon and subsequently in the contrast enhanced CT represented by a steel wire in order to spare this region in the treatment planning if possible.
Gross tumor volume (GTV) consists of the gross tumor based on CT and MRI imaging. The clinical target volume (CTV) covers the surrounding areas at risk for containing microscopic disease. The CTV includes the GTV with a lateral margin of 1-2 cm and a longitudinal margin of 3-4 cm. CTV extension is limited to the anatomical compartments and includes the tumor surrounding edema. The planning target volume (PTV) includes the CTV with an additional margin of 7 mm in beam direction and 5 mm in all other directions (Fig. 1).
Proton/carbon ion therapy
Treatment will be administered on an outpatient basis at the Heidelberg Ion-Beam Therapy Center (HIT) [17, 18]. Treatment planning is realized using a treatment planning system (RayStation) that enables conventional and biological optimization. Proton and carbon ion treatment is performed as active beam application (raster scanning method).
Dose prescription and constraints of critical organs at risk
The prescribed dose to the PTV is 39 Gy (RBE) in 13 fractions (5–6 fractions per week). It is estimated that the α/β value of soft tissue sarcoma is < 10; a consistent value cannot be found in literature. The equivalent photon dose in 2 Gy fractions (EQD2) is in the range of 48.8–42.2 Gy for a α/β = 2–10. There are no risk organs with specific dose constraints to be considered in the extremities.
Toxicity, safety, and quality of life
Adverse events and toxicity will be reported according to International Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 system. The results of clinical examinations as well as imaging studies (MRI or CT) will be included. Each patient will pass a baseline clinical examination after enrollment. Patients are monitored continuously during treatment, acute adverse events will be documented weekly as well as at the end of treatment. MRI of the according extremity will be planned 3 weeks and the resection 4–6 weeks after the end of radiotherapy. The first clinical follow-up presentation is 6 weeks after resection. Hereinafter all follow-ups include imaging studies and are performed 3, 6, 9, and 12 months after the tumor resection (Table 1). The criteria for feasibility and safety are fulfilled, if the rate of wound healing complications within 120 days after surgery is below 15% and if the therapy was not canceled, unless the reason for canceling is clearly not treatment related.
Quality of life (QoL) will be assessed by EORTC QLQ-C30 questionnaires. Repetitive completion of the forms is scheduled before treatment, 3 weeks after the end of radiotherapy, 6 months after surgery, and at the end of the study 12 months after surgery. Statistical analysis will be performed after complete acquisition of data. Changes in QoL before and after radiotherapy and before and after surgery will be determined. The two arms of the study will be compared after the end of radiation and at the end of the whole study.
The effectiveness of treatment is examined by regular MRI of the according extremity and thoracic CT follow-ups. Local control rate depicts the freedom from local progression. Local progression-free survival is defined as the survival probability from the beginning of radiotherapy until local progression. Disease-free survival is defined as the time from the beginning of radiotherapy until local or distant progression. The overall survival is defined as the time from the beginning of radiotherapy until the date of death due to any reason, until the end of the observation period or until the date of the last presentation in case the patient is lost to follow-up (censoring).
This study is performed to deliver basic data for the neoadjuvant hypofractionated carbon ion or proton radiation treatment of patients with extremity soft tissue sarcoma by providing safety and toxicity data for the here presented treatment regimen. The framework of the safety and feasibility considerations is the current standard neoadjuvant normofractionated photon radiotherapy; it is considered as the historical cohort which served for the planning of this pilot study. The randomization will be performed as block randomization at a ratio of 1:1 aiming at equal group sizes by using a web-based randomization tool (randomizer.at).
Due to the pilot character of the trial, all analyses are performed descriptively and the results are to be interpreted accordingly. The primary endpoint is assessed separately in each of the two treatment groups by applying an optimal adaptive two-stage phase II-design with one interim analysis according to Kunzmann and Kieser . This design is an adaptive variant of Simon’s design , where the sample size of stage two is chosen optimally based on the results of the interim analysis. It offers the possibility to prematurely terminate the study due to futility or early success at the timepoint of the interim analysis or allows data-driven recalculation of sample size for the second part of the study while adhering to the specified Type I and Type II error rates. The randomization will be performed as block randomization at a ratio of 1:1. After the interim analysis, dependent on the results, different sample sizes in both treatment arms may be required and the randomization ratio would then be adjusted accordingly. Under the null hypothesis, we would expect in both groups wound complications or dicontinuations to occur in ≥35% of the treated patients within 120 days after surgery, so the expected probability of patients with no wound complications and no discontinuation would be π ≤ 65% for both protons as well as carbon ions. Under the alternative hypothesis, we would expect less than 15% of the patients to have wound complications or discontinue therapy within 120 days after surgery with π ≥ 85% being the rate of patients without wound complications or discontinuation within 120 days after surgery.
Given these probabilities of success for the alternative and null hypothesis for the protons and carbon ion group, a statistical power of 1-β = 0.80 and a one-sided Type I error rate α = 0.05 for each of the two comparisons, the expected sample size under the null hypothesis is 25.59 and under the alternative hypothesis it amounts to 29.97; the maximum sample size in this design is 52. The interim analysis is performed when the data of 21 patients are available and therefore this is the minimum sample size. The recalculated sample sizes for stage 2 in both treatment arms depend on the patient number with a treatment success (no wound complications and no discontinuation). These values as well as the boundaries for early stopping and the decision boundaries after stage two are calculated according to Kunzmann and Kieser  with program code supplied by the authors. The estimation of success rates in both study arms is performed by calculation of point estimators  and calculation of two-sided 95%-Clopper-Pearson-type confidence intervals that take the adaptive two-stage design into account .
Analysis of the secondary time-to-event endpoints LPFS, DFS, and OS will be performed by the Kaplan–Meier method, patients without event will be censored. The treatment groups are compared using the logrank test. Quality of life will be measured by the EORTC-QLQ30 questionnaire and assessed by presentation of mean, standard deviation, median, minimum, and maximum as well as application of a two-sample t test. For the secondary endpoint local control, absolute and relative frequencies are calculated for each treatment group together with two-sided 95% Agresti–Coull confidence intervals, and an unconditional fourfold table test will be applied for treatment group comparison. Adverse and serious adverse events will be listed, and absolute and relative frequencies will be calculated.
The primary analysis for the primary and secondary endpoints is based on the intention-to-treat set including all study patients fulfilling the inclusion/exclusion criteria and having been treated for at least 1 week. Additionally, a per-protocol analysis is performed as sensitivity analysis which is based on all patients who have received the treatment as planned and for whom the relevant data is available. Safety endpoints are evaluated for all study patients for which the treatment has started.
Statistical analysis will be performed by the statistical software SAS v9.4 (SAS Institute, Cary, NC).
Data safety monitoring board
A Data and Safety Monitoring Board (DSMB) is composed of independent experts. The DSMB will monitor the recruitment, the reported (serious) adverse events as well as the quality of data. The goal is to ensure that the study is executed according to current standards of good clinical praxis with focus on the safety interest of the patients. The DSMB will give the principal investigator (PI) recommendations regarding trial modification, continuation, or premature termination.
Regular study end
The estimated period of patient accrual is 2 years. The regular end of treatment for the individual patient is 2 to 3 weeks after beginning of radiation therapy (13 fractions, 5–6 fractions per week). The regular study end for each patient is after 12 months after surgery. Patients will be then monitored by regular follow-ups according the current guidelines.
Premature study termination
Reasons for premature termination of the entire study are:
Unacceptable risks or toxicities (assessment by DSMB)
One toxicity of grade 5 or two consecutive grade 4 toxicities or five consecutive grade 3 toxicities unequivocally associated with the study therapy. The DSMB assesses and concludes whether a toxicity equal or higher than grade 3 is associated with the study treatment.
New scientific findings incompatible with the study treatment.
Collection and management of trial-related data
All data are collected pseudonymously and allocated to individual patient numbers. The study data are collected in form of case report forms. All important trial documents will be archived for at least 10 years according to the German GCP-Regulation. The documentation of written informed consent, the patients’ consent for trial and the documentation of irradiation will be archived for 30 years according to the German Radiation Protection Regulation (StrlSchV). The Study Center at the Department of Radiation Oncology will be responsible for storing all relevant data. For scientific evaluation of the study results, the disease-associated data will be saved pseudonymously. Access to the data will be provided to the patient on demand. The principal investigator can grand access to original files, additionally access can be commissioned by the state authorities. If a patient withdraws informed consent and does not agree with further storage and analysis, the so far acquired data material will be destroyed.
The trial is conducted in accordance to their current versions of the Declaration of Helsinki (2008 version of the Declaration of Helsinki, adopted at the 59th WMA General Assembly, Seoul, October 2008) and the guidelines of Good Clinical Practice (ICH-GCP: International Conference on Harmonization – Good Clinical Practice; May 1, 1996).
For comparison please also refer to the trial protocol of the Retro-Ion trial which investigates this radiotherapy regimen of preoperative hypofractionated particle radiotherapy for retroperitoneal sarcoma .
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