Study design
The study is a multicenter, prospective, open-label, randomized, two-arm, phase III study, which will be conducted at 3 locations in Germany (Heidelberg, Marburg/Gießen, Stuttgart).
Objectives
Patients in the study will be treated either by modern intensity modulated photon irradiation (IMRT) technique (standard arm) or by proton beam radiotherapy (experimental arm). The aim of the GRIPS study is to prospectively test if the theoretical physical advantage of proton beam radiotherapy will translate into a clinical reduction of toxicity during and in the first months after therapy.
Endpoints
The primary endpoint is the cumulative rate of toxicity CTCAE ≥ grade 2 in the first 4 months. Secondary endpoints are progression-free survival (secondary endpoint of special interest), overall survival, acute and late toxicity, quality of life and neurocognition.
Additional scientific program
The influence of the irradiation technique on the lymphocyte count will be evaluated in an additional scientific program.
Inclusion criteria
Patients (Age ≥ 18 years, ECOG 0–2) with histologically confirmed glioblastoma (WHO grade 4) with indication for radiotherapy/chemoradiation.
Exclusion criteria
Patients who are not capable of giving consent, previous radiation therapy to the brain or skull base, active medical implants for which no approval for ion irradiation exists at the time of treatment (e.g., pacemaker, defibrillator, etc.), contraindication to MRI imaging, concurrent participation in another clinical trial that could affect the results of this trial or the other trial.
Randomization
Screened and eligible patients will be enrolled into the study after study initiation. To obtain similar distribution of prognostic variables in both treatment groups, each patient will be randomly assigned to treatment groups (1:1) in balanced permuted blocks. Stratification according to "fractionation scheme" (normofractionated/hypofractionated), "subventricular zone involvement" (yes/no) and synchronous chemotherapy (yes/no) will be applied using the web-based software randomizer.at (provided by the Institute of Medical Informatics, Statistics and Documentation of the Medical University of Graz (https://www.randomizer.at)). According to case number planning, 326 patients should be randomized, see Fig. 1.
Target volume delineation and radiotherapy application
The patient is positioned using a suitable fixation method (e.g. thermoplastic mask). Computed tomography must be performed natively in 3 mm slice thickness or less and, if possible, also with contrast medium.
Target volume definition will be performed according to the ESTRO-ACROP guideline and additional MRI sequences ([8]):
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GTV: contract-enhancing macroscopic tumor and/or resection cavity with contrast-enhancing residual tumor parts, taking into consideration planning MRI with preoperative scans and early postoperative imaging to prove for more precise delineation
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CTV: is defined as the GTV plus a 1.5-2.0 cm margin to account for microscopic spread. It should be defined considering anatomical borders and inclusion of abnormal (postoperative) T2-FLAIR signal
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PTV: CTV + 3 mm
In cases where the CTV accounts for > 25% of the total brain volume, a boost volume should be defined after 50 Gy, which covers only the GTV + 1.5-2 cm (without further consideration of abnormal T2-FLAIR signal).
Organs at risk (OAR) definitions and dose limitations for OARs are chosen according to table 2 of Niyazi et al. [8]. Expansion of OARs to create a planning risk volume (PRV) for OAR is applied when necessary and the margin should reflect the accuracy of daily set-up.
Photon radiotherapy is performed in all participating centers, while proton beam radiotherapy is performed at the Heidelberg ion beam therapy center (HIT) or Marburg ion beam therapy center (MIT) with 5 fractions per week. The applied dose is 30 x 2 Gy(RBE) or 33 x 1.8 Gy(RBE), or for patients treated according to the hypofractionation protocol ((4, 11)) due to age or comorbidities, with 15 x 2.67 Gy(RBE). Photon radiotherapy in the standard arm must be applied as IMRT. Treatment is applied with image guidance with frequency according to the location of the target volume, setup and/or the treating physician´s choice.
A possible administration of additional chemotherapy (synchronous or adjuvant) as well as tumor treating fields is applied in dosage and frequency according to the therapy standard outside of this study. The subject of the examination within this trial is only the different radiation quality.
Timeline of the study
The number and content of clinical visits correspond to those of standard therapy. The study-related additional effort results from the testing of neurocognition by means of the Hopkins Verbal Learning Test (HVLT-R; [9, 10]) and the regular completion of the quality-of-life questionnaires. The timeline with its different examinations is displayed in Table 1. Oncological follow-up begins 4 weeks after the end of radiotherapy. Further follow-up appointments are month 4, month 7, and subsequently every 3 months until month 25 (Table 1).
Table 1
Intervention and assessment schedule for the GRIPS trial
| |
Inclusion examination
|
RT
|
Examination after RT
|
V1: 4 weeks after RT
|
V2: month 4
|
V3: month 7
|
V4: month 10
|
V5: month 13
|
V6: month 16
|
V7: month 19
|
V8: month 22
|
V9: month 25
|
|
Screening
|
x
|
|
|
|
|
|
|
|
|
|
|
|
|
CRF form
|
x
|
|
x
|
x
|
x
|
x
|
x
|
x
|
x
|
x
|
x
|
x
|
|
QLQ-C30 und QLQ-BN20
|
x
|
|
x
|
|
x
|
|
|
x
|
|
|
|
|
|
Hopkins Verbal Learning Test-
Revised
|
x
|
|
x
|
|
x
|
|
|
x
|
|
|
|
|
|
Symptoms/ Toxicity according to CTCAE
|
x
|
|
x
|
x
|
x
|
x
|
x
|
x
|
x
|
x
|
x
|
x
|
|
MRI
|
xa
|
|
|
x
|
x
|
x
|
x
|
x
|
x
|
x
|
x
|
x
|
|
RT
|
|
x
|
|
|
|
|
|
|
|
|
|
|
|
Additional scientific program
|
x
|
|
x
|
x
|
x
|
|
|
|
|
|
|
|
| RT = radiotherapy |
| Screening: includes check of inclusion and exclusion criteria, taking of medical history including surgical and pathological report, medical examination and randomization |
| a MRI less than 4 weeks old, if older at time of inclusion, a new MRI for planning is mandatory |
Patients will be recruited over a period of 4 ¼ years, and the evaluation of the study results regarding the primary endpoint of the study (toxicity grade ≥ 2) will be evaluated 4 months after the end of radiation of the last patient. The end of the study is defined as the end of the follow-up period of the last patient (25 months after start of treatment).
Assessment of safety, toxicity and neurocognition
Acute and late radiotherapy toxicity will be assessed closely during and after therapy at each follow-up appointment using the NCI CTCAE version 5.0 criteria, quality of life will be measured using the EORTC questionnaires QLQ-C30 and QLQ-BN20. Neurocognition will be tested using Hopkins Verbal Learning Test-Revised.
Radiological assessment
Response assessment is evaluated primarily radiologically according to the RANO criteria, see Table 1 of the publication by Wen et al. [11]. Tumor progression is defined as a new contrast uptake outside of the radiation field (beyond the high-dose region or 80% isodose line) or at least a 25% increase in tumor volume (product of two diameters perpendicular to each other). Pseudoprogression is defined as contrast uptake in the first 3 months after radiotherapy if it stabilizes on subsequent MRI scans, according to table 2 by Wen et al. [12]. Newly appeared contrast uptake originating from the ventricular zone and not located in the area of the initial contrast uptake is primarily defined as radiogenic blood brain barrier disruption. If a lesion initially defined as a pseudoprogression or as a radiogenic barrier disruption, which may turn out to be a disease progression in the further course, the date of progression is backdated. All follow up MRIs are reviewed centrally.
Statistical considerations
The primary study objective is to demonstrate that the toxicity rate (rate of CTCAE toxicity grade ≥ 2) under proton therapy, πPr, is lower than the toxicity rate under photon therapy, πPh. Thus, the null hypothesis of the study is that the toxicity rate in the proton group is greater than or equal to the toxicity rate in the photon group, i.e., H0: \({\pi }_{A}^{Pr}\ge {\pi }_{A}^{Ph}\). For sample size planning, rates of \({\pi }_{A}^{Ph}=21\%\)for the photon group and \({\pi }_{A}^{Pr}=9\%\) for the proton group were assumed under the alternative hypothesis. This assumption results from a matched-pair analysis of the Heidelberg patient collective [6]. Under these assumptions, 276 evaluable patients (138 per group) are needed to reject the null hypothesis with a power of 1-β = 80% using the chi-square test at the one-sided significance level α = 0.025. Assuming a dropout rate of 15%, 326 patients (163 per group) will be included in the study. In the analysis, a logistic regression model will be applied for the evaluation of the primary endpoint adjusting for the confounders "fractionation," "subventricular zone involvement", and "synchronous chemotherapy". It is expected that this will increase power as compared to using the chi-square test. The secondary variables will be evaluated with methods of descriptive data analysis.
The intention-to-treat (ITT) population is the primary evaluation population for all efficacy endpoints and patient characteristics. The ITT population comprises all randomized patients which are evaluated in the treatment arm to which they were randomized. The per-protocol (PP) population includes all patients in the ITT population who received the planned therapy in its entirety and for whom documentation is complete with respect to the primary endpoint. The analyses of the PP population serve as sensitivity analyses, which will be used to investigate the robustness of the results from the ITT analysis. All patients in the ITT population in whom the planned therapy was started (at least 1 day) belong to the safety population and will be evaluated in the therapy arm to which they were treated. This is the primary evaluation population for the primary endpoint as well as for all other safety endpoints.
Ethics
The study protocol, patient information and consent form are approved by to the local Ethics Committees (S-204/2019 for Heidelberg, B-F-2021-052 for Stuttgart and positive approval for Marburg/Gießen from 08.05.2020). The procedures set out in this trial protocol are designed to ensure that all persons involved in the trial abide by ICH harmonized tripartite guideline on Good Clinical Practice (ICH-GCP) and the ethical principles described in the applicable version of the Declaration of Helsinki. The trial will be carried out in keeping with local legal and regulatory requirements.
Data quality assurance and Data safety monitoring board
To ensure data quality and consistency, quality control measures are performed regularly. For this purpose, contents are regularly checked by a monitor in 10% of all patients included up to this point (selected at random) as part of quality assurance. Furthermore, an independent Data Safety Monitoring Board (DSMB) will monitor enrollment, reported adverse events, PFS as the primary secondary endpoint, and data quality at least annually. Based on its report, the DSMB will make recommendations to the principal investigator regarding study modification, continuation or termination. The mission of the DSMB will be to ensure the ethical conduct of the study, as well as to protect the safety interests of the patients in the study.