Preoperative Proton Irradiation for High-grade Brain Gliomas.

Official title

Proton PREoperative STereotactic Irradiaiton for High-grade Gliomas (PPrestige): a Single-center Prospective Interventional Pahse 1 Trial

Overview

The goal of this clinical trial is to learn if preopearative proton therapy (PPT) is tolerable in patients with High-grade brain gliomas. It will also learn about the influence on surgical procedure, clinical effects and safety of regular treatment. The main questions it aims to answer are: Does preoprative proton therapy well-tolerated? What maximal dose of PPT is safe? Proposed Treatment Stages 1. Multidisciplinary board (neurosurgeon, radiation therapist, and medical oncologist) decision of patient enrollment. 2. Course of preoperative proton stereotactic radiotherapy (PSRT) directed at the tumor only: GTV=contrast-part of brain giloma, CTV=GTV. Dose regimens: first 3 patients - 4 Gy(RBE) × 5 fractions; subsequent 3 patients - 5 Gy(RBE) × 5 fractions; subsequent 3 patients - 6 Gy(RBE) × 5 fractions. RBE = Relative biological efficacy, equal 1.1 for protons. Should any information regarding unacceptable treatment toxicity emerge, the study will be terminated. 3. Microsurgical resection of the contrast-enhancing portion of the tumor using fluorescence microscopy and, when indicated, neurophysiological monitoring. 4. Contrast-enhanced MRI to assess the resection volume within the first 24-48 hours after surgery. 5. Follow-up evaluation - clinical, morphological, and radiological assessment of the effects of the preoperative and surgical treatment stages, performed 3-4 weeks after the surgical phase. 6. Standard treatment and follow-up: Chemoradiotherapy with a scanned proton beam combined with temozolomide 75 mg/m², given at 2 Gy × 30 fractions, to commence 4-6 weeks after surgery. Adjuvant chemotherapy with temozolomide 150-200 mg/m² on a 5/23 schedule (maintenance chemotherapy), for 12 cycles or until disease progression/unacceptable toxicity. 7. Follow-up - control examinations every 1 month after completion of chemoradiotherapy, then every 3 months for the first year.

Detailed description

High grade gliomas (HGG), especially glioblastomas, are among those disease, for which oncological science doesn't propose any improvements for several decades, since temozolomide became a part of therapy. Preoperative irradiation is a standard of care for various malignant diseases. Historically, for intracranial targets preoperative RT is a taboo. Besides, recent data from preoperative RT of brain metastasis showed promising results and good toxicity profile. We would like to investigate the hypotheses of preoprative proton short-course irradiation can be tolerable and potentially improve outcomes in HGG patients.

High-grade gliomas (astrocytomas CNS WHO grade 3-4, glioblastomas, etc) are the most common primary brain tumors, with an extremely poor survival prognosis and a median overall survival of approximately 15-18 months \[1, 2\]. Recent advances in drug therapy have, unfortunately, not made a substantial contribution to improving treatment outcomes. Therefore, novel approaches to enhance treatment efficacy are more relevant than ever, and over the past decades, the use of radiotherapy has indeed improved survival in these patients. The standard treatment protocol currently includes maximal safe surgical resection followed by chemoradiotherapy, which is initiated 4-6 weeks after surgery \[3\]. However, microscopic foci of tumor cells in the postoperative period may proliferate and become manifest even before the start of radiotherapy. A recent meta-analysis showed that 40-50 % of patients with high-grade gliomas experience disease progression already during the interval between surgery and adjuvant treatment \[4\]. Since complete tumor resection is virtually unattainable, intensification of preoperative treatment may represent an effective option, as it targets the disease at an earlier and potentially more vulnerable stage \[5\].

There is considerable interest in early treatment strategies for high-grade gliomas that target the pre-, intra-, or early postoperative tumor microenvironment \[5\]. Preoperative radiotherapy is of particular interest, given the encouraging results observed in many other tumor types; however, it has never been applied to high-grade gliomas before \[6, 7, 8, 9\]. The preoperative period offers more favorable therapeutic characteristics compared with the postoperative tumor microenvironment, including less tumor hypoxia and molecular heterogeneity, which may consequently enhance the effectiveness of irradiation at this stage \[5\]. Data from dose-escalation safety studies suggest that a radiation dose additional to the standard postoperative regimen (60 Gy/30 fractions) can be delivered safely, but it remains unclear whether dose escalation can improve patient outcomes \[10\]. Currently, there are only a limited number of studies on preoperative radiotherapy for high-grade gliomas at various stages of preclinical and clinical investigation \[6, 11, 12\].

Proton therapy is currently the most sparing modality of radiotherapy, allowing, through its unique dose-distribution characteristics, a significant reduction in exposure to normal tissues-a particularly important consideration when irradiating the brain \[13\]. The use of proton therapy has been widely established both in primary tumors of the nervous system, including extreme dose escalation in glioblastomas, and in re-irradiation settings \[14, 15\]. Accumulated clinical experience suggests that the application of protons in the pre- and postoperative setting in patients with high-grade gliomas of the brain may minimize the risks of radiation complications and open up new therapeutic opportunities for this disease.

Interventions

• Radiation Preoperative irradiation
  After enrollment patientswith radiological signs of HGG will be irradiated by pencil beam protons in the following regimens: 3 pts - 4 GyRBE (RBE = 1.1) x 5 Fx; 3 pts - 5 GyRBE x 5 Fx; 3pts - 6 GyRBE x 5 Fx.

Primary outcome measures

• Acute and late radiation-induced toxicity [Time frame: 12 months]

Secondary outcome measures (3)

• Clinical effects [Time frame: 12 months]
• Maximal dose of preoperative irradiation [Time frame: 12 months]
• Postoperative safety [Time frame: 12 months]

Eligibility criteria

Inclusion criteria

• radiologically confirmed (MRI and/or PET with amino-acids) diagnosis of high-grade glioma
• single foci
• ECOG 0-2 status
• tumor location and volume, eligible for gross total resection (GTR)
• signed informed consent

Exclusion criteria

• multifocal disease
• ECOG 3-4
• inability to achieve GTR

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

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Russia · 1 center

• Proton Therapy Department, A. Tsyb Medical Radiological Research Center - branch of the Na — Obninsk

Publications

• McClelland S 3rd, Yeboa DN. The Emerging Paradigm of Preoperative Stereotactic Radiosurgery for Resectable Brain Metastases. JAMA Oncol. 2023 Aug 1;9(8):1073-1074. doi: 10.1001/jamaoncol.2023.1342. No abstract available. PMID 37289443
• Ivy SP, Siu LL, Garrett-Mayer E, Rubinstein L. Approaches to phase 1 clinical trial design focused on safety, efficiency, and selected patient populations: a report from the clinical trial design task force of the national cancer institute investigational drug steering committee. Clin Cancer Res. 2010 Mar 15;16(6):1726-36. doi: 10.1158/1078-0432.CCR-09-1961. Epub 2010 Mar 9. PMID 20215542
• Bisello S, Cilla S, Benini A, Cardano R, Nguyen NP, Deodato F, Macchia G, Buwenge M, Cammelli S, Wondemagegnehu T, Uddin AFMK, Rizzo S, Bazzocchi A, Strigari L, Morganti AG. Dose-Volume Constraints fOr oRganS At risk In Radiotherapy (CORSAIR): An "All-in-One" Multicenter-Multidisciplinary Practical Summary. Curr Oncol. 2022 Sep 27;29(10):7021-7050. doi: 10.3390/curroncol29100552. PMID 36290829
• Dohopolski M, Schmitt LG, de Vis J, Mostardeiro TR, Anand S, Youssef M, Noch E, Maher E, Sun M, Patel T, Patel A, Barnett S, Lee M, Iakovenko V, Chiu T, Su FC, Pompos A, Lin MH, Cai X, Timmerman R, Dan T, Wardak Z. Comparative Outcomes of Standard Radiation Therapy and 5-Fraction Adaptive Stereotactic Radiation Therapy in Newly Diagnosed Glioblastoma: A Propensity Score-Matched Analysis. Adv Radia PMID 40611877
• Gulidov I, Gordon K, Semenov A, Gogolin D, Lepilina O, Golovanova O, Dujenko S, Medvedeva K, Koryakin S, Ivanov S, Kaprin A. Proton re-irradiation of unresectable recurrent brain gliomas: clinical outcomes and toxicity. J BUON. 2021 May-Jun;26(3):970-976. PMID 34268961
• Matsuda M, Mizumoto M, Kohzuki H, Sugii N, Sakurai H, Ishikawa E. High-dose proton beam therapy versus conventional fractionated radiation therapy for newly diagnosed glioblastoma: a propensity score matching analysis. Radiat Oncol. 2023 Feb 23;18(1):38. doi: 10.1186/s13014-023-02236-1. PMID 36823671
• Kiseleva V, Gordon K, Vishnyakova P, Gantsova E, Elchaninov A, Fatkhudinov T. Particle Therapy: Clinical Applications and Biological Effects. Life (Basel). 2022 Dec 9;12(12):2071. doi: 10.3390/life12122071. PMID 36556436
• Fernandez-Gil BI, Schiapparelli P, Navarro-Garcia de Llano JP, Otamendi-Lopez A, Ulloa-Navas MJ, Michaelides L, Vazquez-Ramos CA, Herchko SM, Murray ME, Cherukuri Y, Asmann YW, Trifiletti DM, Quinones-Hinojosa A. Effects of PreOperative radiotherapy in a preclinical glioblastoma model: a paradigm-shift approach. J Neurooncol. 2024 Sep;169(3):633-646. doi: 10.1007/s11060-024-04765-5. Epub 2024 Jul PMID 39037687

Identifiers

NCT: NCT07710040 · 29_06_2026_PPrestige

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗