Feasibility of Individualized, Model-guided Optimization of Proton Beam Treatment Planning in Patients With Low Grade Glioma (INDIGO)

Prospective Phase II Trial to Assess Feasibility of Individualized, Model-guided Optimization of Proton Beam Treatment Planning in Patients With Low Grade Glioma Multicentric, Prospective Interventional, Randomized, Observer Blind Two Arm (Active Control), Parallel Group Investigator-initiated Phase II Trial

Low-grade glioma (LGG) represent typically slowly growing primary brain tumors with world health organization (WHO) grade I or II who affect young adults around their fourth decade. Radiological feature on MRI is a predominantly T2 hyperintense signal, LGG show typically no contrast uptake. Radiotherapy plays an important role in the treatment of LGG. However, not least because of the good prognosis with long term survivorship the timing of radiotherapy has been discussed controversially. In order to avoid long term sequelae such as neurocognitive impairment, malignant transformation or secondary neoplasms initiation was often postponed as long as possible

Study Overview

• Status: Recruiting
• Conditions: Low Grade Glioma
• Intervention / Treatment: Other: standard treatment plan, no optimization; Other: model-guided optimization of treatment plan

Detailed Description

Since patients with low grade glioma are expected to become long-term survivors, the prevention of long-term sequelae is particularly important. In addition to disease progression, also treatment related side effects such as decline of neurocognitive function, endocrine impairment or sensorineural deficits can have a negative impact on patient's quality of life.

Owing to the biophysical properties of protons with an inverse depth dose profile compared to photons and a steep dose fall of to the normal tissue, there is a strong rationale for the use of PRT in the treatment of patients with low-grade glioma. Although data from large randomized trials are still missing there is increasing evidence from smaller prospective trials and retrospective analyses that the expected advantages indeed transform into clinical advantages.

However, in about 20 % of all patients, late contrast-enhancing brain lesions (CEBL) appear on follow-up MR images 6 - 24 months after treatment. At HIT in Heidelberg and at OncoRay in Dresden, CEBLs have been observed to occur at very distinct locations in the brain and relative to the treatment field. Retrospective analysis has elucidated potential key factors that lead to CEBL occurrence. However, avoidance of CEBLs is hardly feasible using conventional treatment planning strategies. Model-aided risk avoidance denotes the use of model-based CEBL risk calculations as an auxiliary tool for clinical treatment planning: Model-based risk calculations and risk reduction via software-based optimization help the clinician to minimize risk of CEBL occurrence during treatment planning.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Semi Harrabi, MD; Phone Number: 8201 +496221 56; Email: semi.harrabi@med.uni-heidelberg.de
• Study Contact Backup: Name: Adriane Lentz-Hommertgen, Phd; Phone Number: 8201 +496221 56; Email: adriane.lentz-hommertgen@med.uni-heidelberg.de

Study Locations

• Germany
  • Heidelberg, Germany, 69120
    • Recruiting
    • Department of Radiotherapy, University of Heidelberg
    • Contact: Juergen Debus, Prof. Dr. Dr.; Phone Number: 8200 +49 6221 56; Email: juergen.debus@med.uni-heidelberg.de
    • Contact: Adriane Hommertgen, Dr. med.; Phone Number: 34091 0622156; Email: adriane.hommertgen@med.uni-heidelberg.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age > 18 years
• histologically proven low-grade glioma
• indication for definitive or adjuvant radiotherapy
• ability to understand character and personal consequences of the clinical trial
• written informed consent

Exclusion Criteria:

• previous cerebral irradiation
• contraindication for contrast-enhanced MRI
• neurofibromatosis
• participation in another clinical trial with competing objectives

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard treatment plan; Model-based NTCP is calculated after plan approval, however, no further adjustments are to be made to the approved treatment plan	Other: standard treatment plan, no optimization; original treatment plans are not optimized
Experimental: Optimized treatment plan; Allocated to Control Calculation of normal tissue complication probability (NTCP) Model-guided replanning. Replanning is performed with Raysearch Raystation. Optimizations objectives are: the optimization objectives that control the maximum dose in the target volume employ a variable, LETd-dependent model for RBE that allows us to include the RBE-variations predicted by the NTCP model; the periventricular volume, defined as the volume closer than 4 mm to the ventricular wall, is included into the optimization with a constraint on its Equivalent Uniform Dose (EUD) and with the variable RBE model described above. Thereby, the combined effect of the RBE variation and increased sensitivity of the periventricular volume, as predicted by the NTCP model, is included. The effectiveness of the re-planning is verified by a second NTCP computation.	Other: model-guided optimization of treatment plan; original treatmant plans are optimized based on model-based NTCP

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
incidence of contrast enhancing brain leasions	the cumulative incidence of contrast enhancing brain lesions	observed within 24 months after PRT measured by quarterly contrast enhanced MRI of the brain

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
radiation-induced brain injuries	incidence of radiation-induced brain injuries > CTC°II	observed within 24 months after PRT measured by quarterly contrast enhanced MRI of the brain
progression-free survival	number of surviving patients without tumor progression	observed within 24 months after PRT measured by quarterly contrast enhanced MRI of the brain
overall survival	number of surviving patients	observed within 24 months after Proton Beam Therapy (PRT) measured by quarterly contrast enhanced MRI of the brain
patient reported outcome	patient reported outcome according to points on the PRO-CTCAE questionaire, scored 0/1 for absent/present)	up to 24 months after completion of radiotherapy
quality of life QLQ-C30	scores on the QLQ-C30 questionare, scored 0 (absence) to 5 (fully present)	up to 24 months after completion of PRT
quality of life QLQ-BN20	scores on the QLQ-BN20 questionare, scored 0 (absence) to 5 (fully present)	up to 24 months after completion of PRT

Collaborators and Investigators

• Sponsor: University Hospital Heidelberg

Study record dates

Study Major Dates

• Study Start (Actual): November 11, 2023
• Primary Completion (Estimated): November 11, 2026
• Study Completion (Estimated): November 11, 2028

Study Registration Dates

• First Submitted: July 19, 2023
• First Submitted That Met QC Criteria: July 19, 2023
• First Posted (Actual): July 28, 2023

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 4, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioma
• Other Study ID Numbers: RadOnk-Indigo

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No