Study protocol for a multicenter phase II prospective externally controlled non-inferiority trial of hypofractionated re-irradiation in patients with recurrent high-grade glioma (RISinG)

A. M. de Jong; A. T. J. van der Boog; C. C. B. Post; F. Cialdella; D. B. P. Eekers; J. Hendrikse; M. C. A. Kramer; F. J. Lagerwaard; M. van der Meulen; M. E. P. Philippens; P. A. Robe; T. Rozema; F. Y. F. L. de Vos; J. Vos-Westerman; H. L. van der Weide; G. Wester; J. Zindler; T. J. Snijders; J. J. C. Verhoeff

doi:10.1371/journal.pone.0342337

Study protocol for a multicenter phase II prospective externally controlled non-inferiority trial of hypofractionated re-irradiation in patients with recurrent high-grade glioma (RISinG)

A. M. de Jong^*
, A. T. J. van der Boog
, C. C. B. Post
, F. Cialdella
, D. B. P. Eekers
, J. Hendrikse
, M. C. A. Kramer
, F. J. Lagerwaard
, M. van der Meulen
, M. E. P. Philippens
, P. A. Robe
, T. Rozema
, F. Y. F. L. de Vos
, J. Vos-Westerman
, H. L. van der Weide
, G. Wester
, J. Zindler
, T. J. Snijders
, J. J. C. Verhoeff

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Background Reirradiation is a widely accepted option for second-line treatment in patients with recurrent glioma. However, no standard radiation regimen has been defined. Hypofractionation is aimed at reducing patients' burden while maintaining the survival benefit, but may increase the risk of radionecrosis. The primary objective of this study is to determine if reirradiation in just 4 fractions is non-inferior to 10 fractions, regarding survival after reirradiation.Methods RISING trial A was an open label, randomized, non-inferiority, phase III trial with 1:1 allocation for 130 patients among all participating centers but failed to recruit according to planning. RISING trial B will be a phase II, multi-center, clinical trial with a historic control group. The experimental group receives 4 stereotactic fractions. The historic control group has received 10 fractions (standard-of-care) with a biologically equivalent dose on surrounding brain tissue. The primary endpoint is overall survival after reirradiation. The key secondary endpoint is progression-free survival. Other secondary endpoints are recurrence patterns, toxicity (specifically clinically relevant radionecrosis) and anti-edema treatment. We will collect and report on Health-Related Quality of Life (HRQoL) data in the experimental arm.Discussion We expect to demonstrate the non-inferiority and safety of a 4-fraction hypofractionation schedule for reirradiation of gliomas. This schedule may then become a standard-of-care option with minimal burden for patients with recurrent glioma, and limited use of scarce healthcare resources.Trial registration Registered at Netherlands Trial Register (NTR), Trial ID: NL72766.041.20, registered at 07-04-2020, https://www.onderzoekmetmensen.nl/en/trial/52643

Original language	English
Article number	e0342337
Number of pages	20
Journal	PLOS ONE
Volume	21
Issue number	2
DOIs	https://doi.org/10.1371/journal.pone.0342337
Publication status	Published - 9 Feb 2026

Keywords

QUALITY-OF-LIFE
STEREOTACTIC RADIOTHERAPY
ADJUVANT TEMOZOLOMIDE
EORTC QLQ-BN20+2
GLIOBLASTOMA
CONCOMITANT
ESCALATION
VALIDATION
EFFICACY
THERAPY

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10.1371/journal.pone.0342337Licence: CC BY

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de Jong, A. M., van der Boog, A. T. J., Post, C. C. B., Cialdella, F., Eekers, D. B. P., Hendrikse, J., Kramer, M. C. A., Lagerwaard, F. J., van der Meulen, M., Philippens, M. E. P., Robe, P. A., Rozema, T., de Vos, F. Y. F. L., Vos-Westerman, J., van der Weide, H. L., Wester, G., Zindler, J., Snijders, T. J., & Verhoeff, J. J. C. (2026). Study protocol for a multicenter phase II prospective externally controlled non-inferiority trial of hypofractionated re-irradiation in patients with recurrent high-grade glioma (RISinG). PLOS ONE, 21(2), Article e0342337. https://doi.org/10.1371/journal.pone.0342337

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title = "Study protocol for a multicenter phase II prospective externally controlled non-inferiority trial of hypofractionated re-irradiation in patients with recurrent high-grade glioma (RISinG)",

abstract = "Background Reirradiation is a widely accepted option for second-line treatment in patients with recurrent glioma. However, no standard radiation regimen has been defined. Hypofractionation is aimed at reducing patients' burden while maintaining the survival benefit, but may increase the risk of radionecrosis. The primary objective of this study is to determine if reirradiation in just 4 fractions is non-inferior to 10 fractions, regarding survival after reirradiation.Methods RISING trial A was an open label, randomized, non-inferiority, phase III trial with 1:1 allocation for 130 patients among all participating centers but failed to recruit according to planning. RISING trial B will be a phase II, multi-center, clinical trial with a historic control group. The experimental group receives 4 stereotactic fractions. The historic control group has received 10 fractions (standard-of-care) with a biologically equivalent dose on surrounding brain tissue. The primary endpoint is overall survival after reirradiation. The key secondary endpoint is progression-free survival. Other secondary endpoints are recurrence patterns, toxicity (specifically clinically relevant radionecrosis) and anti-edema treatment. We will collect and report on Health-Related Quality of Life (HRQoL) data in the experimental arm.Discussion We expect to demonstrate the non-inferiority and safety of a 4-fraction hypofractionation schedule for reirradiation of gliomas. This schedule may then become a standard-of-care option with minimal burden for patients with recurrent glioma, and limited use of scarce healthcare resources.Trial registration Registered at Netherlands Trial Register (NTR), Trial ID: NL72766.041.20, registered at 07-04-2020, https://www.onderzoekmetmensen.nl/en/trial/52643",

keywords = "QUALITY-OF-LIFE, STEREOTACTIC RADIOTHERAPY, ADJUVANT TEMOZOLOMIDE, EORTC QLQ-BN20+2, GLIOBLASTOMA, CONCOMITANT, ESCALATION, VALIDATION, EFFICACY, THERAPY",

author = "\{de Jong\}, \{A. M.\} and \{van der Boog\}, \{A. T. J.\} and Post, \{C. C. B.\} and F. Cialdella and Eekers, \{D. B. P.\} and J. Hendrikse and Kramer, \{M. C. A.\} and Lagerwaard, \{F. J.\} and \{van der Meulen\}, M. and Philippens, \{M. E. P.\} and Robe, \{P. A.\} and T. Rozema and \{de Vos\}, \{F. Y. F. L.\} and J. Vos-Westerman and \{van der Weide\}, \{H. L.\} and G. Wester and J. Zindler and Snijders, \{T. J.\} and Verhoeff, \{J. J. C.\}",

year = "2026",

month = feb,

day = "9",

doi = "10.1371/journal.pone.0342337",

language = "English",

volume = "21",

journal = "PLOS ONE",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "2",

}

de Jong, AM, van der Boog, ATJ, Post, CCB, Cialdella, F, Eekers, DBP, Hendrikse, J, Kramer, MCA, Lagerwaard, FJ, van der Meulen, M, Philippens, MEP, Robe, PA, Rozema, T, de Vos, FYFL, Vos-Westerman, J, van der Weide, HL, Wester, G, Zindler, J, Snijders, TJ & Verhoeff, JJC 2026, 'Study protocol for a multicenter phase II prospective externally controlled non-inferiority trial of hypofractionated re-irradiation in patients with recurrent high-grade glioma (RISinG)', PLOS ONE, vol. 21, no. 2, e0342337. https://doi.org/10.1371/journal.pone.0342337

Study protocol for a multicenter phase II prospective externally controlled non-inferiority trial of hypofractionated re-irradiation in patients with recurrent high-grade glioma (RISinG). / de Jong, A. M.; van der Boog, A. T. J.; Post, C. C. B. et al.
In: PLOS ONE, Vol. 21, No. 2, e0342337, 09.02.2026.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Study protocol for a multicenter phase II prospective externally controlled non-inferiority trial of hypofractionated re-irradiation in patients with recurrent high-grade glioma (RISinG)

AU - de Jong, A. M.

AU - van der Boog, A. T. J.

AU - Post, C. C. B.

AU - Cialdella, F.

AU - Eekers, D. B. P.

AU - Hendrikse, J.

AU - Kramer, M. C. A.

AU - Lagerwaard, F. J.

AU - van der Meulen, M.

AU - Philippens, M. E. P.

AU - Robe, P. A.

AU - Rozema, T.

AU - de Vos, F. Y. F. L.

AU - Vos-Westerman, J.

AU - van der Weide, H. L.

AU - Wester, G.

AU - Zindler, J.

AU - Snijders, T. J.

AU - Verhoeff, J. J. C.

PY - 2026/2/9

Y1 - 2026/2/9

N2 - Background Reirradiation is a widely accepted option for second-line treatment in patients with recurrent glioma. However, no standard radiation regimen has been defined. Hypofractionation is aimed at reducing patients' burden while maintaining the survival benefit, but may increase the risk of radionecrosis. The primary objective of this study is to determine if reirradiation in just 4 fractions is non-inferior to 10 fractions, regarding survival after reirradiation.Methods RISING trial A was an open label, randomized, non-inferiority, phase III trial with 1:1 allocation for 130 patients among all participating centers but failed to recruit according to planning. RISING trial B will be a phase II, multi-center, clinical trial with a historic control group. The experimental group receives 4 stereotactic fractions. The historic control group has received 10 fractions (standard-of-care) with a biologically equivalent dose on surrounding brain tissue. The primary endpoint is overall survival after reirradiation. The key secondary endpoint is progression-free survival. Other secondary endpoints are recurrence patterns, toxicity (specifically clinically relevant radionecrosis) and anti-edema treatment. We will collect and report on Health-Related Quality of Life (HRQoL) data in the experimental arm.Discussion We expect to demonstrate the non-inferiority and safety of a 4-fraction hypofractionation schedule for reirradiation of gliomas. This schedule may then become a standard-of-care option with minimal burden for patients with recurrent glioma, and limited use of scarce healthcare resources.Trial registration Registered at Netherlands Trial Register (NTR), Trial ID: NL72766.041.20, registered at 07-04-2020, https://www.onderzoekmetmensen.nl/en/trial/52643

AB - Background Reirradiation is a widely accepted option for second-line treatment in patients with recurrent glioma. However, no standard radiation regimen has been defined. Hypofractionation is aimed at reducing patients' burden while maintaining the survival benefit, but may increase the risk of radionecrosis. The primary objective of this study is to determine if reirradiation in just 4 fractions is non-inferior to 10 fractions, regarding survival after reirradiation.Methods RISING trial A was an open label, randomized, non-inferiority, phase III trial with 1:1 allocation for 130 patients among all participating centers but failed to recruit according to planning. RISING trial B will be a phase II, multi-center, clinical trial with a historic control group. The experimental group receives 4 stereotactic fractions. The historic control group has received 10 fractions (standard-of-care) with a biologically equivalent dose on surrounding brain tissue. The primary endpoint is overall survival after reirradiation. The key secondary endpoint is progression-free survival. Other secondary endpoints are recurrence patterns, toxicity (specifically clinically relevant radionecrosis) and anti-edema treatment. We will collect and report on Health-Related Quality of Life (HRQoL) data in the experimental arm.Discussion We expect to demonstrate the non-inferiority and safety of a 4-fraction hypofractionation schedule for reirradiation of gliomas. This schedule may then become a standard-of-care option with minimal burden for patients with recurrent glioma, and limited use of scarce healthcare resources.Trial registration Registered at Netherlands Trial Register (NTR), Trial ID: NL72766.041.20, registered at 07-04-2020, https://www.onderzoekmetmensen.nl/en/trial/52643

KW - QUALITY-OF-LIFE

KW - STEREOTACTIC RADIOTHERAPY

KW - ADJUVANT TEMOZOLOMIDE

KW - EORTC QLQ-BN20+2

KW - GLIOBLASTOMA

KW - CONCOMITANT

KW - ESCALATION

KW - VALIDATION

KW - EFFICACY

KW - THERAPY

U2 - 10.1371/journal.pone.0342337

DO - 10.1371/journal.pone.0342337

M3 - Article

SN - 1932-6203

VL - 21

JO - PLOS ONE

JF - PLOS ONE

IS - 2

M1 - e0342337

ER -

Study protocol for a multicenter phase II prospective externally controlled non-inferiority trial of hypofractionated re-irradiation in patients with recurrent high-grade glioma (RISinG)

Abstract

Keywords

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