Re-irradiation as salvage treatment in recurrent glioblastoma: A comprehensive literature review to provide practical answers to frequently asked questions

doi:10.1016/j.critrevonc.2018.03.024

Critical Reviews in Oncology/Hematology

Volume 126, June 2018, Pages 80-91

https://doi.org/10.1016/j.critrevonc.2018.03.024 Get rights and content

Highlights

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Literature on reirradiation options for glioblastoma was comprehensively reviewed.
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Existing data on the efficacy and toxicity of various schedules have been reviewed.
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Both exclusive and concurrent approach were explored.
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Recommendations for dose prescription and fractionation were provided.
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Practical suggestions about patient selection and radiotherapy planning were given.

Abstract

The primary aim of this review is to provide practical recommendations in terms of fractionation, dose, constraints and selection criteria to be used in the daily clinical routine.

Based on the analysis of the literature reviewed, in order to keep the risk of severe side effects ≤3,5%, patients should be stratified according to the target volume. Thus, patients should be treated with different fractionation and total EQD2 (<12.5 ml: EQD2 < 65 Gy with radiosurgery; >12.5 ml and <35 ml: EQD2 < 50 Gy with hypofractionated stereotactic radiotherapy; >35 ml and <50 ml: EQD2 < 36 Gy with conventionally fractionated radiotherapy).

Concurrent approaches with temozolomide or bevacizumab do not seem to improve the outcomes of reirradiation and may lead to a higher risk of toxicity but these findings need to be confirmed in prospective series.

Introduction

The median overall survival of patients with GBM remains inferior to 15 months and nearly all patients recur eventually: in the long term follow-up of patients included in the European Organization for Research and Treatment of Cancer (EORTC)/ National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) trial (Stupp et al., 2005), only 6% were progression-free at 3 years (Stupp et al., 2009).

Median survival after progression for patients initially treated with temozolomide and radiotherapy is very poor (6.2 months in the EORTC/NCIC-CTG trial (Stupp et al., 2009)).

Feasible approaches for recurrent glioblastoma in patients with a good performance status are second surgery, reirradiation, systemic treatment or multimodal treatment, whereas best supportive care is the preferable option for patients with poor performance status.

In this paper, existing data on the efficacy and toxicity of various radiation treatment options including RS, HFSRT, and CFRT have been reviewed.

The interpretation of the literature is very difficult due to the retrospective nature of the majority of the studies on different treatment modalities, fractionation schedules and selection criteria.

The main pitfall of the existing studies is the extreme heterogeneity in baseline characteristics of the patients: some series included recurrent grade III or II gliomas as well, not only pure astrocytomas; some authors included temozolomide-naïve patients too; while some studies did not exclude cases of early progression, likely to be pseudoprogression.

Moreover, the different measures of the outcome of the different studies further complicated the analysis of the literature findings. Of note, although survival may not be an adequate measure to evaluate the outcome in this scenario (Ballman et al., 2007), other measures of outcome, as PFS, are rarely reported in the literature.

On the other hand, definitive data on radiation-induced severe toxicity are also troublesome to reach not only because the differentiation between tumor recurrence and radionecrosis after reirradiation may be very difficult, but also because some authors did not report the grade of toxicity either for radionecrosis or for other types of side effects.

The literature was thoroughly reviewed and the correlation between dose and response and between dose and toxicity was herein explored in order to define the optimal fractionation and prescription dose in terms of efficacy and tolerability. Moreover, some practical considerations for radiation treatment planning are provided in terms of constraints to use, in order to minimize the expected toxicity.

Section snippets

Materials and methods

Literature data from 1995 to 2015 were identified by searching the PUBMED database with the following as keywords: "recurrent glioblastoma", "radiotherapy", "radiosurgery", "stereotactic radiotherapy", "second radiotherapy", "repeat radiation therapy", only including papers written in English. Only series with more than 5 patients with recurrent GBM were examined.

In order to understand the therapeutic value of repeat radiotherapy, we collected data on treatment characteristics (dose,

Results

Twenty-nine reirradiation studies were identified and stratified according to the fractionation for studies of exclusive radiotherapy or to the concomitant drug for studies of radiochemotherapy. Number of patients, histologic subtypes, tumor volume, prescription dose, dose for fraction, number of fractions were listed. EQD2 values were specified for all the fractionated radiation schedules to allow comparisons of the different series.

Dose and schedule of systemic therapy were specified for

Definition of the target volume

In most cases, the gross tumor volume (GTV) was defined as the contrast-enhancing lesion on MR imaging.

In few experiences, other imaging modalities were used to delineate the GTV: MR-spectroscopy, perfusion-weighted imaging and diffusion-weighted imaging(Conti et al., 2012), 11 C-Methionine positron emission tomography (MET-PET) (Grosu et al., 2005), 18 F-dihydroxyphenylalanine (DOPA) PET (Minniti et al., 2013) or 123I-alpha-methyl-tyrosine (IMT) single-photon computed emission tomography

Selection of patients

An appropriate selection of the patients for a second course of radiation therapy should be based on the prognostic factors that have proven to be important in reirradiation series: both patient-related factors (good performance status (Cho et al., 1999; Cuneo et al., 2012; Fokas et al., 2009; Hall et al., 1995; Hsieh et al., 2005; Martínez-Carrillo et al., 2014), age (Cho et al., 1999; Cuneo et al., 2012; Fogh et al., 2010; Hall et al., 1995; Shrieve et al., 1995) and RPA class (

Toxicity of reirradiation of the brain

An essential component of the decision-making process of treating a relapsing GBM with reirradiation is the expected toxicity of a second radiation treatment.

Obviously, the risk of severe side effects depends on the overlapping of the target volume with the volume previously treated, leading to toxicity to the brain parenchyma. In most cases, overlapping of the target with the previously irradiated tissue is of considerable extent because the relapse of GBM typically occurs in-field or marginal

Practical recommendations

There are some practical recommendations for the centers that are interested in reirradiating patients with recurrent glioblastoma and, more generally, patients with recurrent brain tumors.

First of all, a preventive sparing of the organs at risk may be performed in the first line treatment of brain tumors, as already suggested for head and neck cancers (Farace et al., 2014).

Secondly, all the Dicom files of the initial irradiation must be provided for a proper reirradiation planning (simulation

Reirradiation vs second surgery

When patients are in good performance status, another feasible local approach for recurrent glioblastoma that are located in non-eloquent areas is second surgery. Comparison of these two salvage options is very difficult due to the scarcity of the existing studies that directly compared the outcomes of repeat surgery vs reirradiation, whose interpretation is very difficult due to their retrospective nature with high risk of selection bias.

In a large cohort study from a prospective registry (

Conclusions

This overview of the scarce currently available clinical data on reirradiation of glioblastoma patients suggests that the retreatment of a recurrent glioma must be tailored to each single patient in order to have a relatively good outcome with an acceptable risk of severe toxicity (<3.5%). Firstly, we recommend stratifying patients according to the different volumes of the target (small: <12.5 ml, medium: <35 ml, and large: <50 ml). Then, patients should be treated with the following

Conflicts of interest

There are no known conflicts of interest associated with this publication and there has been no financial support for this work that could have influenced its outcome.

Funding sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Citation Excerpt :
Despite significant advances, outcomes after aggressive salvage multimodality therapy in recurrent/progressive HGG remain dismal, with median survivals ranging around 9–12 months only [16,17]. Selection of local treatment for recurrent/progressive HGG, particularly glioblastoma, largely depends upon remaining life expectancy, patterns of failure, assessment of prognostic factors, and anticipated toxicity [30,31]. The narrow therapeutic index of CNS re-RT is often influenced by multiple factors such as age, RT parameters (technique, dose per fraction, dose, and volume of each course), cumulative total dose, and time-interval between both courses [29,32].
Over the past two decades, high-dose salvage re-irradiation (re-RT) has been used increasingly in the multimodality management of adults with recurrent/progressive diffuse glioma. Several factors that determine outcomes following re-RT have been incorporated into prognostic models to guide patient selection. We aimed to develop a novel four-tiered prognostic model incorporating relevant molecular markers from our single-institutional cohort of patients treated with high-dose salvage re-RT for recurrent/progressive diffuse glioma.
Various patient, disease, and treatment-related factors impacting upon survival following salvage re-RT were identified through univariate analysis. Each of these prognostic factors was further subdivided and assigned scores of 0 (low-risk), 1 (intermediate-risk), or 2 (high-risk). Scores from individual prognostic factors were added to derive the cumulative score (ranging from 0 to 16), with increasing scores indicating worsening prognosis.
A total of 111 adults with recurrent/progressive diffuse glioma treated with salvage high-dose re-RT were included. We could assign patients into four prognostic subgroups (A = 15 patients, score 0–3); (B = 50 patients, score 4–7); (C = 33 patients, score 8–10); and (D = 13 patients, score 11–16) with completely non-overlapping survival curves suggesting the good discriminatory ability. Post-re-RT survival was significantly higher in Group A compared to groups B, C, and D, respectively (stratified log-rank p-value <0.0001).
There exists a lack of universally acceptable ‘standard-of-care’ salvage therapy for recurrent/progressive diffuse glioma. A novel four-tiered prognostic scoring system incorporating traditional factors as well as relevant molecular markers is proposed for selecting patients appropriately for high-dose salvage re-RT that warrants validation in a non-overlapping cohort.
Au cours des deux dernières décennies, la réirradiation de rattrapage à haute dose a été de plus en plus utilisée dans la gestion multimodale des adultes atteints de gliome diffus récidivant/progressif. Plusieurs facteurs qui déterminent les résultats après réirradiation de rattrapage à haute dose ont été incorporés dans des modèles pronostiques pour guider la sélection des patients. Notre objectif était de développer un nouveau modèle pronostique à quatre niveaux incorporant des marqueurs moléculaires pertinents de notre cohorte mono-institutionnelle de patients traités par reérradiation de rattrapage à haute dose pour un gliome diffus récidivant/progressif.
Divers facteurs liés au patient, à la maladie et au traitement ayant un impact sur la survie après une réirradiation de rattrapage ont été identifiés par une analyse unifactorielle. Chacun de ces facteurs pronostiques a été subdivisé et attribué des scores de 0 (faible risque), 1 (risque intermédiaire) ou 2 (risque élevé). Les scores des facteurs pronostiques individuels ont été ajoutés pour obtenir le score cumulé (allant de 0 à 16), avec des scores croissants indiquant une aggravation du pronostic.
Un total de 111 adultes atteints de gliome diffus récidivant/progressif traités avec une ré-irradiation de récupération à haute dose ont été inclus. Nous avons pu répartir les patients en quatre sous-groupes pronostiques (A = 15 patients, score 0–3); (B = 50 patients, score 4–7); (C = 33 patients, score 8–10); et (D = 13 patients, score 11–16) avec des courbes de survie totalement non chevauchantes suggérant la bonne capacité discriminante. La survie après réirradiation de rattrapage était significativement plus élevée dans le groupe A par rapport aux groupes B, C et D, respectivement (valeur de P du log-rank stratifié < 0,0001).
Il existe un manque de thérapie de rattrapage « standard de soins » universellement acceptable pour le gliome diffus récidivant/progressif. Un nouveau système de notation pronostique à quatre niveaux incorporant des facteurs traditionnels ainsi que des marqueurs moléculaires pertinents est proposé pour sélectionner les patients de manière appropriée pour une ré-irradiation de rattrapage à haute dose qui justifie la validation dans une cohorte indépendante.

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Re-irradiation as salvage treatment in recurrent glioblastoma: A comprehensive literature review to provide practical answers to frequently asked questions

Highlights

Abstract

Introduction

Section snippets

Materials and methods

Results

Definition of the target volume

Selection of patients

Toxicity of reirradiation of the brain

Practical recommendations

Reirradiation vs second surgery

Conclusions

Conflicts of interest

Funding sources

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

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Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Clin. Neurol. Neurosurg.

Semin. Radiat. Oncol.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol.

Radiother. Oncol.

Int. J. Radiat. Oncol. Biol. Phys.

World Neurosurg.

Lancet Oncol.

Radiother. Oncol.

Benefit of re-operation and salvage therapies for recurrent glioblastoma multiforme: results from a single institution

J. Neurooncol.

The relationship between six-month progression-free survival and 12-month overall survival end points for phase II trials in patients with glioblastoma multiforme

Neuro. Oncol.

Radiochemotherapy with temozolomide as re-irradiation using high precision fractionated stereotactic radiotherapy (FSRT) in patients with recurrent gliomas

J. Neurooncol.

Generation and validation of a prognostic score to predict outcome after re-irradiation of recurrent glioma

Acta Oncol.

Stereotactic radiosurgery (SRS): treatment option for recurrent glioblastoma multiforme (GBM)

Cancer

Efficacy of fractionated stereotactic reirradiation in recurrent gliomas: long-term results in 172 patients treated in a single institution

J. Clin. Oncol.

Efficacy and toxicity of CyberKnife re-irradiation and “dose dense” temozolomide for recurrent gliomas

Acta Neurochir. (Wien).

Survival and quality of life after hypofractionated stereotactic radiotherapy for recurrent malignant glioma

J. Neurooncol.