Re-irradiation as salvage treatment in recurrent glioblastoma: A comprehensive literature review to provide practical answers to frequently asked questions
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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2022, Cancer/RadiotherapieCitation 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].