Currently, patients with gross total resection (GTR) of recurrent glioblastoma (rGBM) undergo adjuvant chemotherapy or are followed up until progression. Re-irradiation, as one of the most effective treatments in macroscopic rGBM, is withheld in this situation, as uncertainties about the pattern of re-recurrence, the target volume, and also the efficacy of early re-irradiation after GTR exist. Imaging and clinical data from 26 consecutive patients with GTR of rGBM were analyzed. The spatial pattern of recurrences was analyzed according to the RANO-HGG criteria (“response assessment in neuro-oncology criteria for high-grade gliomas”). Progression-free (PFS) and overall survival (OS) were analyzed by the Kaplan–Meier method. Furthermore, a systematic review was performed in PubMed. All but 4 patients underwent adjuvant chemotherapy after GTR. Progression was diagnosed in 20 of 26 patients and 70% of recurrent tumors occurred adjacent to the resection cavity. The median extension beyond the edge of the resection cavity was 20 mm. Median PFS was 6 months; OS was 12.8 months. We propose a target volume containing the resection cavity and every contrast enhancing lesion as the gross tumor volume (GTV), a spherical margin of 5–10 mm to generate the clinical target volume (CTV), and a margin of 1–3 mm to generate the planning target volume (PTV). Re-irradiation of this volume is deemed to be safe and likely to prolong PFS. Re-irradiation is worth considering also after GTR, as the volumes that need to be treated are limited and re-irradiation has already proven to be a safe treatment option in general. The strategy of early re-irradiation is currently being tested within the GlioCave/NOA 17/Aro 2016/03 trial.

Re-irradiation after gross total resection of recurrent glioblastoma

Patterns of re-irradiation for recurrent gliomas and validation of a prognostic score

OBJECTIVES The median survival in glioblastoma (GBM) patients used to be less than 1 year. Surgical removal of the tumor with subsequent concomitant radiation/temozolomide (the Stupp regimen) has been shown to prolong survival. The Stupp protocol was implemented in the county of Jonkoping in 2006. The purpose of this study was to examine if the Stupp treatment has prolonged overall survival, in an unselected patient cohort with histologically verified GBM. MATERIAL AND METHOD This study includes all patients from the county of Jonkoping, with a diagnosis of GBM from January 2001 to December 2012. Patients were divided into 2 cohorts, 2001-2005 and 2006-2012, that is before and after implementation of the Stupp regimen. By reviewing the medical case notes, the dates of the histological diagnosis and of death were identified. The median and mean overall survival and Kaplan-Meier survival analysis were calculated and compared between the 2 cohorts. RESULTS The mean survival was 110 days longer in the cohort treated according to the Stupp regimen. Four patients in the 2006-2012 cohort and 1 patient in the 2001-2005 cohort are still alive. When comparing survival in patients with radical surgery vs biopsy, those that underwent radical surgery survived longer. The significance was slightly greater in the 2001-2005 cohort (mean 163 vs 344 days, P < .001) than in the 2006-2012 cohort (mean 220 vs 397 days, P = .02). CONCLUSION Survival significantly improved after the implementation of the Stupp regimen in the study region of Sweden.

Improved survival of Swedish glioblastoma patients treated according to Stupp.

In case of circumscribed recurrent glioblastoma (rec-GBM), a second surgery (Re-S) and reirradiation (Re-RT) are local strategies to consider. The aim is to provide an algorithm to use in the daily clinical practice. The first step is to consider the life expectancy in order to establish whether the patient should be a candidate for active treatment. In case of a relatively good life expectancy (>3 months) and a confirmed circumscribed disease(i.e. without multiple lesions that are in different lobes/hemispheres), the next step is the assessment of the prognostic factors for local treatments. Based on the existing prognostic score systems, patients who should be excluded from local treatments may be identified; based on the validated prognostic factors, one or the other local treatment may be preferred. The last point is the estimation of expected toxicity, considering patient-related, tumor-related and treatment-related factors impacting on side effects. Lastly, patients with very good prognostic factors may be considered for receiving a combined treatment.

Local treatment for relapsing glioblastoma: A decision-making tree for choosing between reirradiation and second surgery.

Background Glioblastoma is characterized by rich vasculature and abnormal vascular structure and function. Currently, there is no standard treatment for recurrent glioblastoma (rGBM). Bevacizumab (BEV) has established role of inhibiting neovascularization, alleviating hypoxia in the tumor area and activating the immune microenvironment. BEV may exert synergistic effects with re-irradiation (re-RT) to improve the tumor microenvironment for rGBM. Purpose The purpose of this study was to evaluate the safety, tolerability, and efficacy of a combination of BEV and re-RT for rGBM treatment. Methods In this retrospective study, a total of 26 rGBM patients with surgical pathologically confirmed glioblastoma and at least one event of recurrence were enrolled. All patients were treated with re-RT in combination with BEV. BEV was administered until progression or serious adverse events. Results Median follow-up was 21.9 months for all patients, whereas median progression-free survival (PFS) was 8.0 months (95% confidence interval [CI]: 6.5–9.5 months). In addition, the 6-month and 1-year PFS rates were 65.4% and 28.2%, respectively. The median overall survival (OS), 6-month OS rate, and 1-year OS rate were 13.6 months (95% CI: 10.2–17.0 months), 92.3%, and 67.5%, respectively. The patient showed good tolerance during the treatment with no grade > 3 grade side event and radiation necrosis occurrence rate of 0%. Combined treatment of gross total resection (GTR) before re-RT and concurrent temozolomide during re-RT was an independent prognostic factor that affected both OS and PFS in the whole cohort (OS: 0.067, 95% CI: 0.009–0.521, p = 0.010; PFS: 0.238, 95% CI: 0.076–0.744, p = 0.038). Conclusion In this study, re-RT combined with concurrent and maintenance BEV treatment was safe, tolerable, and effective in rGBM patients. Moreover, GTR before re-RT and selective concurrent temozolomide could further improve patient PFS and OS.

/pdf/bevacizumab-combined-with-re-irradiation-in-recurrent-2nfihlxo.pdf

Bevacizumab combined with re-irradiation in recurrent glioblastoma

Objectives
In progressive glioblastoma, salvage treatment remains unstandardized, response is highly variable, and detailed analysis of individual approaches is mandatory. Re-irradiation is an established option in the therapy of progressive glioblastoma. Thus, we analysed outcome and prognostic parameters of patients with re-irradiated glioblastoma treated at our institution since 1998.

Materials and methods
In a total of 51 patients, clinical and treatment parameters were collected and analysed retrospectively. Re-irradiation protocols included radiosurgery, hypofractionated radiotherapy or normofractionated radiotherapy. Outcome was analysed regarding prognostic factors in this highly selected cohort.

Results
Median overall survival after primary diagnosis was 28.8 months. Patients re-irradiated with single-dose stereotactic radiosurgery or hypofractionated regimes showed a superior overall survival after primary diagnosis compared to normofractionated treatment. Positive prognostic factors included a smaller gross tumour volume and younger age. A methylated MGMT promoter approached statistical significance as a positive factor regarding overall survival after re-irradiation. Further well-known prognostic factors as extension of the initial resection and the concomitance of temozolomide with the initial radiation treatment only appeared relevant in a subgroup of four long-term survivors.

Conclusions
The favourable results regarding overall survival are probably due to patient selection for re-irradiation. If technically feasible, stereotactic radiosurgery or hypofractionated regimes should be preferred. In this highly selected re-irradiation cohort, only some of the well-known prognostic factors of the primary tumour setting were found to influence overall survival significantly. In contrast, also some patients presenting with unfavourable predictive parameters showed an encouraging course of disease and thus should not be excluded from re-irradiation.

Prognostic parameters and outcome after re-irradiation for progressive glioblastoma.

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Prognostic parameters and outcome after re-irradiation for progressive glioblastoma.