Reirradiation For High-grade Glioma Research Articles

P17.08.B Single institutional retrospective review of re-irradiation in High Grade Gliomas in a tertiary UK centre

Abstract Background Recurrent high grade gliomas (HGG) pose a treatment challenge as no definite guidelines exist. Re-excision could be appropriate in some cases while systemic therapy options are only a handful. We thus need to resort to the option of re-irradiation at some point but there could be a wide variety of techniques, volumes & doses to choose from due to lack of robust evidence. The UK wide BRIOCHe study for Glioblastoma Multiforme (GBM) will help in providing some standardisation. With this retrospective study, we aim to review our institutional practice with re-irradiation & our patient outcomes. Material and Methods Electronic health records over a period of 3 years from 1 Jun 2019 to 30 May 2021 were searched for patients with HGG that underwent a course of re-irradiation. Various patient factors, tumour & treatment factors at baseline and at recurrence and survival data were collected. Results Total of 8 patients received re-irradiation with all except one having a performance status of 1 at the time of treatment. Seven patients had GBM, one had transformation from baseline G2 glioma and the eighth patient had anaplastic oligodendroglioma (ODG). MGMT was methylated in 62.5% patients while IDH mutation was present only in the transformed glioma. Majority patients had radiotherapy dose of 60Gy/30 fractions with concurrent temozolomide (TMZ) at baseline to a median CTV volume of 186cc. A median of 6 cycles of TMZ were given in the adjuvant setting. Median time to recurrence from completion of adjuvant treatment was 6.7 months (range: 0.9 - 171.6 months). Most recurrences were in the same or an adjacent lobe whereas 1 patient had a multi-focal recurrence. Half the patients at recurrence underwent a re-resection. All patients had salvage chemotherapy at the time of recurrence with a median of 2 regimens and a median of 6 cycles prior to re-irradiation. All patients received a re-irradiation dose of 35Gy in 10 fractions to a median CTV volume of 149cc. The median interval from previous radiotherapy was 18.9 months (range: 11.6 - 190.5 months). The median time to progression from re-RT was 5.4 months (CI: 3.4 - 7.4) and median survival from re-RT was 7 months (CI: 6.2 - 7.8). The median overall survival since diagnosis was 35.1 months (CI: 22.2 - 48.1), one patient was lost to follow up. Conclusion Re-irradiation is a safe & feasible treatment option in carefully selected cases of high grade glioma.

Re-irradiation for high-grade gliomas: Has anything changed?

Optimal management after recurrence or progression of high-grade gliomas is still undefined and remains a challenge for neuro-oncology multidisciplinary teams. Improved radiation therapy techniques, new imaging methods, published experience, and a better radiobiological knowledge of brain tissue have positioned re-irradiation (re-RT) as an option for many of these patients. Decisions must be individualized, taking into account the pattern of relapse, previous treatment, and functional status, as well as the patient’s preferences and expected quality of life. Many questions remain unanswered with respect to re-RT: Who is the most appropriate candidate, which dose and fractionation are most effective, how to define the target volume, which imaging technique is best for planning, and what is the optimal timing? This review will focus on describing the most relevant studies that include re-RT as salvage therapy, with the aim of simplifying decision-making and designing the best available therapeutic strategy.

Target treatment with stereotactic radiation for recurrent gliomas.

High grade gliomas (HGG) have a propensity to recur locally and have poor outcomes. As such, safe and effective treatment is paramount. Target treatment with stereotactic radiation allows safe re-irradiation through minimizing normal brain tissue radiation due to its high precision. In this review, we evaluated the clinical experiences using SRS and FSRT for re-irradiation in HGG. We report the radiobiological advantages and disadvantages of both modalities as well as the safety and efficacy published in current literature.

Digital biomarkers: Importance of patient stratification for re-irradiation of glioma patients – Review of latest developments regarding scoring assessment

PurposeTo review scoring assessments in re-irradiation of high-grade glioma (HGG) patients and how to use scoring for patient stratification. The next aim was to investigate the different approaches employed by the scoring systems and the way they can be applied to build homogeneous patient groups for a reliable prognosis. MethodsWe searched the Medline/Pubmed and Web of science databases for relevant articles regarding scores for re-irradiation of recurrent HGG. All references were divided into the following groups: novel score establishment (n = 5), score validation (n = 6), not relevant to this evaluation (n = 26). ResultsWe identified five scoring systems. Two are modifications of an already existing score. Calculations differ immensely from easy point addition to a more complex formula with including three up to 10 individual parameters. Six validation articles were found for three of the scores; one was validated four times. Two scores were never validated. ConclusionFor recurrent HGG, the clinical situation remains demanding. Due to the heterogeneity of data at re-irradiation, patient stratification is important. Several scoring systems have been developed to predict prognosis. As a digital biomarker, scores are of high value regarding quick patient assessment and therapy decision making. For the next generation of digital biomarkers, easy calculation, and inclusion of easily available parameters are crucial.

OS09.5 Synergistic effect of reirradiation and PD-1 inhibitors in recurrent high-grade gliomas

Abstract Background: To date, studies of single agent PD-1 or PDL-1 inhibitors in recurrent high-grade gliomas (HGG) have shown infrequent responses (< 10%) and limited efficacy. Reirradiation is considered one of the standard salvage regimens for selected patients with recurrent gliomas but tumor responses are also infrequent (< 5%). Radiotherapy counteracts the immunosuppressive tumor microenvironment by increasing MHC class I expression and enhancing tumor neoantigen presentation and has a significant synergistic effect with PD-1 inhibition in preclinical models of glioma. Methods: From December 2014 to June 2016, 20 patients (14 men, 6 women) with recurrent HGG were treated with the combination of reirradiation and PD-1 inhibitors. 18 patients had a glioblastoma, 1 anaplastic astrocytoma and 1 anaplastic oligodendroglioma. The median KPS at the start of this regimen was 70 (50 to 80). The median number of prior treatments for recurrent tumor was 2 (1–4), 100% had prior radaition, 95% prior temozolomide and 55% prior bevacizumab. 8 patients received pembrolizumab (2 mg/Kg every 3 weeks) and 12 patients received nivolumab (3 mg/Kg or 240 mg flat dose every 2 weeks). Median reirradiation dose was 35 Gy (12 Gy to 35 Gy). Results: There were 7 confirmed partial responses (35% objective response rate, ORR), 5 stable disease and 8 progressive disease. The median duration of response was 5 months (2.2 to 10+ months). Median PFS was 4 months and median OS was 10 months. Most common side effects were increased ALT (3 patients) and fatigue (2 patients). There was no obvious case of cerebral edema related to treatment. 5 patients required a mild increase of dexamethasone (2–4 mg) and all other 15 patients had decreased or stable dexamethasone dosage after the reirradiation. Conclusions: PD-1 inhibitors in combination with re-irradiation can be administered safely to patients with recurrent HGG. The ORR of 35% is an early signal of the potential synergist effect of the combination of PD-1 inhibitors with re-irradiation in HGG. This retrospective analysis of a heavily pre-treated population of recurrent HGG showed significantly higher ORR than either PD-1 inhibitors or re-irradiation alone. A clinical trial under development to test this hypothesis.

Synergistic effect of reirradiation and PD-1 inhibitors in recurrent high-grade gliomas.

105 Background: To date, studies of single agent PD-1 or PDL-1 inhibitors in recurrent high-grade gliomas (HGG) have shown infrequent responses ( &lt; 10%) and limited efficacy. Reirradiation is considered one of the standard salvage regimens for selected patients with recurrent gliomas but tumor responses are also infrequent ( &lt; 5%). Radiotherapy counteracts the immunosuppressive tumor microenvironment by increasing MHC class I expression and enhancing tumor neoantigen presentation and has a significant synergistic effect with PD-1 inhibition in preclinical models of glioma. Methods: From December 2014 to June 2016, 20 patients (14 men, 6 women) with recurrent HGG were treated with the combination of reirradiation and PD-1 inhibitors. 18 patients had a glioblastoma, 1 anaplastic astrocytoma and 1 anaplastic oligodendroglioma. The median KPS at the start of this regimen was 70 (50 to 80). The median number of prior treatments for recurrent tumor was 2 (1-4), 100% had prior radaition, 95% prior temozolomide and 55% prior bevacizumab. 8 patients received pembrolizumab (2 mg/Kg every 3 weeks) and 12 patients received nivolumab (3 mg/Kg or 240 mg flat dose every 2 weeks). Median reirradiation dose was 35 Gy (12 Gy to 35 Gy). Results: There were 7 confirmed partial responses (35% objective response rate, ORR), 5 stable disease and 8 progressive disease. The median duration of response was 5 months (2.2 to 10+ months). Median PFS was 4 months and median OS was 10 months. Most common side effects were increased ALT (3 patients) and fatigue (2 patients). There was no obvious case of cerebral edema related to treatment. 5 patients required a mild increase of dexamethasone (2-4 mg) and all other 15 patients had decreased or stable dexamethasone dosage after the reirradiation. Conclusions: PD-1 inhibitors in combination with re-irradiation can be administered safely to patients with recurrent HGG. The ORR of 35% is an early signal of the potential synergist effect of the combination of PD-1 inhibitors with re-irradiation in HGG. This retrospective analysis of a heavily pre-treated population of recurrent HGG showed significantly higher ORR than either PD-1 inhibitors or re-irradiation alone. A clinical trial under development to test this hypothesis.

Prognostic value of 18F-FET PET imaging in re-irradiation of high-grade glioma: Results of a phase I clinical trial

Background and purposePositron emission tomography (PET) provides quantitative metabolic information and potential biomarkers of treatment outcome. We aimed to determine the prognostic value of early 18F-fluoroethyl-tyrosine (18F-FET) PET scans acquired during re-irradiation for recurrent high-grade glioma (HGG). Material and methodsA phase I clinical trial of re-irradiation of HGG was carried out. MRI and 18F-FET PET were used for target delineation and follow-up. Images were acquired at baseline, during radiotherapy and 4weeks post-treatment and compared by measuring the metabolically active biological tumor volume (BTV) and maximal activity (Tmax/B). Correlations with outcomes were assessed by multivariate Cox regression analysis. ResultsThirty-one patients were included and all patients have died. The median overall survival was 7.0 mos. Both baseline BTV and baseline MRI volume (necrotic/cystic cavities subtracted) were prognostic for overall survival (OS) in multivariate analysis (HR=1.3 p<0.01 and HR=1.3 p<0.01, respectively). Early changes in BTV and Tmax/B were observed but they carried no independent prognostic information. ConclusionsBaseline biological tumor volume (BTV) defined by 18F-FET PET was prognostic for OS in multivariate analysis, as was MRI volume (necrotic/cystic cavities subtracted). Tumor volume may aid in identifying patients whose life expectancy is too short to warrant re-irradiation.

Réirradiation cérébrale des tumeurs primitives malignes ou secondaires

The purpose of this review was to analyze data available on reirradiation for high-grade glioma or brain metastasis. This reirradiation can be 3D conformal or stereotactic. There are no randomized trials. No definitive recommendations can be given but solutions can be proposed. In high-grade gliomas, results of 3D conformal irradiation are fair. Stereotactic irradiation produces more encouraging survival rates but the range of doses delivered is too large for allowing recommendations. However, fractions less than 5 Gy seem better tolerated. In brain metastases, total brain irradiation seems useful if metastases are multiple and the patient in good condition. With radiosurgery, local control rates are high and survival encouraging. In a retrospective study, bifractionated irradiation looked interesting when compared to radiosurgery. Overall prospective trials seem to be necessary.

Reirradiation and lomustine in patients with relapsed high-grade gliomas

Purpose: The aim of this study was to evaluate the toxicity, response, and survival of patients with relapsed high-grade gliomas after radiation therapy (RT) combined with lomustine (CCNU).Methods and Materials: Thirty-one patients with relapsed gliomas at least 6 months after completion of RT were reirradiated. Twenty-four patients had a pathological diagnosis of high-grade gliomas, whereas 7 had a radiological diagnosis of relapsed malignant gliomas. The study focused on patients with high-grade relapsed gliomas. A total dose of 34.5 Gy was delivered in 23 fractions over 4.5 weeks. Oral administration of CCNU (130 mg/m2) was begun at the same time as RT, and was repeated every 6 weeks until disease progression, or up to 12 courses.Results: Twelve of 24 patients had surgery before RT plus CCNU treatment. Median interval between RT courses was 14 months (range 6–73). All patients received a complete course of RT, and 22 of 24 patients received at least one course of CCNU. Objective responses were seen in 14 evaluable patients: 3 with partial response, 5 with stable disease, and 6 with progressive disease. Duration of partial response was 20, 9, and 8 months. Median time to progression and overall survival from the onset of retreatment were 8.4 months (range 1–22) and 13.7 months (range 1–63+), respectively. One case of G4 thrombocytopenia was observed. Five patients had G1 or G2 leucopenia and 3 patients had G3 leucopenia. Moderate nausea and vomiting were reported in 4 patients. One patient, after one course of CCNU, refused further chemotherapy. No significant difference in survival from relapse was found between patients who underwent surgery before RT plus CCNU and those who received only RT plus CCNU (p = 0.74).Conclusion: Overall, the acute toxicity was moderate, and patient compliance was good. Reirradiation of high-grade glioma was associated with modest subjective and objective response rates. It is remarkable that median overall survival from relapse was 13.7 months.