Anlotinib alone or in combination with bevacizumab in the treatment of recurrent high-grade glioma: a prospective single-arm, open-label phase II trial.

BACKGROUND: Anlotinib is a multi-target tyrosine kinase inhibitor (TKI) targeting the vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and c-Kit. This phase II study aimed to assess the efficacy and safety of anlotinib, either alone or in combination with bevacizumab (Bev) for recurrent high-grade glioma (rHGG) (NCT04822805, 30/03/2021). METHODS: Eligible patients had a histological diagnosis of rHGG with first or subsequent recurrences. All patients received oral anlotinib 12 mg or 10 mg on days 1-14 (repeated every 21 days). In cases where brain magnetic resonance imaging examination revealed an increase in peritumoral edema without worsening of symptoms, patients received a temporary treatment of intravenous bevacizumab 10 mg/kg to alleviate edema. The primary endpoint was the median progression-free survival (mPFS), and the secondary endpoints included median overall survival (mOS), objective response rate (ORR), disease control rate (DCR), and safety. RESULTS: Twenty-five patients with rHGG were included in the efficacy and safety assessments. Eighteen patients received anlotinib alone, and seven patients received anlotinib in combination with Bev. For all patients, the mPFS and mOS were 5.0 months and 13.6 months, respectively. The ORR was 32%, and the DCR was 96%. It is noteworthy that the survival and response data of recurrent glioblastoma (rGBM) exhibit similarities to those of rHGG. For rGBM patients, there were no significant differences in mPFS, mOS, ORR, or DCR between the anlotinib alone and anlotinib + Bev groups. However, the incidence of treatment-related adverse events of any grade was higher in the anlotinib + Bev group compared to the anlotinib alone group (100% vs. 78%, p = 0.041). CONCLUSIONS: Both anlotinib alone and its combination with Bev demonstrated good efficacy and safety in the treatment of rHGG.

Re-irradiation for recurrent high-grade glioma: an analysis of prognostic factors for survival and predictors of radiation necrosis.

PURPOSE: Recurrent high-grade glioma (rHGG) is a heterogeneous population, and the ideal patient selection for re-irradiation (re-RT) has yet to be established. This study aims to identify prognostic factors for rHGG patients treated with re-RT. METHODS: We retrospectively reviewed consecutive adults with rHGG who underwent re-RT from 2009 to 2020 from our institutional database. The primary objective was overall survival (OS). Secondary endpoints included prognostic factors for early death (< 6 months after re-RT) and predictors of radiation necrosis (RN). RESULTS: For the 79 patients identified, the median OS after re-RT was 9.9 months (95% CI 8.3-11.6). On multivariate analyses, re-resection at progression (HR 0.56, p = 0.027), interval from primary treatment to first progression ≥ 16.3 months (HR 0.61, p = 0.034), interval from primary treatment to re-RT ≥ 23.9 months (HR 0.35, p < 0.001), and re-RT PTV volume < 112 cc (HR 0.27, p < 0.001) were prognostic for improved OS. Patients who had unmethylated-MGMT tumours (OR 12.4, p = 0.034), ≥ 3 prior systemic treatment lines (OR 29.1, p = 0.022), interval to re-RT < 23.9 months (OR 9.0, p = 0.039), and re-RT PTV volume ≥ 112 cc (OR 17.8, p = 0.003) were more likely to die within 6 months of re-RT. The cumulative incidence of RN was 11.4% (95% CI 4.3-18.5) at 12 months. Concurrent bevacizumab use (HR < 0.001, p < 0.001) and cumulative equivalent dose in 2 Gy fractions (EQD2, α/ß = 2) < 99 Gy2 (HR < 0.001, p < 0.001) were independent protective factors against RN. Re-RT allowed for less corticosteroid dependency. Sixty-six percent of failures after re-RT were in-field. CONCLUSION: We observe favorable OS rates following re-RT and identified prognostic factors, including methylation status, that can assist in patient selection and clinical trial design. Concurrent use of bevacizumab mitigated the risk of RN.

Ga-68 PSMA PET/CT in recurrent high-grade gliomas: evaluating PSMA expression in vivo.

PURPOSE: We planned this prospective study to evaluate PSMA expression in recurrent high-grade gliomas (rHGG), including anaplastic astrocytoma and glioblastoma using Glu-NH-CO-NH-Lys-(Ahx)-[Ga-68 (HBED-CC)]- (Ga-68 PSMA) positron emission tomography (PET), with its theranostic potential in mind. METHODS: This was a prospective study enrolling patients with clinical and MRI evidence of rHGG on follow-up. Three treated cases of HGG with RN on MRI were also included as negative controls. Abnormal tracer accumulation in the brain parenchyma, more than the contralateral hemisphere was interpreted as positive study. For semiquantitative analysis, a 3D spherical region of interest (ROI) was drawn around the site of the abnormal Ga-68 PSMA uptake, and the ratio of SUVmax of tumor (T) to SUVmax of the contralateral corresponding area (TBR) was calculated. Each patients' PSMA brain PET was fused to the corresponding MRI and reviewed for concordance. RESULTS: Thirty patients were included in the study, a total of 49 lesions were detected on MRI, and fused PET/MR images showed increased Ga-68 PSMA uptake in all these lesions. Multifocal lesions were better appreciated on fused PET-MR images, and concordance between MRI and PET was 100 % for patient and lesion-wise detection. Recurrent glioma lesions showed SUVmax and SUVmean values (median and IQR) 6.0 (4.4-8.2) and 3.3 (2.8-3.7), respectively. Lesions labeled as radiation necrosis on MRI did not show tracer accumulation. CONCLUSION: Ga-68 PSMA has potential utility for evaluating recurrence in HGG and its potential for theranostics would encourage its use in the evaluation of these patients.

Safety and efficacy of Hypofractionated stereotactic radiosurgery for high-grade Gliomas at first recurrence: a single-center experience.

BACKGROUND: The optimal treatment for recurrent high-grade gliomas (rHGGs) remains uncertain. This study aimed to investigate the efficacy and safety of hypofractionated stereotactic radiosurgery (HSRS) as a first-line salvage treatment for in-field recurrence of high-grade gliomas. METHODS: Between January 2016 and October 2019, 70 patients with rHGG who underwent HSRS were retrospectively analysed. The primary endpoint was overall survival (OS), and secondary endpoints included both progression-free survival (PFS) and adverse events, which were assessed according to Common Toxicity Criteria Adverse Events (CTCAE) version 5. The prognostic value of key clinical features (age, performance status, planning target volume, dose, use of bevacizumab) was evaluated. RESULTS: A total of 70 patients were included in the study. Forty patients were male and 30 were female. Forty-nine had an initial diagnosis of glioblastoma (GBM), and the rest (21) were confirmed to be WHO grade 3 gliomas. The median planning target volume (PTV) was 16.68 cm3 (0.81-121.96 cm3). The median prescribed dose was 24 Gy (12-30 Gy) in 4 fractions (2-6 fractions). The median baseline of Karnofsky Performance Status (KPS) was 70 (40-90). With a median follow-up of 12.1 months, the median overall survival after salvage treatment was 17.6 months (19.5 and 14.6 months for grade 3 and 4 gliomas, respectively; p = .039). No grade 3 or higher toxicities was recorded. Multivariate analysis showed that concurrent bevacizumab with radiosurgery and KPS > 70 were favourable prognostic factors for grade 4 patients with HGG. CONCLUSIONS: Salvage HSRS showed a favourable outcome and acceptable toxicity for rHGG. A prospective phase II study (NCT04197492) is ongoing to further investigate the value of hypofractionated stereotactic radiosurgery (HSRS) in rHGG.

5-Aminolevulinic acid fluorescence guided surgery for recurrent high-grade gliomas.

INTRODUCTION: Fluorescence guided surgery (FGS) with five-aminolevulinic acid (5-ALA) is expected to revolutionize neurosurgical care of patients with high-grade gliomas (HGG). After the recent landmark FDA approval, this optical agent is now available to neurosurgeons in the United States. METHODS: This review is designed to highlight the evidence for the use of 5-ALA in recurrent HGG surgery for the neurosurgical community. The manuscript was prepared in accordance with the PRISMA guidelines. RESULTS: Intra-operatively, a strong fluorescent signal is highly correlated with the presence of cellular tumor in recurrent HGG, giving it a high positive predictive value (PPV). Similar to what is observed in primary HGG surgery, false-negative results can occur if tumor cells do not emit fluorescence. In addition, false-positive fluorescence signals in tissues devoid of tumor cells can be observed more frequently in recurrent HGG compared to the primary setting. However, these areas overwhelmingly contain reactive/regressive tissue, resection of which is unlikely to cause functional deficits. The safety profile of 5-ALA is similarly favorable in primary and recurrent HGG. CONCLUSIONS: 5-ALA FGS is a powerful adjunct in the resection of recurrent HGG with a high PPV and favorable safety profile. It is therefore the authors' opinion to routinely employ this fluorescent agent as a standard of care.

Concurrent hyperthermia and re-irradiation for recurrent high-grade gliomas.

Salvage therapy for recurrent high grade gliomas (HGG) includes surgery, radiotherapy and chemotherapy, however, standard treatment does not exist. We evaluated the tolerability and efficacy of re-irradiation (re-RT) with hyperthermia (HT) for patients with recurrent HGG. From September 2010 to July 2015, 20 patients with recurrent HGG were treated with re-RT and HT. The radiotherapy dose of 30 Gray (Gy) was delivered with 2 Gy per fraction daily, and HT was performed twice weekly. Primary endpoints were treatment compliance and toxicity. Second endpoints were overall survival (OS) and progression free survival (PFS). The median interval between initial RT and re-RT was 11 months. During re-RT with HT, there were no significant acute morbidities over grade 3. Median overall survival (OS) from re-irradiation was 8.4 months and the 6 and 12 months survival rate were 67% and 30%, respectively. The median progression free survival (PFS) from re-irradiation was 4.1 month. Our findings suggested that concurrent re-RT with HT was a safe and well-tolerated. In addition, the combination re-RT and HT could be a valuable salvage treatment option for selected recurrent HGG patients with poor performance status.

Phase I trial of panobinostat and fractionated stereotactic re-irradiation therapy for recurrent high grade gliomas.

Panobinostat is an oral HDAC inhibitor with radiosensitizing activity. We investigated the safety, tolerability and preliminary efficacy of panobinostat combined with fractionated stereotactic re-irradiation therapy (FSRT) for recurrent high grade gliomas. Patients with recurrent high grade gliomas were enrolled in a 3 + 3 dose escalation study to determine dose limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, tolerability, and preliminary efficacy. FSRT was prescribed to 30-35 Gy delivered in 10 fractions. Panobinostat was administrated concurrently with radiotherapy. Of 12 evaluable patients, 8 had recurrent GBM, and 4 had recurrent anaplastic astrocytoma. There were three grade 3 or higher toxicities in each the 10 and 30 mg cohorts. In the 30 mg cohort, there was one DLT; grade 4 neutropenia. One patient developed late grade 3 radionecrosis. The median follow up was 18.8 months. The PFS6 was 67, 33, and 83 % for 10, 20, and 30 mg cohorts, respectively. The median OS was 7.8, 6.1 and 16.1 months for the 10, 20 and 30 mg cohorts, respectively. Panobinostat administrated with FSRT is well tolerated at 30 mg. A phase II trial is warranted to assess the efficacy of panobinostat plus FSRT for recurrent glioma.

Re-resection for recurrent high-grade glioma in the setting of re-irradiation: more is not always better.

The optimal treatment for patients with recurrent high grade glioma (HGG) remains controversial. Available therapies include surgery, re-irradiation, alternating electric fields or systemic therapy. Here we investigate whether re-resection will improve survival in patients receiving repeat radiotherapy for tumor recurrence. 231 consecutive patients with recurrent HGG treated with re-irradiation between 1994 and 2012 were analyzed. 105 patients underwent re-resection. Re-irradiation was delivered using daily fractions of 3.5 Gy to a median total dose of 35 Gy. Survival was then analyzed comparing patients with and without re-resection. Overall survival (OS) and survival from the first recurrence are reported. Univariate and cox-proportional hazard modeling was performed in a step-wise multivariate analysis using known prognostic factors. The median follow-up time from initial diagnosis was 25.7 months. The median OS from initial diagnosis of the entire group was 22.5 months. There was no significant difference in median overall survival between patients who received re-resection versus no re-resection, 23 versus 21.9 months respectively (p = 0.6). Additionally, there was no difference in median survival from the time of first recurrence 10.5 months without re-resection versus 11.1 months with re-resection (p = 0.09). After adjusting for known prognostic variables, only age remained significant. Re-irradiation is an effective salvage therapy for patients with localized, progressive high grade glioma, achieving a median survival of 10-11 months from re-irradiation. Our data reveals no significant improvement in survival with the addition of re-resection to re-irradiated patients with HGG.

AB048. Evidence of effectiveness of neoadjuvant camrelizumab and apatinib in patients with recurrent high-grade gliomas.

BACKGROUND: Recurrent high-grade glioma (HGG) is a challenge with limited treatment options and a poor prognosis. We conducted an open-label phase II study: neoadjuvant camrelizumab and apatinib in patients with recurrent high-grade gliomas (NCT04588987), and interim analysis showed very promising results. We are further searching for evidence of the effectiveness of this strategy. METHODS: Patients with recurrent HGG received neoadjuvant treatment with camrelizumab (intravenous injection 200 mg on day 1) and apatinib (oral 250 mg per day on days 1-7), and 14 days later received surgery for recurrent tumor resection. Sequential therapy began 2 weeks after surgery with the biweekly camrelizumab (200 mg) and 4 weeks after surgery with the daily apatinib (250 mg) until investigator assessed progressive disease or unable to tolerate toxicity. The primary endpoint was overall survival (OS). When patients suspected progress during per-protocol treatment, re-surgery for resection of lesion was done, and the tissue was further examined. RESULTS: Between October 9, 2020, and March 30, 2024, 24 patients were enrolled [19 glioblastomas, one World Health Organization (WHO) grade 4 diffuse astrocytoma, three anaplastic astrocytoma, and one anaplastic oligodendroglioma]. Nineteen patients with interim analysis data, and showed the median progression-free survival (PFS) was 4.8 months [95% confidence interval (CI): 4.4-5.2], the median OS was 12.9 months (95% CI: 9.3-16.4) respectively, with a median follow-up time of 17.5 months (95% CI: 9.0-26.1). There were two patients who suspected progress and received second surgery. One patient showed real tumor progression with active tumor cells. While another patient the histology revealed mainly necrosis with inflammatory cells. Five patients initially showed increased enhancement on magnetic resonance imaging (MRI) but without increased symptoms, and showed continuous improvement when receiving further treatment. CONCLUSIONS: This immuno-target combination neoadjuvant therapy in recurrent HGG demonstrated encouraging efficacy and revealed some evidence of efficacy, and worth to further investigate.

Phase I study of chlorogenic acid injection for recurrent high-grade glioma with long-term follow-up.

OBJECTIVE: This study was aimed at analyzing the efficacy and safety of an injectable form of chlorogenic acid (CGA) in patients with recurrent high-grade glioma after standard of care treatments, through a first-in-human, open-label, dose-escalation phase I trial. METHODS: A total of 26 eligible patients were enrolled, received intramuscular CGA injections at 5 dose levels, and were followed up for 5 years. CGA was well tolerated, and the maximum tolerated dose was 5.5 mg/kg. RESULTS: The most common treatment-related adverse events occurred at the sites of injection. No grade 3 or 4 adverse events (e.g., drug allergy) were reported for these patients except for induration at the injection sites. A clinical pharmacokinetic study showed that CGA was rapidly eliminated from the plasma, with a t1/2 of 0.95-1.27 h on day 1 and 1.19-1.39 h on day 30, and no detectable CGA was observed on days 9, 11, 13, 23, 25, 27, and 29 before CGA administration. After the first treatment cycle, 52.2% of patients (12 of 23) achieved stable disease. Long-term follow-up indicated an estimated median overall survival of 11.3 months for all 23 evaluable patients. Of the 18 patients with grade 3 glioma, the median overall survival was 9.5 months. Two patients remained alive at the cutoff day. CONCLUSIONS: This phase I study demonstrated that CGA has a favorable safety profile (with no severe toxicity), and provides preliminary clinical benefits for patients with high grade glioma relapsing after prior standard therapies, thus shedding light on the potential clinical application of CGA for recurrent grade 4 glioma.