Efficacy and indications of gamma knife radiosurgery for recurrent low-and high-grade glioma.

PURPOSE: To investigate the indications and efficacy of gamma knife radiosurgery (GKRS) as a salvage treatment for recurrent low-and high-grade glioma. METHODS: This retrospective study of 107 patients with recurrent glioma treated with GKRS between 2009 and 2022, including 68 high-grade glioma (HGG) and 39 low-grade glioma (LGG) cases. The Kaplan-Meier method was used to calculate the overall survival (OS) and progression-free survival (PFS). The log-rank test was used to analyze the multivariate prognosis of the Cox proportional hazards model. Adverse reactions were evaluated according to the Common Terminology Criteria for Adverse Events version 4.03. The prognostic value of main clinical features was estimated, including histopathology, Karnofsky performance status (KPS), recurrence time interval, target location, two or more GKRS, surgery for recurrence, site of recurrence, left or right side of the brain and so on. RESULTS: The median follow-up time was 74.5 months. The median OS and PFS were 17.0 months and 5.5 months for all patients. The median OS and PFS were 11.0 months and 5.0 months for HGG, respectively. The median OS and PFS were 49.0 months and 12.0 months for LGG, respectively. Multivariate analysis showed that two or more GKRS, left or right side of the brain and brainstem significantly affected PFS. Meanwhile, the KPS index, two or more GKRS, pathological grade, and brainstem significantly affected OS. Stratified analysis showed that surgery for recurrence significantly affected OS and PFS for LGG. KPS significantly affected OS and PFS for HGG. No serious adverse events were noted post-GKRS. CONCLUSION: GKRS is a safe and effective salvage treatment for recurrent glioma. Moreover, it can be applied after multiple recurrences with tolerable adverse effects.

Repeat surgery of recurrent glioma for molecularly informed treatment in the age of precision oncology: A risk-benefit analysis.

PURPOSE: Surgery for recurrent glioma provides cytoreduction and tissue for molecularly informed treatment. With mostly heavily pretreated patients involved, it is unclear whether the benefits of repeat surgery outweigh its potential risks. METHODS: Patients receiving surgery for recurrent glioma WHO grade 2-4 with the goal of tissue sampling for targeted therapies were analyzed retrospectively. Complication rates (surgical, neurological) were compared to our institutional glioma surgery cohort. Tissue molecular diagnostic yield, targeted therapies and post-surgical survival rates were analyzed. RESULTS: Between 2017 and 2022, tumor board recommendation for targeted therapy through molecular diagnostics was made for 180 patients. Of these, 70 patients (38%) underwent repeat surgery. IDH-wildtype glioblastoma was diagnosed in 48 patients (69%), followed by IDH-mutant astrocytoma (n = 13; 19%) and oligodendroglioma (n = 9; 13%). Gross total resection (GTR) was achieved in 50 patients (71%). Tissue was processed for next-generation sequencing in 64 cases (91%), and for DNA methylation analysis in 58 cases (83%), while immunohistochemistry for mTOR phosphorylation was performed in 24 cases (34%). Targeted therapy was recommended in 35 (50%) and commenced in 21 (30%) cases. Postoperatively, 7 patients (11%) required revision surgery, compared to 7% (p = 0.519) and 6% (p = 0.359) of our reference cohorts of patients undergoing first and second craniotomy, respectively. Non-resolving neurological deterioration was documented in 6 cases (10% vs. 8%, p = 0.612, after first and 4%, p = 0.519, after second craniotomy). Median survival after repeat surgery was 399 days in all patients and 348 days in GBM patients after repeat GTR. CONCLUSION: Surgery for recurrent glioma provides relevant molecular diagnostic information with a direct consequence for targeted therapy under a reasonable risk of postoperative complications. With satisfactory postoperative survival it can therefore complement a multi-modal glioma therapy approach.

Intraoperative functional remapping unveils evolving patterns of cortical plasticity.

The efficiency with which the brain reorganizes following injury not only depends on the extent and the severity of the lesion, but also on its temporal features. It is established that diffuse low-grade gliomas (DLGG), brain tumours with a slow-growth rate, induce a compensatory modulation of the anatomo-functional architecture, making this kind of tumours an ideal lesion model to study the dynamics of neuroplasticity. Direct electrostimulation (DES) mapping is a well-tried procedure used during awake resection surgeries to identify and spare cortical epicentres which are critical for a range of functions. Because DLGG is a chronic disease, it inevitably relapses years after the initial surgery, and thus requires a second surgery to reduce tumour volume again. In this context, contrasting the cortical mappings obtained during two sequential neurosurgeries offers a unique opportunity to both identify and characterize the dynamic (i.e. re-evolving) patterns of cortical re-arrangements. Here, we capitalized on an unprecedented series of 101 DLGG patients who benefited from two DES-guided neurosurgeries usually spaced several years apart, resulting in a large DES dataset of 2082 cortical sites. All sites (either non-functional or associated with language, speech, motor, somatosensory and semantic processing) were recorded in Montreal Neurological Institute (MNI) space. Next, we used a multi-step approach to generate probabilistic neuroplasticity maps that reflected the dynamic rearrangements of cortical mappings from one surgery to another, both at the population and individual level. Voxel-wise neuroplasticity maps revealed regions with a relatively high potential of evolving reorganizations at the population level, including the supplementary motor area (SMA, Pmax = 0.63), the dorsolateral prefrontal cortex (dlPFC, Pmax = 0.61), the anterior ventral premotor cortex (vPMC, Pmax = 0.43) and the middle superior temporal gyrus (STG Pmax = 0.36). Parcel-wise neuroplasticity maps confirmed this potential for the dlPFC (Fisher's exact test, PFDR-corrected = 6.6 × 10-5), the anterior (PFDR-corrected = 0.0039) and the ventral precentral gyrus (PFDR-corrected = 0.0058). A series of clustering analyses revealed a topological migration of clusters, especially within the left dlPFC and STG (language sites); the left vPMC (speech arrest/dysarthria sites) and the right SMA (negative motor response sites). At the individual level, these dynamic changes were confirmed for the dlPFC (bilateral), the left vPMC and the anterior left STG (threshold free cluster enhancement, 5000 permutations, family-wise error-corrected). Taken as a whole, our results provide a critical insight into the dynamic potential of DLGG-induced continuing rearrangements of the cerebral cortex, with considerable implications for re-operations.

Clinical significance of histopathological features of paired recurrent gliomas: a cohort study from a single cancer center.

OBJECTIVE: To explore the histopathological characteristics of paired recurrent gliomas and their clinical significance. METHODS: Glioma patients who received both primary surgery and reoperation when recurrence at Sun Yat-sen University Cancer Center from June 2001 to June 2019 were enrolled. Clinical and pathological characteristics were analyzed retrospectively, and histopathology of reoperation specimens was divided into three categories according to tumor cell activity and the degree of necrosis: active group, low-activity group, and necrosis group. RESULTS: A total of 89 patients were included in this study. The 2016 WHO grade of the first operation pathology and IDH1 status were related to survival time after the first operation, but there was no significant association with survival time after reoperation. The time interval between primary and reoperation was shorter for primary high-grade glioma and/or IDH1 wild-type tumor patients than for low-grade glioma and/or IDH1 mutant tumor patients (P < 0.001). Histopathological types of recurrent gliomas were analyzed, and 67 cases (75.3%) were classified into the active group, 14 (15.8%) into the low-activity group, and 8 (8.9%) into the necrosis group. The low-activity or necrosis group was associated with a higher radiotherapy dose and shorter operation interval. Further univariate and multivariate Cox survival analyses showed the histopathological patterns of recurrent gliomas to be related to survival time after reoperation. CONCLUSION: Primary WHO low grade or IDH1 mutant gliomas appeared survival benefit mainly on later recurrence, but was not a prognostic predictor following recurrence. Histopathological feature of recurrent glioma is related to previous treatment, including radiotherapy dosage and chemotherapy treatment, and is also an important independent prognostic factor for patients after reoperation.

Prevalence, risk factors and prognostic value of anxiety and depression in recurrent glioma patients.

Anxiety and depression are frequently noticed in glioma patients, while few studies report this issue in recurrent glioma patients. Hence, this study aimed to evaluate the prevalence of anxiety and depression, as well as their risk factors and prognostic value in recurrent glioma patients. Eighty recurrent glioma patients, 40 newly-diagnosed glioma patients, and 40 healthy controls were enrolled in this study. Then, the Hospital Anxiety and Depression Scale for anxiety (HADS-A) and for depression (HADS-D) were used to assess the anxiety and depression status of all subjects. The HADS-A score (8.6 ± 3.3 vs. 7.0 ± 2.9 vs. 4.3 ± 2.5), anxiety rate (58.8% vs. 32.5% vs. 10.0%), HADS-D score (7.9 ± 3.0 vs. 6.9 ± 3.1 vs. 4.0 ± 2.6), and depression rate (45.0% vs. 30.0% vs. 7.5%) were all highest in recurrent glioma patients, followed by newly-diagnosed glioma patients, and were lowest in healthy controls (all P < 0.001). Furthermore, female sex (vs. male sex) was independently correlated with anxiety (odds ratio (OR): 3.042, P = 0.029); meanwhile, higher World Health Organization (WHO) pathological grade was independently correlated with depression (OR: 2.573, P = 0.019) in recurrent glioma patients. Additionally, anxiety was correlated with shortened progression-free survival (PFS) (P = 0.028) and overall survival (OS) (P = 0.047), while depression only had a correlation trend with shortened PFS (without statistical significance) (P = 0.069) and was associated with shortened OS (P = 0.035) in recurrent glioma patients. The prevalence of anxiety and depression is high in recurrent glioma patients, which relates to gender, WHO pathological grade, and estimates worsen survival.

Online calculator to predict early mortality in patient with surgically treated recurrent lower-grade glioma.

PURPOSE: The aim of this study was to investigate the epidemiological characteristics and associated risk factors of recurrent lower-grade glioma [LGG] (WHO grades II and III) according to the 2016 updated WHO classification paradigm and finally develop a model for predicting early mortality (succumb within a year after reoperation) in recurrent LGG patients. METHODS: Data were obtained from consecutive patients who underwent surgery for primary LGG and reoperation for tumor recurrence. The end point "early mortality" was defined as death within 1 year after the reoperation. Predictive factors, including basic clinical characteristics and laboratory data, were retrospectively collected. RESULTS: A final nomogram was generated for surgically treated recurrent LGG. Factors that increased the probability of early mortality included older age (P = 0.042), D-dimer> 0.187 (P = 0.007), RDW > 13.4 (P = 0.048), PLR > 100.749 (P = 0.014), NLR > 1.815 (P = 0.047), 1p19q intact (P = 0.019), IDH1-R132H Mutant (P = 0.048), Fib≤2.80 (P = 0.018), lack of Stupp concurrent chemoradiotherapy (P = 0.041), and an initial symptom of epilepsy (P = 0.047). The calibration curve between the prediction from this model and the actual observations showed good agreement. CONCLUSION: A nomogram that predicts individualized probabilities of early mortality for surgically treated recurrent LGG patients could be a practical clinical tool for counseling patients regarding treatment decisions and optimizing therapeutic approaches. Free online software implementing this nomogram is provided at https://warrenwrl.shinyapps.io/RecurrenceGliomaEarlyM/.

A multi-center prospective study of re-irradiation with bevacizumab and temozolomide in patients with bevacizumab refractory recurrent high-grade gliomas.

PURPOSE: Survival is dismal for bevacizumab refractory high-grade glioma patients. We prospectively investigated the efficacy of re-irradiation, bevacizumab, and temozolomide in bevacizumab-naïve and bevacizumab-exposed recurrent high-grade glioma, without volume limitations, in a single arm trial. METHODS: Recurrent high-grade glioma patients were stratified based on WHO grade (4 vs. < 4) and prior exposure to bevacizumab (yes vs. no). Eligible patients received radiation using a simultaneous integrated boost technique (55 Gy to enhancing disease, 45 Gy to non-enhancing disease in 25 fractions) with bevacizumab 10 mg/kg every 2 weeks IV and temozolomide 75 mg/m2 daily followed by maintenance bevacizumab 10 mg/kg every 2 weeks and temozolomide 50 mg/m2 daily for 6 weeks then a 2 week holiday until progression. Primary endpoint was overall survival. Quality of life was studied using FACT-Br and FACT-fatigue scales. RESULTS: Fifty-four patients were enrolled. The majority (n = 36, 67%) were bevacizumab pre-exposed GBM. Median OS for all patients was 8.5 months and 7.9 months for the bevacizumab pre-exposed GBM group. Patients ≥ 36 months from initial radiation had a median OS of 13.3 months compared to 7.5 months for those irradiated < 36 months earlier (p < 0.01). FACT-Br and FACT-Fatigue scores initially declined during radiation but returned to pretreatment baseline. Treatment was well tolerated with 5 patients experiencing > grade 3 lymphopenia and 2 with > grade 3 thrombocytopenia. No radiographic or clinical radiation necrosis occurred. CONCLUSIONS: Re-irradiation with bevacizumab and temozolomide is a safe and feasible salvage treatment for patients with large volume bevacizumab-refractory high-grade glioma. Patients further from their initial radiotherapy may derive greater benefit with this regimen.

Evidence for improved survival with bevacizumab treatment in recurrent high-grade gliomas: a retrospective study with ("pseudo-randomized") treatment allocation by the health insurance provider.

INTRODUCTION: Despite a large number of trials, the role of bevacizumab (BEV) in the treatment of recurrent high-grade gliomas is still controversial. Evidence regarding an effect on overall survival in this context is ultimately inconclusive. At the Department of Radiation Oncology at Erlangen, Germany we treated a large cohort of patients with recurrent gliomas where bevacizumab use was determined exclusively by the health care provider's approval of reimbursement. METHODS: 61 patients (between 06/2008 and 01/2014) with recurrent high-grade gliomas had reimbursement requests for BEV sent to their health insurance. 37 patients out of 61 (60.7%) had their requests approved and therefore received bevacizumab (BEV-arm) as part of their treatment. The remaining 24 (39.3%) patients received standard therapy without bevacizumab (non-BEV-arm). Survival endpoints were defined with reference to the first BEV request to the health insurance provider. RESULTS: Median overall survival (OS) for the whole cohort was 7.0 months. OS was significantly better for BEV vs. Non-BEV patients (median, 10.3 vs. 4.2 months, logrank p = 0.023). There was an increased BEV benefit in cases of higher-order recurrences (first order recurrence BEV vs. Non-BEV, 12.5 vs. 10.2 months, p = 0.578) (second or higher order of recurrence, 9.9 vs. 2.6 months, p = 0.010). On multivariate analysis for overall survival the prognostic impact of bevacizumab (HR = 0.43, p = 0.034) remained significant. CONCLUSION: Our results suggest an influence of BEV on overall survival in a heavily pretreated patient population suffering from high-grade gliomas with BEV benefit being greatest in case of second or later recurrence.

Re-irradiation for recurrent glioma: outcome evaluation, toxicity and prognostic factors assessment. A multicenter study of the Radiation Oncology Italian Association (AIRO).

INTRODUCTION: The prognosis of glioma is dismal, and almost all patients relapsed. At recurrence time, several treatment options are considered, but to date there is no a standard of care. The Neurooncology Study Group of the Italian Association of Radiation Oncology (AIRO) collected clinical data regarding a large series of recurrent glioma patients who underwent re-irradiation (re-RT) in Italy. METHODS: Data regarding 300 recurrent glioma patients treated from May 2002 to November 2017, were analyzed. All patients underwent re-RT. Surgical resection, followed by re-RT with concomitant and adjuvant chemotherapy was performed. Clinical outcome was evaluated by neurological examination and brain MRI performed, 1 month after radiation therapy and then every 3 months. RESULTS: Re-irradiation was performed at a median interval time (IT) of 16 months from the first RT. Surgical resection before re-RT was performed in 19% of patients, concomitant temozolomide (TMZ) in 16.3%, and maintenance chemotherapy in 29%. Total doses ranged from 9 Gy to 52.5 Gy, with a median biological effective dose of 43 Gy. The median, 1, 2 year OS were 9.7 months, 41% and 17.7%. Low grade glioma histology (p  ≪ 0.01), IT > 12 months (p = 0.001), KPS > 70 (p = 0.004), younger age (p = 0.001), high total doses delivered (p = 0.04), and combined treatment performed (p = 0.0008) were recorded as conditioning survival. CONCLUSION: our data underline re-RT as a safe and feasible treatment with limited rate of toxicity, and a combined ones as a better option for selected patients. The identification of a BED threshold able to obtain a greater benefit on OS, can help in designing future prospective studies.

CT-guided interstitial HDR-brachytherapy for recurrent glioblastoma multiforme: a 20-year single-institute experience.

PURPOSE: To report our results of computed tomography-guided interstitial high-dose-rate (HDR) brachytherapy (BRT) in the treatment of patients with recurrent inoperable glioblastoma multiforme (GBM). PATIENTS AND METHODS: Between 1995 and 2014, 135 patients were treated with interstitial HDR BRT for inoperable recurrent GBM located within previously irradiated volumes. Patient's median age was 57.1 years (14-82 years). All patients were pretreated with surgery, postoperative external beam radiation therapy (EBRT) and systemic chemotherapy (ChT). The median recurrent tumor volume was 42 cm3 (2-207 cm3). The prescribed HDR dose was median 40 Gy (30-50 Gy) delivered in twice-daily fractions of 5.0 Gy over consecutive days. No repeat surgery or ChT was administered in conjunction with BRT. Survival from BRT, progression-free survival (PFS), toxicity as well as the impact of several prognostic factors were evaluated. RESULTS: At a median follow-up of 9.2 months, the median overall survival following BRT and the median PFS were 9.2 and 4.6 months, respectively. Of the prognostic variables evaluated in univariate analysis, extent of surgery at initial diagnosis, tumor volume at recurrence, as well as time from EBRT to BRT reached statistical significance, retained also in multivariate analysis. Eight patients (5.9%) developed treatment-associated complications including intracerebral bleeding in 4 patients (2.9%), symptomatic focal radionecrosis in 3 patients (2.2%), and severe convulsion in 1 patient (0.7%). CONCLUSIONS: For patients with recurrent GBM, interstitial HDR BRT is an effective re-irradiation method for even larger tumors providing palliation without excessive toxicity.

Timing of re-irradiation in recurrent high-grade gliomas: a single institution study.

There is no standard treatment available for recurrent high-grade gliomas. This monoinstitutional retrospective analysis evaluates the differences in overall survival and progression-free survival in patients according to the timing of re-irradiation. Patients suffering from a glioblastoma who received re-irradiation for recurrence were evaluated retrospectively. The median overall survival (OS) and the median progression-free survival were compared with different treatment options and within various time periods. From January 2007 until March 2015, 41 patients suffering from recurrent high-grade gliomas received re-irradiation [median dose of 30.6 Gy (range 20-40 Gy) in median 4 Gy fractions (range 1.8-5 Gy)] in our institution after initial postoperative irradiation or combined radiochemotherapy. The OS in this population was 34 months, and the OS after recurrence (OS-R) was 13 months. After diagnosis of recurrence, patients underwent additional surgical resection after a median of 1.2 months, received a second-line systemic therapy after 2.2 months with or without re-irradiation after 5.7 months. Growth of the tumour was assessed 4.3 months after the start of re-irradiation. The OS after the second surgical resection was 12.2 months, 11.7 months after the start of the second-line systemic therapy, and 6.7 months after the start of re-irradiation. The OS-R was not significantly correlated with the start of re-irradiation after a diagnosis of recurrence or the time period after the previous surgery. At this institution, re-irradiation was performed later compared to other treatment options. However, select patients could benefit from irradiation at an earlier time point. A precise time point should still be evaluated on an individual basis due to the patient's diverse conditions.

Quantitative dynamic susceptibility contrast perfusion-weighted imaging-guided customized gamma knife re-irradiation of recurrent high-grade gliomas.

INTRODUCTION: Treatment of recurrent high-grade gliomas (rHGG) has always been challenging. This study aimed to explore the treatment effect of quantitative dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI)-guided gamma knife radiosurgery (GKRS) on rHGG. METHODS: Between April 2014 and July 2016, 26 consecutive patients were treated by quantitative DSC-PWI-guided GKRS as salvage treatment for rHGG. The gross tumor volume (GTV) was defined as the high perfusion area on absolute cerebral blood volume maps, with a cutoff value of 22 ml/100 g. The clinical target volume (CTV) encompassed the GTV by 3 mm. Overall survival (OS) and progression-free survival (PFS) were calculated by the Kaplan-Meier method. Prognostic factors were tested by the log-rank (Mantel-Cox) test. RESULTS: With a median follow-up of 32 months, the median PFS after GKRS was 8 months (95% CI [6, 12]); the 1- and 2-year survival rates were 30.8 and 11.5%, respectively. The median OS was 25.5 months (95% CI [18, 40]); the 1- and 2-year survival rates were 96.2 and 57.7%, respectively. Pathology grade and CTV were identified as prognostic factors for PFS. However, none of the parameters tested were independent prognostic factors for OS among these selected patients. No severe radiotoxicity was observed among all patients. CONCLUSIONS: Quantitative DSC-PWI-guided GKRS is feasible for the treatment of rHGG and that these outcomes remain to be validated. Despite this, we think that carefully selected patients can benefit from this treatment method.

A predictive value of von Willebrand factor for early response to Bevacizumab therapy in recurrent glioma.

Bevacizumab (BV), a neutralizing monoclonal antibody against the vascular endothelial growth factor ligand, is recognized as a potent anti-angiogenic agent with antitumor activity. The aim of this single-center, retrospective, longitudinal study was to investigate the possible predictive value of baseline demographic, clinical and laboratory parameters for early 3-month response to BV therapy in patients with recurrent glioma. Forty-nine patients with recurrent glioma received BV at 10 mg/kg intravenously every 3 weeks alone or in association with chemotherapy were included in this study. Blood samples were collected from all patients before the first (baseline), the second and the third administration of BV. After 3 months of BV therapy, patients with partial response were defined as responders whereas patients with stable or progressive disease were defined as non-responders. The median overall follow-up was 8 months (range 1-73), the median overall survival (OS) was 8 months (95% CI 6-10) and the median progression free survival (PFS) was 4 months (95% CI 3-5). Thirty-five % of patients were responders and showed significantly lower von Willebrand factor (VWF) levels than non-responders at all sample times (p < .02 for all). Also, on multivariate analysis the baseline VWF value was the only predictor for an early response to BV therapy. Furthermore, D-dimer and prothrombin fragment 1+2 were predictive factors for OS while Karnofsky performance status resulted predictive for PFS. VWF antigen value is a possible predictive biomarker for an early 3-month response to BV therapy in recurrent glioma.

Utility of intravoxel incoherent motion magnetic resonance imaging and arterial spin labeling for recurrent glioma after bevacizumab treatment.

Background Detecting recurrence of glioma on magnetic resonance imaging (MRI) is getting more and more important, especially after administration of new anti-tumor agent. However, it is still hard to identify. Purpose To examine the utility of intravoxel incoherent motion (IVIM) MRI and arterial spin labeling-cerebral blood flow (ASL-CBF) for recurrent glioma after initiation of bevacizumab (BEV) treatment. Material and Methods Thirteen patients (7 men, 6 women; age range = 41-82 years) with glioma (high grade, n = 11; low grade, n = 2) were enrolled in the study. IVIM parameters including apparent diffusion coefficient (ADC), true diffusion coefficient (D), and perfusion fraction (f) were obtained with 14 different b-values. We identified tumor progression during BEV therapy by MRI monitoring consisting of diffusion-weighted imaging (DWI), fluid-attenuated inversion recovery (FLAIR) imaging, and contrast-enhanced T1-weighted (CE-T1W) imaging by measuring tumor area. We also measured each parameter of IVIM and ASL-CBF, and calculated relative ADC (rADC), relative D (rD), relative f (rf), and relative CBF (rCBF) by obtaining the ratio between each area and the contralateral cerebral white matter. We calculated the rate of change (Δ) by subtracting values from those from the preceding MRI study, and obtained Spearman's rank correlation coefficient (rs). Results Tumor progression was identified in nine patients (high grade, n = 7; low grade, n = 2). Negative correlations were identified between ΔrD and ΔDWI area (rs = -0.583), and between ΔrD and ΔCE-T1W imaging area (rs = -0.605). Conclusion Tumor progression after BEV treatment can be identified by decreasing rD.

Survival outcomes following repeat surgery for recurrent glioblastoma: a single-center retrospective analysis.

The aim of the present study is to evaluate the impact of extent of resection at initial and repeat craniotomy on overall survival of patients with recurrent glioblastoma. The authors retrospectively reviewed the records of all adults patients who underwent repeat resection of recurrent glioblastoma following radiation and chemotherapy at an academic tertiary-care institution between 2011 and 2015. We evaluated the survival outcomes with regard to extent of resection considering both the initial and repeat resections. The role of possible prognostic factors that may affect survival after repeat resection, including age, preoperative performance status, tumor location and adjuvant treatment, was evaluated using Cox regression analyses. Forty-eight patients were included in this study. The overall median survival of 14 patients who had subtotal resection at recurrence after initial subtotal resection did not statistically differ from seven patients who had gross-total resection at recurrence after initial subtotal resection (18 months vs. 22 months, p = 0.583). The overall median survival of 13 patients who had gross-total resection at recurrence after initial gross-total resection was significantly increased compared with survival of 13 patients who had subtotal resection at recurrence after initial gross-total resection (47 months vs. 14 months, p = 0.009). A Cox proportional hazards model was created demonstrating that preoperative performance status at recurrence (HR 0.418, p = 0.035) and the extent of repeat resection (HR 0.513, p = 0.043) were independent predictors of survival. Gross-total resection at repeat craniotomy is associated with longer overall survival and should be performed whenever possible in patients with recurrent glioblastoma and in good performance status.

Improving the utility of 1H-MRS for the differentiation of glioma recurrence from radiation necrosis.

Proton magnetic resonance spectroscopy (1H-MRS) has shown promise in distinguishing recurrent high-grade glioma from posttreatment radiation effect (PTRE). The purpose of this study was to establish objective 1H-MRS criteria based on metabolite peak height ratios to distinguish recurrent tumor (RT) from PTRE. A retrospective analysis of magnetic resonance imaging and 1H-MRS data was performed. Spectral metabolites analyzed included N-acetylaspartate, choline (Cho), creatine (Cr), lactate (Lac), and lipids (Lip). Quantitative 1H-MRS criteria to differentiate RT from PTRE were identified using 81 biopsy-matched spectral voxels. A receiver operating characteristic curve analysis was conducted for all metabolite ratio combinations with the pathology diagnosis as the classification variable. Forward discriminant analysis was used to identify ratio variables that maximized the correct classification of RT versus PTRE. Our results were applied to 205 records without biopsy-matched voxels to examine the percent agreement between our criteria and the radiologic diagnoses. Five ratios achieved an acceptable balance [area under the curve (AUC) ≥ 0.700] between sensitivity and specificity for distinguishing RT from PTRE, and each ratio defined a criterion for diagnosing RT. The ratios are as follows: Cho/Cr > 1.54 (sensitivity 66%, specificity 79%), Cr/Cho ≤ 0.63 (sensitivity 65%, specificity 79%), Lac/Cho ≤ 2.67 (sensitivity 85%, specificity 58%), Lac/Lip ≤ 1.64 (sensitivity 54%, specificity 95%), and Lip/Lac > 0.58 (sensitivity 56%, specificity 95%). Application of our ratio criteria in prospective studies may offer an alternative to biopsy or visual spectral pattern recognition to distinguish RT from PTRE in patients with gliomas.

Salvage stereotactic radiosurgery for recurrent gliomas with prior radiation therapy.

This study aims to assess the viability of salvage stereotactic radiosurgery (SRS) for recurrent malignant gliomas through assessing overall survival, local control and toxicity. We performed a retrospective review of 65 patients with 76 lesions (55 high-grade, 21 low-grade) treated with salvage SRS between 2002 and   2012. Median follow-up from salvage SRS was 14.9 months (IQR: 0.9-28.1), 8.3 months (IQR: 4.0-13.3) and 8.5 months (IQR: 3.9-15.8) for low-grade, high-grade, and combined, respectively. A 12-month overall survival from salvage SRS was 68.4, 38.7 and 47.3% for low-grade, high-grade and combined respectively. A total of 6-month local control was 86.2, 53.8 and 65.3% for low-grade, high-grade and combined, respectively. Our results indicate salvage SRS can provide acceptable survival and local control with minimal toxicity.

Phase I study of low-dose metronomic temozolomide for recurrent malignant gliomas.

BACKGROUND: The treatment goal for recurrent malignant gliomas centers on disease stabilization while minimizing therapy-related side effects. Metronomic dosing of cytotoxic chemotherapy has emerged as a promising option to achieve this objective. METHODS: This phase I study was performed using metronomic temozolomide (mTMZ) at 25 or 50 mg/m2/day continuously in 42-day cycles. Correlative studies were incorporated using arterial spin labeling MRI to assess tumor blood flow, analysis of matrix metalloproteinase-2 (MMP-2) and MMP-9 activities in the cerebrospinal fluid (CSF) as surrogates for tumor angiogenesis and invasion, as well as determination of CSF soluble interleukin-2 receptor alpha (sIL-2Rα) levels as a marker of immune modulation. RESULTS: Nine subjects were enrolled and toxicity consisted of primarily grade 1 or 2 hematological and gastrointestinal side effects; only one patient had a grade 3 elevated liver enzyme level that was reversible. Tumor blood flow was variable across subjects and time, with two experiencing a transient increase before a decrease to below baseline level while one exhibited a gradual drop in blood flow over time. MMP-2 activity correlated with overall survival but not with progression free survival, while MMP-9 activity did not correlate with either outcome parameters. Baseline CSF sIL-2Rα level was inversely correlated with time from initial diagnosis to first progression, suggesting that subjects with higher sIL-2Rα may have more aggressive disease. But they lived longer when treated with mTMZ, probably due to drug-related changes in T-cell constituency. CONCLUSIONS: mTMZ possesses efficacy against recurrent malignant gliomas by altering blood flow, slowing invasion and modulating antitumor immune function.

Re-irradiation strategies in combination with bevacizumab for recurrent malignant glioma.

The place of bevacizumab (BEV) in salvage re-irradiation (Re-RT) settings of malignant glioma is poorly defined. In the current study risk/benefit profiles of two BEV-based Re-RT protocols were analyzed and compared with that of salvage BEV plus irinotecan (BEV/IRI). According to interdisciplinary tumor board recommendations, patients were assigned to one of three BEV-based treatment protocols: (1) BEV/IRI, (2) Re-RT (36 Gy/18 fx) with concomitant BEV (Re-RT/BEV), and (3) Re-RT with concomitant/maintenance BEV (Re-RT/BEV→BEV). Prognostic factors were obtained from proportional hazards models. Adverse events were classified according to the NCI CTCAE, v4.0. 105 consecutive patients were enrolled from 08/2008 to 05/2014. Patients undergoing Re-RT experienced longer time intervals from initial diagnosis to BEV treatment (median: 22.0 months vs. 13.7 months, p = 0.001); those assigned to Re-RT/BEV→BEV rated better on the performance scale (median KPSREC: 90 vs. 70, p = 0.013). Post-recurrence survival after BEV-based treatment (PRS) was longest after Re-RT/BEV→BEV (median: 13.1 months vs. 8 months, p = 0.006). PRS after Re-RT/BEV and BEV/IRI was similar. Multivariately, higher KPSREC and Re-RT/BEV→BEV were associated with longer PRS. Treatment toxicity did not differ among groups. Re-RT/BEV→BEV is safe, feasible and effective and deserves further prospective evaluation.

Aggressive repeat surgery for focally recurrent primary glioblastoma: outcomes and theoretical framework.

OBJECT The relative benefit of repeat surgery for recurrent glioblastoma is unclear, in part due to the very heterogeneous nature of the patient population and the effect of clinician philosophy on the duration and aggressiveness of treatment. The authors sought to investigate the role of time to last recurrence on patient outcomes following aggressive repeat surgery for recurrent glioblastoma. METHODS The authors present outcomes in 104 patients undergoing repeat surgery for focally recurrent glioblastoma with at least 95% resection and adjuvant treatment at most recent prior surgery. In addition to common variables, they provide data regarding the period of progression-free survival (PFS) following an aggressive lesionectomy for focally recurrent primary glioblastoma (T2) and the time the tumor took to recur since the previous surgery (T1). They term the ratio T1/T2 the relative aggressivity index (RAI). RESULTS The median PFS was 7.8 months, 6.0 months, and 4.8 months following the second, third, and fourth-sixth craniotomies, respectively. Importantly, there was a wide range of outcomes, with time to postoperative recurrence ranging from 1 to 24 months in this group. Analysis showed no meaningful relationship between T1 and T2, meaning that previous PFS is entirely unable to predict the PFS that another surgery will provide the patient. CONCLUSIONS Repeat surgery for glioblastoma is beneficial in many cases, however this is hard to predict preoperatively. Often, surgery can provide the patient with a good period of disease freedom, but this is variable and in general it is not possible to reliably predict who these patients are.