Treatment Of Recurrent High-grade Gliomas Research Articles

Evidence for improved survival with bevacizumab treatment in recurrent high-grade gliomas: a retrospective study with (\u201cpseudo-randomized\u201d) treatment allocation by the health insurance provider

IntroductionDespite 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.Methods61 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.ResultsMedian 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.ConclusionOur 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.

Lysosomal acid lipase deficiency across ages: Unraveling the clinical spectrum of an under-recognized genetic disorder

Based on the effective radiological responses, bevacizumab (BEV) has been widely used in the treatment of recurrent high-grade glioma. Although the current standard dose is 5 mg/kg/week, the optimal dosage of BEV is controversial, as few dose-response studies have been performed in recent years. Therefore, we conducted a meta-analysis to explore the value of reduced-dose bevacizumab versus standard-dose bevacizumab in recurrent high-grade glioma treatment.Three major electronic databases (PubMed, EMBASE and the Cochrane Library) were searched for eligible documents published before February 2020. Literature on low-dose bevacizumab versus conventional dose in progressive high-grade glioma was included, and the endpoints of eligible researches should be progression-free survival (PFS) and overall survival (OS). All available data were collected and then analyzed with Stata software.Four cohort studies were evaluated, including 552 patients (reduced-dose BEV group: 257, standard-dose BEV group: 295). Low dose BEV seems to slightly improve survival compared to conventional dose as HR < 1 indicates a protective effect, but no significant differences in OS (HR 0.77; 95 % CI 0.53–1.10; P = 0.151) and PFS (HR 0.66; 95 % CI 0.37–1.20; P = 0.175) were found between the two groups in this study.Reduced-dose bevacizumab schedule resulted in similar OS and PFS to standard-dose bevacizumab in recurrent high-grade glioma, with less side effects and less cost of treatment. Therefore, low-dose bevacizumab represents a promising therapeutic option for recurrent high-grade glioma patients. Further prospective randomized trials are needed to confirm our results.

Radiological Recurrence Patterns after Bevacizumab Treatment of Recurrent High-Grade Glioma: A Systematic Review and Meta-Analysis.

ObjectiveTo categorize the radiological patterns of recurrence after bevacizumab treatment and to derive the pooled proportions of patients with recurrent malignant glioma showing the different radiological patterns.Materials and MethodsA systematic literature search in the Ovid-MEDLINE and EMBASE databases was performed to identify studies reporting radiological recurrence patterns in patients with recurrent malignant glioma after bevacizumab treatment failure until April 10, 2019. The pooled proportions according to radiological recurrence patterns (geographically local versus non-local recurrence) and predominant tumor portions (enhancing tumor versus non-enhancing tumor) after bevacizumab treatment were calculated. Subgroup and meta-regression analyses were also performed.ResultsThe systematic review and meta-analysis included 17 articles. The pooled proportions were 38.3% (95% confidence interval [CI], 30.6–46.1%) for a geographical radiologic pattern of non-local recurrence and 34.2% (95% CI, 27.3–41.5%) for a non-enhancing tumor-predominant recurrence pattern. In the subgroup analysis, the pooled proportion of non-local recurrence in the patients treated with bevacizumab only was slightly higher than that in patients treated with the combination with cytotoxic chemotherapy (34.9% [95% CI, 22.8–49.4%] versus 22.5% [95% CI, 9.5–44.6%]).ConclusionA substantial proportion of high-grade glioma patients show non-local or non-enhancing radiologic patterns of recurrence after bevacizumab treatment, which may provide insight into surrogate endpoints for treatment failure in clinical trials of recurrent high-grade glioma.

Stereotactic Radiosurgery for the Treatment of Recurrent High-grade Gliomas: Long-term Follow-up.

High-grade gliomas (HGG) are the most frequent primary central nervous system tumors; treatment of HCGs includes surgery and post-operative conformal radiotherapy associated with temozolomide (TMZ or procarbazine/lomustine/vincristine [PCV], specifically in patients with anaplastic oligodendrogliomas or anaplastic oligoastrocytomas). However, recurrence is common. Re-irradiation has been utilized in this setting for years and remains a feasible option, although there is always a concern regarding toxicity. Modern high-precision conformal techniques, including stereotactic radiosurgery (SRS), could improve the therapeutic ratio by delivering high biologically equivalent doses while reducing high-dose radiotherapy (RT) to normal brain tissue. In this paper, we present the results obtained after prolonged follow-up in patients who underwent SRS as a treatment for recurrent high-grade gliomas at San Francisco Hospital in Madrid, Spain

DNX-2401: an investigational drug for the treatment of recurrent glioblastoma

ABSTRACTIntroduction: High-grade gliomas (HGG) are extremely aggressive brain malignancies that are fatal. Despite maximal resection, chemotherapy, and radiation, these tumors inevitably recur and present a poor median overall survival (mOS); hence a pressing need for improved treatments.Areas covered: This review assesses DNX-2401 as a treatment of recurrent HGG. Phase I data on efficacy, safety, and tolerability are examined while insights and perspectives on future directions are offered.Expert opinion: This phase I study assessed DNX-2401 in two study groups; one received an intratumoral injection without tumor resection while the second received an intratumoral injection followed by surgical resection 14 days later with a second injection into the resection cavity. In patients that did not receive resection, the mOS was 9.5 months while patients in the resection group had a mOS of 13 months, a promising extension of survival compared to historical controls. Furthermore, this study had numerous long-term survivors living for greater than 2 years. DNX-2401 was well tolerated with no Grade 3/4 adverse events; it provoked an immunologic response to the tumor which may contribute to the complete responses in some patients. Randomized-control trials are necessary and further studies are warranted to identify patients who will benefit most.

OS12.2 Targeting epigenetic pathways in the treatment of recurrent high-grade glioma

Abstract BACKGROUND High grade glioma (HGG) patients develop resistance to standard treatment leading to disease progression and limited life expectancy. Advances in the molecular characterisation of treatment-naïve HGGs based on next-generation sequencing and DNA methylation analyses have led to a better delineation of HGG subtypes and the identification of distinct genomic abnormalities. Furthermore, using large patient cohorts of longitudinal tumor samples, comprehensive genomic profiling studies emerged to investigate therapy-associated evolution of gliomas. All together, those studies point out the need for personalised treatment strategies, where applied drugs will be adapted to the unique patient-specific genetic abnormalities. MATERIAL AND METHODS We collected fresh samples of more than 800 brain tumors containing almost 300 glioma specimen with approximately 100 longitudinal samples of initial and recurrent tumors from 43 matched patients. By now, we have successfully established 34 patient-derived orthotopic xenografts (PDOXs) in mice. We performed comprehensive molecular profiling using array comparative genomic hybridisation, DNA methylation analysis and targeted DNA sequencing on patient specimen and their derivatives such as 3D tumor organoids and PDOXs. The custom-design sequencing panel comprises 234 genes that reflect both established genetic identifiers for individual glioma subtype classification and novel genes encoding mainly epigenetic effector genes. Based on patient-derived material we carried out drug response screening on 3D tumor organoids using a compound library matching the majority of genes that were assessed by targeted sequencing. RESULTS We succeeded in generating a live biobank of HGG patient-derived xenografts and 3D organoids that neatly recapitulates the mutational spectrum including structural DNA variation and methylation-based subtypes of gliomas. A highlight is the generation of 19 PDOXs of paired initial and relapse HGGs from a total of 9 glioma patients. A detailed analysis of the paired longitudinal samples indicated that PDOX models closely recapitulate the evolutionary trajectory of the parental tumors. Targeted sequencing of longitudinal HGG PDOXs suggests that relapse tumors accumulate somatic mutations in epigenetic effectors compared with the Initial. Differential drug responses between initial and relapse tumors were observed after screening of in vitro 3D tumor organoids. CONCLUSION Response assessment of naïve initial gliomas and recurrences provides crucial information on the differential sensitivity between initial and relapsed HGGs and offers novel personalised therapeutic options in the relapse setting. Furthermore, in depth correlation of the profiled somatic molecular landscape with drug response will enable pharmacogenomic predictions of potential inhibitors in the clinical setting.

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

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. 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 22ml/100g. The clinical target volume (CTV) encompassed the GTV by 3mm. 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. With a median follow-up of 32 months, the median PFS after GKRS was 8months (95% CI [6, 12]); the 1- and 2-year survival rates were 30.8 and 11.5%, respectively. The median OS was 25.5months (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. 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.

Treatment of recurrent high-grade gliomas with GliaSite brachytherapy: a prospective mono-institutional Italian experience.

The present study evaluated toxicity, local control, and survival in patients with relapsed high-grade glioma after surgery and external beam radiation therapy and treated with re-operation and GliaSite brachytherapy. Between 2006 and 2008, 15 patients with recurrent high-grade glioma underwent re-operation and GliaSite brachytherapy. Ten patients were males and 5 females. Median age was 40 years (range, 20-71). Karnofsky performance status was ≥70. All patients but one received GliaSite irradiation of the surgical cavity wall at the dose of 4500 cGy at a depth of 1 cm. No severe acute side effects were observed during GliaSite brachytherapy. Pathologically documented, symptomatic late radiation necrosis was observed in 3 patients (20%); 2 subsequently died of further complications. Two patients were alive at a median follow-up 13 months (range, 1-30). Median overall survival after GliaSite brachytherapy was 13 months. Patients with recurrent high-grade glioma can be treated with additional surgery and GliaSite brachytherapy, delivering 4500 cGy at 1 cm depth without significant acute side effects but with a significant rate (20%) of late radiation necrosis, resulting in 13% of treatment-related deaths. Compared with the literature, survival results in our study appear to be satisfactory, but they may be related to patient selection criteria. Re-intervention followed by GliaSite brachytherapy should not be offered as a standard treatment for recurrent high-grade glioma, because of the high rate of late complications, treatment-related deaths, and high treatment costs.

Hypofractionated Stereotactic Radiotherapy as a Salvage Therapy for Recurrent High-Grade Gliomas: Single-Center Experience.

Background and Purpose:The aim of this study was to investigate the survival outcomes and safety of hypofractioned stereotactic radiotherapy as a salvage treatment for recurrent high-grade glioma.Patients and Methods:Between March 2012 and March 2017, 32 consecutive patients (12 women, 20 men) treated in a single center were retrospectively included in this study. Grade III gliomas were diagnosed in 14 patients and grade IV in 18 patients. Thirty-four lesions were treated with hypofractionated stereotactic radiotherapy on a linear accelerator. Hypofractionated stereotactic radiotherapy delivered a median dose of 30 Gy (27-30) in 6 fractions (3-6) of 5 Gy (5-9). The treatment plans were normalized to 100% at the isocenter and prescribed to the 80% isodose line. Clinical outcomes and prognostic factors were analyzed.Results:Median follow-up was 20.9 months. Median overall survival following hypofractionated stereotactic radiotherapy was 15.6 months (median overall survival for patients with glioblastoma and grade III glioma was 8.2 and 19.5 months, respectively; P = .0496) and progression-free survival was 3.7 months (median progression-free survival for patients with glioblastoma and grade III glioma was 3.6 and 4.5 months, respectively; P = .2424). In multivariate analysis, tumor grade III (P = .0027), an Eastern Cooperative Oncology Group status <2 at the time of reirradiation (P = .0023), and a mean dose >35 Gy (P = .0055) significantly improved overall survival. A maximum reirradiation dose above 38 Gy (P = .0179) was significantly associated with longer progression-free survival.Conclusion:Hypofractionated stereotactic radiotherapy is well tolerated and offers an effective salvage option for the treatment of recurrent high-grade gliomas with encouraging overall survival. Our results suggest that the dose distribution had an impact on survival.

127P - Apatinib combined with irinotecan in treatment of recurrent high-grade gliomas

127P - Apatinib combined with irinotecan in treatment of recurrent high-grade gliomas

Stereotactic Laser Interstitial Thermal Therapy for Recurrent High-Grade Gliomas.

The value of maximal safe cytoreductive surgery in recurrent high-grade gliomas (HGGs) is gaining wider acceptance. However, patients may harbor recurrent tumors that may be difficult to access with open surgery. Laser interstitial thermal therapy (LITT) is emerging as a technique for treating a variety of brain pathologies, including primary and metastatic tumors, radiation necrosis, and epilepsy. To review the role of LITT in the treatment of recurrent HGGs, for which current treatments have limited efficacy, and to discuss the possible role of LITT in the disruption of the blood-brain barrier to increase delivery of chemotherapy locoregionally. A MEDLINE search was performed to identify 17 articles potentially appropriate for review. Of these 17, 6 reported currently commercially available systems and as well as magnetic resonance thermometry to monitor the ablation and, thus, were thought to be most appropriate for this review. These studies were then reviewed for complications associated with LITT. Ablation volume, tumor coverage, and treatment times were also reviewed. Sixty-four lesions in 63 patients with recurrent HGGs were treated with LITT. Frontal (n = 34), temporal (n = 14), and parietal (n = 16) were the most common locations. Permanent neurological deficits were seen in 7 patients (12%), vascular injuries occurred in 2 patients (3%), and wound infection was observed in 1 patient (2%). Ablation coverage of the lesions ranged from 78% to 100%. Although experience using LITT for recurrent HGGs is growing, current evidence is insufficient to offer a recommendation about its role in the treatment paradigm for recurrent HGGs. BBB, blood-brain barrierFDA, US Food and Drug AdministrationGBM, glioblastoma multiformeHGG, high-grade gliomaLITT, laser interstitial thermal therapy.

GEINOFOTE: efficacy and safety of fotemustine in patients with high-grade recurrent gliomas and poor performance status.

The treatment of recurrent high-grade gliomas (HGG) is controversial. There are different therapeutic schedules but without a clear orientation about which of them should be used in each clinical situation. In addition, when patients suffer a second recurrence or they have poor performance status, they are excluded from clinical trials, although second recurrences and poor performance status are indeed more and more real and common situations in the clinical setting. In this study, we assessed the efficacy and safety of fotemustine (FTM) in HGG [fundamentally, glioblastomas (GB)], independent of time of recurrence or performance status. Retrospective study in HGG patients treated with FTM in second or further line according to standard, the Addeo or any other scheme, starting treatment prior to 30 November 2012. Included patients reflect the regular situation in which the drug is used in terms of comorbidities and analytic situation (hematologic, renal and hepatic functions). Response assessment was performed by MRI and according to the clinical protocols of each center (every 8-12weeks). Clinical situation and supportive care drugs were evaluated in each medical consultation. Clinical end-points analyzed, among others, were: PFS-6, PFS, OS, response rates, toxicity, quality of life and neurocognitive impact. In terms of activity, an overall response rate of 8% was observed: partial response 6% (7 patients) and complete response 2% (2 patients). The median time to achieve the greater response with FTM was 73days (4-841days). Patients treated according to the Addeo schedule had a shorter time to greater response in comparison with other schedules (85.9 vs 114days), although without statistical significance. There were no significant differences in progression-free survival (PFS) when comparing different FTM schedules or using FTM in first or second recurrence. Median PFS: 3months. PFS-6: 30.3%. Overall survival (OS): although without significant differences, a tendency to better survival when using the Addeo schedule versus other schedules was observed (at 6months, 44.6 vs 34.5%; at 12months, 25 vs 23.6%; at 18months, 11.5 vs 7.9%), as well as if earlier use (second vs third line) concerning OS-12 (33.7 vs 18.2%). Median OS: 5.2months. Grades 3-4 toxicity was 28% (31 patients), being neutropenia (4%) and thrombocytopenia (17%) the most frequent adverse reactions. From quality of life and neuro-cognitive function perspectives, 11 patients (10%) and 16 (14%) improved the Karnofsky Index and neurological impairment, respectively, after FTM treatment. This study has shown that FTM is safe and has a comparable activity with other available therapeutic options of use in the treatment of recurrent HGG.

RTRB-04STEREOTACTIC RADIOSURGERY FOR RECURRENT HIGH-GRADE GLIOMAS: PATIENT SELECTION AND THE ROLE OF BEVACIZUMAB

RTRB-04. STEREOTACTIC RADIOSURGERY FOR RECURRENT HIGH-GRADE GLIOMAS: PATIENT SELECTION AND THE ROLE

The efficacy and safety of various dose-dense regimens of temozolomide for recurrent high-grade glioma: a systematic review with meta-analysis

The goal of this meta-analysis was to identify the temozolomide (TMZ) regimen with optimal efficacy and tolerance for treatment of recurrent high-grade glioma (HGG). The PubMed and EMBASE databases were searched from the earliest records to February 2015, which identified 33 studies with 1760 participants that met the inclusion criteria. The standard schedule and three most common dose-dense regimens of TMZ therapy for recurrent HGG were included in this meta-analysis. The schedule of 7 days on/7 days off for the treatment of grade IV gliomas was significantly superior to the standard regimen with respect to progression-free survival at 6 months (34.8 %; 95 % confidence interval (CI) 27.0-43.4 %) and 12 months (15.5 %; 95 % CI 10.7-21.8 %). For grade III gliomas, this regimen conveyed a significantly greater overall survival (OS) rate at 12 months (79.0 %; 95 % CI 56.2-91.7 %), as compared to the standard schedule. Also, the 21 days on/7 days off regimen had significantly longer OS rates at 6 months (73.6 %; 95 % CI 63.4-81.8 %) and 12 months (40.6 %; 95 % CI 32.6-48.6 %) than the standard regimen for grade IV gliomas. In addition, the standard schedule showed a significantly higher clinical benefit rate than the 7 days on/7 days off and 21 days on/7 days off regimens. However, the grade 3-4 toxicity rate of lymphopenia of the standard schedule was 76.5 % (95 % CI 45.5-92.7 %), which was the highest among the four regimens. Recurrent HGG patients receiving personalized treatment should be closely followed up, especially those with concurrent hematological diseases.

Abstract 5310: Prognostic and predictive biomarkers of clinical response to Bevacizumab in recurrent WHO grade 3 malignant glioma patients

Abstract Background: Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor A (VEGF-A), has proven activity in treatment of recurrent high-grade glioma. High response rates have been demonstrated, but particularly in WHO grade 3 malignant gliomas, efforts to identify predictors of clinical response have been limited. Predictive biomarkers and prognostic models are required in order to individualize treatment for this patient population. The primary end-point of this study was identification of prognostic and potentially predictive clinical and paraclinical factors of response. The secondary end-point was to identify prognostic factors associated with progression-free survival (PFS) and overall survival (OS). Materials and methods: A total of 64 recurrent grade 3 glioma patients treated with bevacizumab and irinotecan were retrospectively evaluated. Eligible patients from our center had a WHO performance status of 0-2 and were administered bevacizumab and irinotecan between December 2005 and November 2014 according to a previously published clinical protocol. The possibly relevant prognostic baseline factors screened for included: Age, gender, WHO grade 3 diagnosis, tumor size and location, multifocal disease, extent of resection, number of prior chemotherapy regiments, response to prior chemotherapy, first-line treatment, number of previous recurrences, neurological deficit, corticosteroid use, performance status, necrosis, vascular proliferation, neutrophil-to-lymphocyte ratio, and expression of p53, EGFR, Mib-1, MGMT, IDH-1 and ATRX. Candidate factors were subjected to univariate analysis and factors with P-values below 0.10 were considered for multivariate analysis. Prognostic models were generated by logistic regression and Cox regression, modeling response and survival end-points. P-values below 0.05 were considered statistically significant. Results will be presented. Citation Format: Anders Toft, Thomas Urup, Kirsten Grunnet, Ib J. Christensen, Signe R. Michaelsen, Helle Broholm, Vibeke A. Larsen, Michael Kosteljanetz, Ulrik Lassen, Hans S. Poulsen. Prognostic and predictive biomarkers of clinical response to Bevacizumab in recurrent WHO grade 3 malignant glioma patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5310. doi:10.1158/1538-7445.AM2015-5310

431P - Bevacizumab and Fotemustine for Recurrent High Grade Gliomas

ABSTRACT Aim: Primary tumours of the central nervous system account for approximately 3% of all cancers. High-grade gliomas (HGG) account for 70% of all gliomas and include anaplastic astrocytomas, anaplastic oligoastrocytomas and anaplastic oligodendrogliomas (WHO grade III), as well as glioblastomas (WHO grade IV). Median survival is 12-18 months for WHO grade IV and 2 to 5 years for WHO grade III. At recurrence there is no accepted standard of care. Recent phase II trials have demonstrated activity of nitrosoureas such as fotemustine (FTM) in recurrent HGG. Bevacizumab, a monoclonal antibody that binds to vascular endothelial growth factor, is the first antiangiogenic agent with documented activity in HGG. Methods: We have investigated the role of the combination of FTM and bevacizumab in glioblastoma (GBM) and WHO grade III gliomas (non-GBM) at first recurrence after prior therapy. From January 2011 to January 2014, data of 30 patients were collected. From recurrence, we estimated 6-month progression-free survival (PFS-6), overall survival (OS) and toxicities therapies-related. The treatment consisted of an induction phase with FTM at 75 mg/m2 intravenously on day 1, 8 and 15 and bevacizumab at 10 mg/kg intravenously on day 1 and 15, followed after an interval of 4-5 weeks by a maintenance phase with bevacizumab at 10 mg/kg every 2 weeks and FTM at 75 mg/m2 every 3 weeks until tumour progression or unacceptable toxicity. Patients who required progressive FTM dose reductions received bevacizumab alone. Results: The median time from original diagnosis to recurrence was 13 months for GBM and 35 months for non-GBM gliomas. All patients completed the induction phase and a median of 11 maintenance cycles were administered for GBM and 13 cycles for non-GBM patients. PFS-6 rate was 45% for GBM and 67% for non-GBM; median OS was 14 months for GBM and 21 months for non-GBM patients. Most patients experienced grade 1 toxicities (hypertension, fatigue, proteinuria); grade 2 toxicities were predominantly hematologic (thrombocitopenia). Conclusions: In our study the combination of FTM and bevacizumab was well tolerated and PFS-6 and OS confirmed published literature. Further studies are needed to demonstrate the benefit of this combination in the treatment of recurrent HGG. Disclosure: All authors have declared no conflicts of interest.

Impact of health-related quality of life and fatigue on survival of recurrent high-grade glioma patients.

Quality of life (QoL) impairment and fatigue are frequently experienced during treatment for recurrent high-grade glioma (HGG). Fatigue and QoL impairments can be due to primary neurological dysfunction, cytotoxic treatments, mood disturbances, and supportive medications. We now seek to understand how QoL and fatigue impacts survival in recurrent HGG. Using a prospective observational design, 237 patients with recurrent HGG and KPS ≥70 completed a self-administered questionnaire that evaluated QoL and fatigue. QoL was assessed with Functional Assessment of Cancer Therapy-General (FACT-G) and FACT-Brain (FACT-Br) scales while fatigue was assessed using Functional Assessment of Chronic Illness Therapy (FACIT-F) scale. Cox proportional hazard models were utilized to evaluate the association between QoL and fatigue and survival. Seventy-three (31%) subjects had recurrent WHO grade III gliomas and 164 (69%) had recurrent WHO grade IV gliomas. Median follow-up analysis was 27.60months. In univariate Cox analyses, the FACT-Br specific subscale (HR 0.88; CI 95%, 0.77-1; p=0.048) and FACIT-F (HR 0.82; CI 95%, 0.68-0.99; p=0.045) were both significant predictors of survival. Fatigue added prognostic information beyond that provided by KPS, age, sex, tumor grade, and number of prior progressions (HR 0.80; CI 95%, 0.68-0.9; p=0.031). A greater degree of fatigue was associated with poorer survival in recurrent HGG patients. In multivariable analyses, FACT-G and FACT-Br are not independent predictors of prognosis. Fatigue is a strong independent predictor of survival that provides incremental prognostic value to the traditional markers of prognosis in recurrent HGG. Pharmacological or non-pharmacological strategies to treat fatigue warrant investigation.

Reoperation for recurrent high-grade glioma: a current perspective of the literature.

Optimal treatment for recurrent high-grade glioma continues to evolve. Currently, however, there is no consensus in the literature on the role of reoperation in the management of these patients. In this analysis, we reviewed the literature to examine the role of reoperation in patients with World Health Organization grade III or IV recurrent gliomas, focusing on how reoperation affects outcome, perioperative complications, and quality of life. An extensive literature review was performed through the use of the PubMed and Ovid Medline databases for January 1980 through August 2013. A total 31 studies were included in the final analysis. Of the 31 studies with significant data from single or multiple institutions, 29 demonstrated a survival benefit or improved functional status after reoperation for recurrent high-grade glioma. Indications for reoperation included new focal neurological deficits, tumor mass effect, signs of elevated intracranial pressure, headaches, increased seizure frequency, and radiographic evidence of tumor progression. Age was not a contraindication to reoperation. Time interval of at least 6 months between operations and favorable performance status (Karnofsky Performance Status score ≥70) were important predictors of benefit from reoperation. Extent of resection at reoperation improved survival, even in patients with subtotal resection at initial operation. Careful patient selection such as avoiding those individuals with poor performance status and bevacizumab within 4 weeks of surgery is important. Although limited to retrospective analysis and patient selection bias, mounting evidence suggests a survival benefit in patients receiving a reoperation at the time of high-grade glioma recurrence.

Progress of temozolomide in the treatment of recurrent high-grade gliomas

High-grade gliomas are central nervous system malignancies which are difficult to treat. Surgery, temozolomide combined with radiotherapy postoperatively and adjuvant chemotherapy with temozolomide have been established as the standard treatment options for high-grade gliomas. Nevertheless, the prognosis of patients with high-grade gliomas remains poor. At present, there is no standard therapy for recurrent or relapsed high-grade gliomas. Temozolomide is still an effective drug for the treatment of recurrent high-grade gliomas. According to the characteristics of patients, there have been many kinds of temozolomide administration and other treatments in combination. Individual therapy were paid more attention, so that the patients with high-grade gliomas recurrence could get greater survival benefit. This paper aims to introduce the progress of temozolomide in the treatment of recurrent high-grade gliomas in recent years. doi：10.3969/j.issn.1672-6731.2013.12.012

Recurrent high-grade glioma treated with bevacizumab: prognostic value of MGMT methylation, EGFR status and pretreatment MRI in determining response and survival

Although bevacizumab represented an important advance in treatment of recurrent high-grade gliomas (HGG), responses occur in fewer than half of patients. There are no validated biomarkers for anti-angiogenic therapy that are available for routine clinical use. We assessed the prognostic values of imaging and molecular markers in this patient population. MRI scans from 191 patients with recurrent HGG obtained prior to initiating bevacizumab were reviewed for areas of enhancement, necrosis, T2/FLAIR abnormality, and ADC values. Serial MRI scans following the initiation of bevacizumab were evaluated for response and progression. Non-radiographic markers including EGFR and MGMT status were also assessed with respect to response and patient survival. 65 of 191 patients (34 %) showed complete or partial response at the time of their best response MRI and demonstrated longer progression free survival (PFS) and overall survival (OS) compared to the group without response (PFS: 6.9 vs 3.5 months, OS: 10.9 vs 6.1 months). Minimum ADC values within enhancing and non-enhancing regions were lower in responders compared to those of non-responders (1,099 vs 984 × 10(-6) mm(2)/s, p = 0.006). Smaller enhancing area was associated with longer OS (HR = 1.99, p = 0.017). The ratio of T2/FLAIR to enhancing area was prognostic of OS for only the Grade III HGG subgroup (HR = 0.14, p = 0.004). Area of enhancing tumor at baseline can stratify survival in patients with recurrent HGG treated with bevacizumab. The extent of edema relative to enhancing area may have a prognostic role specific to Grade III HGG.