Temozolomide Era Research Articles

Repeat resection for recurrent glioblastoma in the temozolomide era: a real-world multi-centre study

Introduction In contrast to standard-of-care treatment of newly diagnosed glioblastoma, there is limited consensus on therapy upon disease progression. The role of resection for recurrent glioblastoma remains unclear. This study aimed to identify factors for overall survival (OS) and post-progression survival (PPS) as well as to validate an existing prediction model. Methods This was a multi-centre retrospective study that reviewed consecutive adult patients from 2006 to 2019 that received a repeat resection for recurrent glioblastoma. The primary endpoint was PPS defined as from the date of second surgery until death. Results 1032 glioblastoma patients were identified and 190 (18%) underwent resection for recurrence. Patients that had second surgery were more likely to be younger (<70 years) (adjusted OR: 0.3; 95% CI: 0.1–0.6), to have non-eloquent region tumours (aOR: 1.7; 95% CI: 1.1–2.6) and received temozolomide chemoradiotherapy (aOR: 0.2; 95% CI: 0.1–0.4). Resection for recurrent tumour was an independent predictor for OS (aOR: 1.5; 95% CI: 1.3–1.7) (mOS: 16.9 months versus 9.8 months). For patients that previously received temozolomide chemoradiotherapy and subsequent repeat resection (137, 13%), the median PPS was 9.0 months (IQR: 5.0–17.5). Independent PPS predictors for this group were a recurrent tumour volume of >50cc (aOR: 0.6; 95% CI: 0.4–0.9), local recurrence (aOR: 1.7; 95% CI: 1.1–3.3) and 5-ALA fluorescence-guided resection during second surgery (aOR: 1.7; 95% CI: 1.1–2.8). A National Institutes of Health Recurrent Glioblastoma Multiforme Scale score of 0 conferred an mPPS of 10.0 months, a score of 1–2, 9.0 months and a score of 3, 4.0 months (log-rank test, p-value < 0.05). Conclusion Surgery for recurrent glioblastoma can be beneficial in selected patients and carries an acceptable morbidity rate. The pattern of recurrence influenced PPS and the NIH Recurrent GBM Scale was a reliable prognostication tool.

Patterns of care and survival of Chinese glioblastoma patients in the temozolomide era: a Hong Kong population-level analysis over a 14-year period.

The aim of this study is to address the paucity of epidemiological data regarding the characteristics, treatment patterns and survival outcomes of Chinese glioblastoma patients. This was a population-level study of Hong Kong adult (>18 years) Chinese patients with newly diagnosed histologically confirmed glioblastoma between 2006 and 2019. The age standardized incidence rate (ASIR), patient-, tumor- treatment-related characteristics, overall survival (OS) as well as its predictors were determined. One thousand and ten patients with a median follow-up of 10.0 months were reviewed. The ASIR of glioblastoma was 1.0 per 100 000 population with no significant change during the study period. The mean age was 57 + 14 years. The median OS was 10.6 months (IQR: 5.2-18.4). Independent predictors for survival were: Karnofsky performance score >80 (adjusted OR: 0.8; 95% CI: 0.6-0.9), IDH-1 mutant (aOR: 0.7; 95% CI: 0.5-0.9) or MGMT methylated (aOR: 0.7; 95% CI: 0.5-0.8) glioblastomas, gross total resection (aOR: 0.8; 95% CI: 0.5-0.8) and temozolomide chemoradiotherapy (aOR 0.4; 95% CI: 0.3-0.6). Despite the significant increased administration of temozolomide chemoradiotherapy from 39% (127/326) of patients in 2006-2010 to 63% (227/356) in 2015-2019 (P-value < .001), median OS did not improve (2006-2010: 10.3 months vs 2015-2019: 11.8 months) (OR: 1.1; 95% CI: 0.9-1.3). The incidence of glioblastoma in the Chinese general population is low. We charted the development of neuro-oncological care of glioblastoma patients in Hong Kong during the temozolomide era. Although there was an increased adoption of temozolomide chemoradiotherapy, a corresponding improvement in survival was not observed.

Therapeutic management of gliosarcoma in the stupp protocol and temozolomide era

Background: The clinical management of primary gliosarcoma grade IV with curative intent is not entirely defined and the available data are limited, so the therapeutic management may be a challenge The application of the Stupp protocol may be the only effective treatment option. Case report: We report the case of a 57-year-old woman with a gliosarcoma of the left frontal lobe treated in a curative intent. She underwent craniotomy, followed by adjuvant radioterapy and 6 cycles of temozolomide, according to the Stupp protocol, resulting in complete response after 3.5 years from diagnosis. Conclusions: Gliosarcoma and glioblastoma are different histopathological entities and the use of the Stupp protocol, specifically studied for glioblastoma, is an off label application of the treatment protocol. Efforts should be focused in order to assess the efficacy of this treatment modality and then on the prognosis carried by gliosarcoma tumor type.

BIOM-30. BLOOD COUNTS THROUGH TREATMENT COURSE IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS RECEIVING CHEMORADIATION

Abstract BACKGROUND Glioblastoma (GBM) patients are treated with radiation therapy (RT), temozolomide, and corticosteroids which can affect hematologic and immunologic parameters. We examined lymphocytes, neutrophil-to-lymphocyte ratio and platelet measurements and their association with progression-free survival (PFS) overall survival (OS). METHODS We identified 759 newly diagnosed adult GBM patients treated at our institution in the temozolomide (TMZ) era with blood counts that could be automatically extracted from the electronic medical record during chemoradiation (CRT, defined as within 42 days of RT) and at first recurrence. Linear regression and Cox modeling were used to evaluate outcomes. RESULTS Median age was 60.3 years; 87% had KPS ≥ 70, 37.5% had gross total resection, and 90% received TMZ. Prior to RT, 56.4% (375/665) patients had a lymphocyte measurement &amp;lt; 1.0 × 1000 cells [K]/μL. Within 42 days of CRT, 81.7% (536/656) had a lymphocyte measurement &amp;lt; 1.0 K/μL, 37.8% (248/656) &amp;lt; 0.5 K/μL. 10.7% (58/544) patients developed grade 2 or higher neutropenia, 9.1% (50/547) patients developed grade 2 or higher thrombocytopenia. On multivariable analysis (MVA), older age (AHR1.03, p&amp;lt; 0.001), unmethylated MGMT status (AHR2.56,p&amp;lt; 0.001), lower RT dose (&amp;lt;54Gy, AHR 3.45, p&amp;lt; 0.001), male sex (AHR1.45, p=0.02), non-gross total resection (AHR1.63, p&amp;lt; 0.001), lymphopenia during CRT (AHR0.63, p=0.008) and higher NLR during CRT (AHR1.02, p=0.001) were significantly associated with worse OS. Older age (AHR1.01, p=0.02), unmethylated MGMT status (AHR2.44, p&amp;lt; 0.001), lower RT dose (AHR1.82, p=0.02), higher NLR during CRT (AHR1.03, p &amp;lt; 0.001) were significantly associated with worse PFS on MVA. At first recurrence, median lymphocyte count was 0.7 K/μL with 74% (348/468) patients &amp;lt; 1.0 K/μL and 27% &amp;lt; 0.5 K/μL. CONCLUSION Lymphopenia and higher neutrophil-to-lymphocyte ratio are associated with inferior outcomes. Persistent lymphopenia at time of first recurrence may have implications for clinical trial eligibility and immunotherapy approaches in recurrent GBM.

Radiotherapy intensification for glioblastoma: enhancing the backbone of treatment

Given the impact of radiotherapy on survival outcomes for patients with glioblastoma (GBM), intensification of radiotherapy through dose-escalation and/or dose-per-fraction escalation has been an important area of ongoing investigation. Prior to the introduction of temozolomide, radiotherapy intensification beyond 60-Gy conventionally fractionated radiotherapy did not yield a survival benefit. With the emergence of temozolomide and its radio-sensitizing properties, as well as greater understanding of the patterns of first progression after 60-Gy radiotherapy, hypotheses regarding the impact of radiotherapy intensification have arisen. This article will discuss ongoing and future investigations of radiotherapy intensification in the modern temozolomide era of GBM management. These efforts have focused on better radiotherapy delivery techniques and/or improved tumor imaging to identify high-risk regions of progression.

Do elderly patients (≥ 75years old) with glioblastoma benefit from more radical surgeries in the era of temozolomide?

This study assesses the effect of extent of resection (EOR) on the longer-term survival and early mortality of elderly patients (≥ 75years old) with glioblastoma. We used the Surveillance, Epidemiology, and End Results (SEER) database and data from our center to evaluate the effect of EOR on the long-term survival and early mortality of patients with glioblastoma. We included 50 elderly patients (≥ 75years old) with glioblastoma visiting our hospital. The median overall survival of the patients who underwent a gross total resection, a subtotal resection, and a partial resection were 278, 200, and 83days, respectively. The multivariate analysis showed that gross total resection (HR: 0.100; 95% CI: 0.015-0.671, p < 0.001) and subtotal reresection (HR: 0.134, 95% CI: 0.022-0.831, p < 0.001) were independent predictors of favorable prognosis when compared with partial resection. The data extracted from the SEER database also indicated that EOR was an independent predictor of OS, CCS, and early mortality. The stratification analysis revealed that gross total resection was the best protective factor of OS, early mortality, and CCS. Radical resection may improve the OS and CCS of glioblastoma patients aged ≥ 75years and decrease early mortality.

RADT-25. EVALUATING LYMPHOCYTE COUNTS IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS RECEIVING CHEMORADIATION

Abstract BACKGROUND Glioblastoma (GBM) patients are treated with chemotherapy, radiation therapy (RT) and often corticosteroids, which can all contribute to lymphopenia. We examined lymphopenia with respect to incidence, predictors, and association with progression-free survival (PFS) and overall survival (OS). METHODS We reviewed 349 newly diagnosed adult GBM patients treated at our institution in the temozolomide (TMZ) era with available lymphocyte and RT records. Data was reviewed from diagnosis through the chemoradiation (CRT) phase, defined as the period upto 6 weeks after RT. Linear regression and Cox proportional hazards modeling were used to evaluate outcomes. RESULTS Median age was 60 years (range, 19-90); 86% had KPS ≥ 70, 30% had gross total resection (GTR), and 91% received TMZ. Prior to RT, 60% (205/341) patients had a lymphocyte measurement &amp;lt; 1.0 x 1000 cells [K]/μL and 15% (50/341) had &amp;lt; 0.5 K/μL. During the CRT phase of therapy, 83% (270/324) had at least one lymphocyte measurement &amp;lt; 1.0 K/μL, 42% (135/324) &amp;lt; 0.5 K/μL, and 5% (16/324) &amp;lt; 0.2 K/μL. Older age was associated with lower lymphocytes pre-RT, while subtotal resection, TMZ use, and RT dose was associated with lower lymphocyte counts during CRT (p&amp;lt; 0.05). On multivariable analysis (MVA), age (AHR 1.03, p&amp;lt; 0.01), KPS &amp;gt; 70 (AHR 0.35, p&amp;lt; 0.01), MGMT status (AHR 0.47, p&amp;lt; 0.01), GTR (AHR 0.67, p=0.03), TMZ (AHR 0.27, p&amp;lt; 0.01) and lymphopenia during CRT (AHR 1.80, p&amp;lt; 0.01) were significantly associated with OS. Pre-RT lymphocyte level was associated with PFS on UVA (HR 0.81, p=0.03) but not on MVA (p=0.27). Lymphocyte count during CRT was not associated with PFS (p=0.24). CONCLUSION Lymphopenia is common in GBM, and chemoradiation-related lymphopenia was associated with inferior OS relative to patients without lymphopenia. Further characterization of the mechanism and optimal treatment of patients with lymphopenia are warranted to improve outcomes.

Immunohistochemistry for O6-methylguanin-DNA methyltransferase in glioblastomas defined by WHO2016: Correlation with promoter methylation status and patients’ progression-free survival with the cut-off value determined by ROC analysis

Although promoter methylation status is known to correlate with response to alkylating agents, immunohistochemistry (IHC) is the only available method for MGMT status in many institutions. However, the clinical utility of MGMT IHC is controversial. A hundred and twenty four cases of primary glioblastoma diagnosed by morphology-based criteria over 2 decades were re-appraised based on WHO 2016 classification. Tumor MGMT status was evaluated by IHC and methylation-specific PCR (MSP) to see if any correlation between the results of the 2 methods. The association with patients’ prognoses was also investigated. Among 124 cases, 116 were confirmed to be glioblastoma by definition of WHO2016, and median overall survival (OS) of glioblastoma, IDH-wildtype and epithelioid glioblastoma were 18 and 27 months, respectively. MGMT promoter methylation status significantly correlated with progression-free survival (PFS) (p = 0.014) but not with OS (p = 0.364) in patients with glioblastoma by the integrated diagnosis. With the cut-off value of 24.5% of positive cell ratio as determined by receiver operating characteristic (ROC) analysis, there was a good correlation between the results of IHC and MSP (p = 0.08 × 10−24). Accordingly, there was a marginal association between the results of IHC and patients’ PFS (p = 0.063), but not OS (p = 0.563). When the patients were divided into pre and post temozolomide era, the association of MGMT promoter methylation status with PFS was only noted in the patients of temozolomide era (pre, p = 0.432; post, p = 0.015).

Accelerated hyperfractionated radiochemotherapy with temozolomide is equivalent to normofractionated radiochemotherapy in a retrospective analysis of patients with glioblastoma

BackgroundCurrent standard of treatment for newly diagnosed patients with glioblastoma (GBM) is surgical resection with adjuvant normofractionated radiotherapy (NFRT) combined with temozolomide (TMZ) chemotherapy. Hyperfractionated accelerated radiotherapy (HFRT) which was known as an option from randomized controlled trials before the temozolomide era has not been compared to the standard therapy in a randomized setting combined with TMZ.MethodsData of 152 patients with newly diagnosed GBM treated from 10/2004 until 7/2018 at a single tertiary care institution were extracted from a clinical database and retrospectively analyzed. Thirty-eight patients treated with NFRT of 60 Gy in 30 fractions (34 with simultaneous and 2 with sequential TMZ) were compared to 114 patients treated with HFRT of 54.0 Gy in 30 fraction of 1.8 Gy twice daily (109 with simultaneous and 3 with sequential TMZ). The association between treatment protocol and other variables with overall survival (OS) was assessed using univariable and multivariable Cox regression analysis; the latter was performed using variables selected by the LASSO method.ResultsMedian overall survival (OS) was 20.3 month for the entire cohort. For patients treated with NFRT median OS was 24.4 months compared to 18.5 months in patients treated with HFRT (p = 0.131). In univariable regression analysis the use of dexamethasone during radiotherapy had a significant negative impact on OS in both patient groups, HR 2.21 (95% CI 1.47–3.31, p = 0.0001). In multivariable analysis adjusted for O6-methylguanine-DNA methyl-transferase (MGMT) promotor methylation status, salvage treatment and secondary GBM, the use of dexamethasone was still a negative prognostic factor, HR 1.95 (95% CI 1.21–3.13, p = 0.006). Positive MGMT-methylation status and salvage treatment were highly significant positive prognostic factors. There was no strong association between treatment protocol and OS (p = 0.504).ConclusionsOur retrospective analysis supports the hypothesis of equivalence between HFRT and the standard protocol of treatment for GBM. For those patients who are willing to obtain the benefit of shortening the course of radiochemotherapy, HFRT may be an alternative with comparable efficacy although it was not yet tested in a large prospective randomized study against the current standard. The positive influence of salvage therapy and negative impact of concomitant use of corticosteroids should be addressed in future prospective trials. To confirm our results, we plan to perform a pooled analysis with other tertiary clinics in order to achieve better statistical reliability.

Radiosensitizers in the temozolomide era for newly diagnosed glioblastoma.

Glioblastoma (GBM) is a challenging diagnosis with almost universally poor prognosis. Though the survival advantage of postoperative radiation (RT) is well established, around 90% of patients will fail in the RT field. The high likelihood of local failure suggests the efficacy of RT needs to be improved to improve clinical outcomes. Radiosensitizers are an established method of enhancing RT cell killing through the addition of a pharmaceutical agent. Though the majority of trials using radiosensitizers have historically been unsuccessful, there continues to be interest with a variety of approaches having been employed. Epidermal growth factor receptor inhibitors, histone deacetylase inhibitors, antiangiogenic agents, and a number of other molecularly targeted agents have all been investigated as potential methods of radiosensitization in the temozolomide era. Outcomes have varied both in terms of toxicity and survival, but some agents such as valproic acid and bortezomib have demonstrated promising results. However, reporting of results in phase 2 trials in newly diagnosed GBM have been inconsistent, with no standard in reporting progression-free survival and toxicity. There is a pressing need for investigation of new agents; however, nearly all phase 3 trials of GBM patients of the past 25 years have demonstrated no improvement in outcomes. One proposed explanation for this is the selection of agents lacking sufficient preclinical data and/or based on poorly designed phase 2 trials. Radiosensitization may represent a viable strategy for improving GBM outcomes in newly diagnosed patients, and further investigation using agents with promising phase 2 data is warranted.

Low Levels of Quantified MGMT Methylation Status Impart Positive Impact on Survival

MGMT methylation status is a significant prognostic factor for glioblastoma (GBM), particularly in the era of temozolomide (TMZ). However, there is no standardization of MGMT methylation methodology or optimal cutoff criteria. We developed and implemented a quantitative assay for MGMT methylation (mMGMT) and investigated association with clinical outcomes. We retrospectively reviewed GBM patients at our institution treated with standard chemoradiation, from 2008 to 2018. DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue. A real-time PCR assay was performed to amplify a 62 base-pair region of MGMT including the first 12 CpG islands after ATG initiation codon for both methylated and unmethylated alleles. PCR products underwent high-resolution melt (HRM) analysis and the fraction of methylated DNA was determined by comparison with a standard curve generated from specimens with known percentages of methylation. Patient demographics, treatment records, and clinical outcomes were collected. Kaplan-Meier and log-rank tests were performed to compare survival. Cox proportional hazard model was used for predicting prognostic factors. Optimal cutoff point was evaluated with maximally selected log-rank statistics. Statistical analysis was conducted on R (v3.5). A total of 108 patients (68 men, 40 women) with newly diagnosed GBM were included in the study. Median age was 61 years old (31-85), and KPS was 80 (50-100). A total of 32 pts (29.6%) had gross total resection (GTR), 61 pts (56.4%) had subtotal resection, and 15 pts (13.9%) had biopsy only. With a median follow-up of 9 months (1-73 months), the median PFS and OS were 6 months and 14.4 months, respectively. At 1 and 2 years, PFS was 25.2% and 17.8% while OS was 58.1% and 23.8%, respectively. A total of 44 patients (40.7%) had detectable MGMT methylation, with median methylation level of 23.36% (range 0.2%-78.2%; IQR 4.77-31.88%). On both univariate and multivariate analysis, detectable MGMT methylation (HR 0.06, 95% CI [0.008-0.4223]; p=0.004) and GTR (HR 0.18, 95% CI [0.07-0.43]; p>0.001) were associated with improved OS, while GTR alone improved PFS (HR 0.38, 95% CI [0.16-0.89]; p=0.028). Patients with any detectable mMGMT had improved OS (19.3 vs 11.1 months; p=0.003). Optimal cutoff point for quantifying MGMT methylation for maximum survival difference was estimated as ∼ 1.9% (p=0.007). MGMT methylation at even low levels may have a positive impact on survival for GBM patients. Further refinement of a cutoff point for our MGMT assay with a validation set is warranted.

Ongoing improvements in postoperative survival of glioblastoma in the temozolomide era: a population-based data linkage study.

Translating outcomes achieved by clinical trials into routine care is crucial to improving outcomes of glioblastoma (GBM). This study examines the extent to which an advance in treatment for GBM has translated into meaningful, population-level survival benefits in New South Wales (NSW), Australia. This retrospective cohort study used linked population-based cancer registry, admitted patient, and mortality datasets. The cohort (n = 2604) included NSW residents aged ≥18 years with a histologically confirmed GBM and a surgical resection between July 2001 and December 2012. The study outcome was all-cause survival, examined using multivariable proportional hazard models. The main study factor was period of surgery, categorized into 4 periods corresponding to different eras in temozolomide (TMZ) use. Survival was examined over time by age (≤70 and >70 years) and for a subcohort selected to approximate the seminal European Organisation for Research and Treatment of Cancer (Stupp) protocol trial cohort. TMZ use was estimated using aggregate prescription claims data. Median survival in 2001-2003, 2004-2006, 2007-2009, and 2010-2012 was 7.4, 9.0, 9.8, and 10.6 months, and risk-adjusted 2-year survival was 8.2%, 13.8%, 15.5%, and 18.3%, respectively. Survival improved for those aged ≤70 years and those aged >70 years. In the proxy trial subcohort, median and 2-year survival were 14.3 months and 27.3%, respectively. The volume of TMZ prescribed annually increased rapidly from 2005. Introduction of TMZ into standard care in 2005 coincided with improvements in survival and a rapid increase in TMZ prescribing. Optimization of care has continued to improve survival of people with GBM in subsequent years.

Dose-intensified chemoradiation is associated with altered patterns of failure and favorable survival in patients with newly diagnosed glioblastoma.

We evaluated whether dose-intensified chemoradiation alters patterns of failure and is associated with favorable survival in the temozolomide era. Between 2003 and 2015, 82 patients with newly diagnosed glioblastoma were treated with 66-81Gy in 30 fractions using conventional magnetic resonance imaging. Progression-free (PFS) and overall survival (OS) were calculated using Kaplan-Meier methods. Factors associated with improved PFS, OS, and time to progression were assessed using multivariate Cox model and linear regression. Median follow-up was 23months (95% CI 4-124months). Sixty-one percent of patients underwent subtotal resection or biopsy, and 38% (10/26) of patients with available data had MGMT promoter methylation. Median PFS was 8.4months (95% CI 7.3-11.0) and OS was 18.7months (95% CI 13.1-25.3). Only 30 patients (44%) experienced central recurrence, 6 (9%) in-field, 16 (23.5%) marginal and 16 (23.5%) distant. On multivariate analysis, younger age (HR 0.95, 95% CI 0.93-0.97, p = 0.0001), higher performance status (HR 0.39, 95% CI 0.16-0.95, p = 0.04), gross total resection (GTR) versus biopsy (HR 0.37, 95% CI 0.16-0.85, p = 0.02) and MGMT methylation (HR 0.25, 95% CI 0.09-0.71, p = 0.009) were associated with improved OS. Only distant versus central recurrence (p = 0.03) and GTR (p = 0.02) were associated with longer time to progression. Late grade 3 neurologic toxicity was rare (6%) in patients experiencing long-term survival. Dose-escalated chemoRT resulted in lower rates of central recurrence and prolonged time to progression compared to historical controls, although a significant number of central recurrences were still observed. Advanced imaging and correlative molecular studies may enable targeted treatment advances that reduce rates of in- and out-of-field progression.

Optimal extent of resection for glioblastoma according to site, extension, and size: a population-based study in the temozolomide era.

The effect of the extent of resection (EOR) on prognosis in glioblastoma may differ depending on various conditions. We evaluated the prognostic impact of the EOR for glioblastoma according to the tumor site, extension, and size. Data from glioblastoma patients who underwent gross total resection (GTR), subtotal resection (STR), or open biopsy between 2005 and 2014 were retrieved from the Surveillance, Epidemiology, and End Results database. Univariate and multivariate analyses for overall survival (OS) were performed. Between 2005-2009 and 2010-2014, the proportion of GTR and STR performed increased from 41.4 to 42.3% and 33.0 to 37.1%, respectively. EOR only affected OS in the 3years after diagnosis. Median survival in the GTR (n = 4155), STR (n = 3498), and open biopsy (n = 2258) groups was 17, 13, and 13months, respectively (p < .001). STR showed no significant difference in OS from open biopsy (p = .33). GTR increased OS for midline-crossing tumors. Although STR was more frequently performed than GTR for tumors ≥ 6cm in size, GTR significantly increased the OS rate relative to STR for tumors 6-8cm in size (p=.001). For tumors ≥ 8cm, STR was comparable to GTR (p = .61) and superior to open biopsy (p = .05). GTR needs to be performed more frequently for glioblastoma measuring ≥ 6cm or that have crossed the midline to increase OS. STR was marginally superior to open biopsy when the tumor was ≥ 8cm.

P.049 Repeat surgery in recurrent glioblastoma: a systematic review and meta-analysis

Background: Recurrent glioblastoma portends a poor prognosis and the role of repeat surgery in improving survival remains uncertain. Our systematic review and meta-analysis aims to address whether re-resection provides a meaningful survival benefit and to what degree. Methods: Articles were collected from Pubmed, -CINAHL, EMBASE, Medline and Cochrane from January 1990 to 2018. Studies in the temozolomide era with both single surgery and re-resection cohorts were included. Primary outcomes were odds ratio for survival at 6, 12, and 24 months following re-resection and initial surgery. Results: Fourteen articles were included for analysis (3048 patients). Meta-analysis showed improved overall survival following re-resection at 6- (OR 1.73, 95% CI 1.23-2.45, p&lt;0.05), 12- (OR 1.71, 95% CI 1.20-2.45, p&lt;0.05), and 24-months (OR 2.24, 95% CI 1.01-4.95, p&lt;0.05). Overall survival from diagnosis or first surgery was also improved in patients who underwent re-resection at -recurrence, similarly at 6- (OR 8.22, 95% CI 5.23-12.93, p&lt;0.01), 12- (OR 4.16, 95% CI 3.25-5.36, p&lt;0.01), and 24- (2.35, 95% CI 1.77-3.11, p&lt;0.05) months. Subgroup analyses were done for patients stratified by age, performance status, and number of re-resections. Conclusions: Repeat surgery for recurrent glioblastoma is associated with a significant survival advantage independent of other salvage therapies that include chemotherapy, radiation, and other antineoplastic regimens.

37 The impact of repeated surgery on survival for patients with recurrent glioblastoma

Background: Recurrent glioblastoma portends a poor prognosis and the role of repeat surgery in improving survival remains uncertain. Therefore, we undertook a systematic review and meta-analysis in order to determine if repeat surgical resection provides a meaningful survival benefit for patients with recurrent glioblastoma. Methods: Two independent reviewers searched for articles that reported on overall-survival of patients with recurrent glioblastoma using MEDLINE, Embase, Google Scholar, and Cochrane from January 2000 to 2018. Studies that compared overall survival of patients treated with single surgery compared to repeat surgery in the temozolomide era were included for analysis.Primary outcomes were odds ratio for survival at 6, 12, and 24 months from date of initial diagnosis. Secondary outcomes were ratio odds ratio for survival at 6, 12, and 24 months from date of repeat surgery. The proportions of patients who had the outcomes of interest were pooled using random-effects model. Quality assessment was performed using the Newcastle Ottawa Scale. Heterogeneity across trials was quantified by the I2 statistic. Publication bias was evaluated visually using funnel plots and quantified by the Egger regression. Results: Fourteen articles reporting on 3048 patients were included for analysis. The majority of articles were deemed to be of high quality with Newcastle Ottawa scale greater than 7 points. Pooled analysis showed improved overall survival following repeat surgery at 6- (OR 1.73, 95% CI 1.23-2.45, p&lt;0.05), 12- (OR 1.71, 95% CI 1.20-2.45, p&lt;0.05), and 24-months (OR 2.24,95% CI 1.01-4.95, p&lt;0.05) and from date of initial diagnosis at 6- (OR 8.22, 95% CI 5.23-12.93, p&lt;0.01), 12- (OR 4.16, 95% CI 3.25-5.36, p&lt;0.01), and 24- (2.35, 95% CI 1.77-3.11, p&lt;0.05) months. Conclusions: Repeat surgery for recurrent glioblastoma is associated with a significant survival advantage independent of other salvage therapies that include chemotherapy, radiation, and other antineoplastic regimens.

A Comparative Analysis of the Usefulness of Survival Prediction Models for Patients with Glioblastoma in the Temozolomide Era: The Importance of Methylguanine Methyltransferase Promoter Methylation, Extent of Resection, and Subventricular Zone Location

Several survival prediction models for patients with glioblastoma have been proposed, but none is widely used. This study aims to identify the predictors of overall survival (OS) and to conduct an independent comparative analysis of 5 prediction models. Multi-institutional data from 159 patients with newly diagnosed glioblastoma who received adjuvant temozolomide concomitant chemoradiotherapy (CCRT) were collected. OS was assessed by Cox proportional hazards regression and adjusted for known prognostic factors. An independent CCRT patient cohort was used to externally validate the 1) RTOG (Radiation Therapy Oncology Group) recursive partitioning analysis (RPA) model, 2) Yang RPA model, and 3) Wee RPA model, Chaichana model, and the RTOG nomogram model. The predictive accuracy for each model at 12-month survival was determined by concordance indices. Calibration plots were performed to ascertain model prediction precision. The median OS for patients who received CCRT was 19.0 months compared with 12.7 months for those who did not (P < 0.001). Independent predictors were:1)subventricular zone II tumors (hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.0-2.5); 2) methylguanine methyltransferase promoter methylation (HR, 0.36; 95% CI, 0.2-0.6); and 3) extent of resection of >85% (HR, 0.59; 95% CI, 0.4-0.9). For 12-month OS prediction, the RTOG nomogram model was superior to the RPA models with a c-index of 0.70. Calibration plots for 12-month survival showed that none of the models was precise, but the RTOG nomogram performed relatively better. The RTOG nomogram best predicted 12-month OS. Methylguanine methyltransferase promoter methylation status, subventricular zone tumor location, and volumetric extent of resection should be considered when constructing prediction models.

Evaluation of high-grade astrocytoma recurrence patterns after radiotherapy in the era of temozolomide: A single institution experience.

Evaluating the recurrence patterns of high-grade astrocytomas in patients who were treated with radiotherapy (RT) plus temozolomide (TMZ). The current literature suggests that reducing the margins added to the CTV does not significantly change the risk of recurrence and overall survival; thus, we decided to analyze our data and to examine the possibility of changing the adopted margins. From February 2008 till September 2013, 55 patients were treated for high-grade astrocytomas, 20 patients who had been confirmed to have recurrence were selected for the present study. Post-operative MRI was superimposed on the planning CT images in order to correlate the anatomical structures with the treatment targets. Recurrences were defined according to the Response Assessment Criteria for Glioblastoma. The mean margins of the PTVinitial and PTVboost were 1.2cm and 1.4cm, respectively. The analysis of the percentage of the recurrence volume (Volrec) within the 100% isodose surface was based on the following criteria: (I) Central: >95% of the Volrec; (II) In-field: 81-95% of the Volrec; (III) Marginal: 20-80% of the Volrec; and (IV) Outside: <20% of the Volrec. Of the 20 patients, 13 presented with central recurrences, 3 with in-field recurrences, 2 with marginal recurrences and 2 with outside recurrences. Therefore, the lower Volrec within 100% of the prescribed dose was considered in the classification. Of the selected patients, 80% had ≥81-95% of the Volrec within 100% of the prescribed dose and predominantly had central or in-field recurrences. These results are comparable with those from the literature.

Short delay in initiation of radiotherapy for patients with glioblastoma-effect of concurrent chemotherapy: a secondary analysis from the NRG Oncology/Radiation Therapy Oncology Group database

We previously reported the unexpected finding of significantly improved survival for newly diagnosed glioblastoma in patients when radiation therapy (RT) was initiated later (>4 wk post-op) compared with earlier (≤2 wk post-op). In that analysis, data were analyzed from 2855 patients from 16 NRG Oncology/Radiotherapy Oncology Group (RTOG) trials conducted prior to the era of concurrent temozolomide (TMZ) with RT. We now report on 1395 newly diagnosed glioblastomas from 2 studies, treated with RT and concurrent TMZ followed by adjuvant TMZ. Our hypothesis was that concurrent TMZ has a synergistic/radiosensitizing mechanism, making RT timing less significant. Data from patients treated with TMZ-based chemoradiation from NRG Oncology/RTOG 0525 and 0825 were analyzed. An analysis comparable to our prior study was performed to determine whether there was still an impact on survival by delaying RT. Overall survival (OS) was investigated using the Kaplan-Meier method and Cox proportional hazards model. Early progression (during time of diagnosis to 30 days after RT completion) was analyzed using the chi-square test. Given the small number of patients who started RT early following surgery, comparisons were made between >4 and ≤4 weeks delay of radiation from time of operation. There was no statistically significant difference in OS (hazard ratio = 0.93; P = 0.29; 95% CI: 0.80-1.07) after adjusting for known prognostic factors (recursive partitioning analysis and O6-methylguanine-DNA methyltransferase methylation status). Similarly, the rate of early progression did not differ significantly (P = 0.63). We did not observe a significant prognostic influence of delaying radiation when given concurrently with TMZ for newly diagnosed glioblastoma. The effects of early (1-3 wk post-op) or late (>5 wk) initiation of radiation tested in our prior study could not be replicated.

Risk Factors for Malignant Transformation of Low-Grade Glioma

The incidence, risk factors, and outcomes of low-grade glioma patients who undergo malignant transformation (MT) in the era of temozolomide are not well known. This study evaluates these factors in a large group of World Health Organization grade 2 glioma patients treated at a tertiary-care institution. Patient, tumor, and treatment factors were analyzed using an institutional review board-approved low-grade glioma database. Characteristics were compared using χ2 and Wilcoxon signed rank tests. Time to event was summarized using proportional hazards models. Univariate and multivariate survival analyses were performed. Of a total of 599 patients, 124 underwent MT; 76 (61.3%) had biopsy-proven MT. The MT incidence was 21%, and the median time to MT was 56.4months. The 5-and 10-year progression-free survival rates were 30.6%±4.2% and 4.8%±1.9%, respectively, for MT patients and 60%±2.4% and 38%±2.7%, respectively, for non-MT patients. The 5- and 10-year overall survival rates were 75%±4.0% and 46%±5.0%, respectively, for MT patients and 87%±1.7% and 78%±2.3%, respectively, for non-MT patients. On multivariate analysis, older age (P = .001), male sex (P = .004), multiple tumor locations (P = .004), chemotherapy alone (P = .012), and extent of resection (P = .045) remained significant predictors of MT. MT affects survival. Risk factors include older age, male sex, multiple tumor locations, use of chemotherapy alone, and presence of residual disease. Our finding that initial interventions could affect the rate of MT is provocative, but these data should be validated using data from prospective trials. In addition to improving survival, future therapeutic efforts should focus on preventing MT.