In patients with glioblastoma, the addition of bevacizumab to radiotherapy and temozolomide induction therapy and the use of bevacizumab maintenance therapy did not influence overall survival. ...Freedom from progression was slightly increased but at the cost of increased toxic effects.
Tumor progression in glioblastoma, the most common primary brain cancer,
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is associated with deterioration in neurocognitive function,
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decreased functional independence,
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and a progressive decrease in health-related quality of life.
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After surgical resection, the standard of care for patients with newly diagnosed glioblastoma and a good Karnofsky performance score (≥70, on a scale of 0 to 100, with higher numbers indicating better functioning) is concurrent radiotherapy and temozolomide, followed by adjuvant temozolomide.
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The prognosis remains poor; no further improvements in outcomes have been documented since the introduction of radiotherapy–temozolomide therapy in 2005.
Glioblastomas are characterized by overexpression . . .
Older patients with glioblastoma appear to benefit more from treatment combining a shorter course (3 weeks rather than 6 weeks) of radiotherapy together with temozolomide than from radiotherapy ...alone.
Glioblastoma is a fatal illness that is associated with a median survival of less than 2 years. Population studies of glioblastoma have shown that survival declines with increasing age,
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and the incidence of glioblastoma is increasing, especially among the elderly.
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Older patients have been underrepresented in most randomized trials, in which the average age of participants is approximately 55 years, as compared with the population-based median for patients with glioblastoma of 65 years of age.
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In 2005, a phase 3 trial of radiotherapy alone (60 Gy over a period of 6 weeks) versus radiotherapy plus temozolomide showed longer survival . . .
The addition of bevacizumab to lomustine in patients with recurrent glioblastoma failed to increase overall survival but was associated with a small increase in progression-free survival.
Clinical outcomes for glioblastoma remain poor. Treatment with immune checkpoint blockade has shown benefits in many cancer types. To our knowledge, data from a randomized phase 3 clinical trial ...evaluating a programmed death-1 (PD-1) inhibitor therapy for glioblastoma have not been reported.
To determine whether single-agent PD-1 blockade with nivolumab improves survival in patients with recurrent glioblastoma compared with bevacizumab.
In this open-label, randomized, phase 3 clinical trial, 439 patients with glioblastoma at first recurrence following standard radiation and temozolomide therapy were enrolled, and 369 were randomized. Patients were enrolled between September 2014 and May 2015. The median follow-up was 9.5 months at data cutoff of January 20, 2017. The study included 57 multicenter, multinational clinical sites.
Patients were randomized 1:1 to nivolumab 3 mg/kg or bevacizumab 10 mg/kg every 2 weeks until confirmed disease progression, unacceptable toxic effects, or death.
The primary end point was overall survival (OS).
A total of 369 patients were randomized to nivolumab (n = 184) or bevacizumab (n = 185). The MGMT promoter was methylated in 23.4% (43/184; nivolumab) and 22.7% (42/185; bevacizumab), unmethylated in 32.1% (59/184; nivolumab) and 36.2% (67/185; bevacizumab), and not reported in remaining patients. At median follow-up of 9.5 months, median OS (mOS) was comparable between groups: nivolumab, 9.8 months (95% CI, 8.2-11.8); bevacizumab, 10.0 months (95% CI, 9.0-11.8); HR, 1.04 (95% CI, 0.83-1.30); P = .76. The 12-month OS was 42% in both groups. The objective response rate was higher with bevacizumab (23.1%; 95% CI, 16.7%-30.5%) vs nivolumab (7.8%; 95% CI, 4.1%-13.3%). Grade 3/4 treatment-related adverse events (TRAEs) were similar between groups (nivolumab, 33/182 18.1%; bevacizumab, 25/165 15.2%), with no unexpected neurological TRAEs or deaths due to TRAEs.
Although the primary end point was not met in this randomized clinical trial, mOS was comparable between nivolumab and bevacizumab in the overall patient population with recurrent glioblastoma. The safety profile of nivolumab in patients with glioblastoma was consistent with that in other tumor types.
ClinicalTrials.gov Identifier: NCT02017717.
Anaplastic oligodendroglioma are chemotherapy-sensitive tumors. We now present the long-term follow-up findings of a randomized phase III study on the addition of six cycles of procarbazine, ...lomustine, and vincristine (PCV) chemotherapy to radiotherapy (RT).
Adult patients with newly diagnosed anaplastic oligodendroglial tumors were randomly assigned to either 59.4 Gy of RT or the same RT followed by six cycles of adjuvant PCV. An exploratory analysis of the correlation between 1p/19q status and survival was part of the study. Retrospectively, the methylation status of the methyl-guanine methyl transferase gene promoter and the mutational status of the isocitrate dehydrogenase (IDH) gene were determined. The primary end points were overall survival (OS) and progression-free survival based on intent-to-treat analysis.
A total of 368 patients were enrolled. With a median follow-up of 140 months, OS in the RT/PCV arm was significantly longer (42.3 v 30.6 months in the RT arm, hazard ratio HR, 0.75; 95% CI, 0.60 to 0.95). In the 80 patients with a 1p/19q codeletion, OS was increased, with a trend toward more benefit from adjuvant PCV (OS not reached in the RT/PCV group v 112 months in the RT group; HR, 0.56; 95% CI, 0.31 to 1.03). IDH mutational status was also of prognostic significance.
The addition of six cycles of PCV after 59.4 Gy of RT increases both OS and PFS in anaplastic oligodendroglial tumors. 1p/19q-codeleted tumors derive more benefit from adjuvant PCV compared with non-1p/19q-deleted tumors.
The DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) antagonizes the genotoxic effects of alkylating agents. MGMT promoter methylation is the key mechanism of MGMT gene silencing and ...predicts a favorable outcome in patients with glioblastoma who are exposed to alkylating agent chemotherapy. This biomarker is on the verge of entering clinical decision-making and is currently used to stratify or even select glioblastoma patients for clinical trials. In other subtypes of glioma, such as anaplastic gliomas, the relevance of MGMT promoter methylation might extend beyond the prediction of chemosensitivity, and could reflect a distinct molecular profile. Here, we review the most commonly used assays for evaluation of MGMT status, outline the prerequisites for standardized tests, and evaluate reasons for difficulties in reproducibility. We critically discuss the prognostic and predictive value of MGMT silencing, reviewing trials in which patients with different types of glioma were treated with various chemotherapy schedules, either up-front or at recurrence. Standardization of MGMT testing requires comparison of different technologies across laboratories and prospectively validated cut-off values for prognostic or predictive effects. Moreover, future clinical trials will need to determine, for each subtype of glioma, the degree to which MGMT promoter methylation is predictive or prognostic, and whether testing should become routine clinical practice.
Standard therapy for glioblastoma (GBM) is temozolomide (TMZ) administration, initially concurrent with radiotherapy (RT), and subsequently as maintenance therapy. The radiologic images obtained in ...this setting can be difficult to interpret since they may show radiation-induced pseudoprogression (psPD) rather than disease progression.
Patients with histologically confirmed GBM underwent radiotherapy plus continuous daily temozolomide (75 mg/m(2)/d), followed by 12 maintenance temozolomide cycles (150 to 200 mg/m(2) for 5 days every 28 days) if magnetic resonance imaging (MRI) showed no enhancement suggesting a tumor; otherwise, chemotherapy was delivered until complete response or unequivocal progression. The first MRI scan was performed 1 month after completing combined chemoradiotherapy.
In 103 patients (mean age, 52 years range 20 to 73 years), total resection, subtotal resection, and biopsy were obtained in 51, 51, and 1 cases, respectively. MGMT promoter was methylated in 36 patients (35%) and unmethylated in 67 patients (65%). Lesion enlargement, evidenced at the first MRI scan in 50 of 103 patients, was subsequently classified as psPD in 32 patients and early disease progression in 18 patients. PsPD was recorded in 21 (91%) of 23 methylated MGMT promoter and 11 (41%) of 27 unmethylated MGMT promoter (P = .0002) patients. MGMT status (P = .001) and psPD detection (P = .045) significantly influenced survival.
PsPD has a clinical impact on chemotherapy-treated GBM, as it may express the glioma killing effects of treatment and is significantly correlated with MGMT status. Improvement in the early recognition of psPD patterns and knowledge of mechanisms underlying this phenomenon are crucial to eliminating biases in evaluating the results of clinical trials and guaranteeing effective treatment.
Addition of temozolomide (TMZ) to radiotherapy (RT) improves overall survival (OS) in patients with glioblastoma (GBM), but previous studies suggest that patients with tumors harboring an ...unmethylated MGMT promoter derive minimal benefit. The aim of this open-label, phase III CheckMate 498 study was to evaluate the efficacy of nivolumab (NIVO) + RT compared with TMZ + RT in newly diagnosed GBM with unmethylated MGMT promoter.
Patients were randomized 1:1 to standard RT (60 Gy) + NIVO (240 mg every 2 weeks for eight cycles, then 480 mg every 4 weeks) or RT + TMZ (75 mg/m2 daily during RT and 150-200 mg/m2/day 5/28 days during maintenance). The primary endpoint was OS.
A total of 560 patients were randomized, 280 to each arm. Median OS (mOS) was 13.4 months (95% CI, 12.6 to 14.3) with NIVO + RT and 14.9 months (95% CI, 13.3 to 16.1) with TMZ + RT (hazard ratio HR, 1.31; 95% CI, 1.09 to 1.58; P = .0037). Median progression-free survival was 6.0 months (95% CI, 5.7 to 6.2) with NIVO + RT and 6.2 months (95% CI, 5.9 to 6.7) with TMZ + RT (HR, 1.38; 95% CI, 1.15 to 1.65). Response rates were 7.8% (9/116) with NIVO + RT and 7.2% (8/111) with TMZ + RT; grade 3/4 treatment-related adverse event (TRAE) rates were 21.9% and 25.1%, and any-grade serious TRAE rates were 17.3% and 7.6%, respectively.
The study did not meet the primary endpoint of improved OS; TMZ + RT demonstrated a longer mOS than NIVO + RT. No new safety signals were detected with NIVO in this study. The difference between the study treatment arms is consistent with the use of TMZ + RT as the standard of care for GBM.ClinicalTrials.gov NCT02617589.
Summary Background In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) ...reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years. Methods Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT , was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with Clinicaltrials.gov , number NCT00006353. Findings Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27·2% (95% CI 22·2–32·5) at 2 years, 16·0% (12·0–20·6) at 3 years, 12·1% (8·5–16·4) at 4 years, and 9·8% (6·4–14·0) at 5 years with temozolomide, versus 10·9% (7·6–14·8), 4·4% (2·4–7·2), 3·0% (1·4–5·7), and 1·9% (0·6–4·4) with radiotherapy alone (hazard ratio 0·6, 95% CI 0·5–0·7; p<0·0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60–70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy. Interpretation Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide. Funding EORTC, NCIC, Nélia and Amadeo Barletta Foundation, Schering-Plough.
Glioblastoma is the most frequent malignant brain tumor and is characterized by poor prognosis, increased invasiveness, and high recurrence rates. Standard treatment for glioblastoma includes maximal ...safe surgical resection, radiation, and chemotherapy with temozolomide. Despite treatment advances, only 15-20% of glioblastoma patients survive to 5 years, and no therapies have demonstrated a durable survival benefit in recurrent disease. In the last 10 years, significant advances in knowledge of the biology and molecular pathology of the malignancy have opened the way to new treatment options. Clinical management of patients (pseudo-progressions, side effects of therapies, best supportive care, centralization in expertise care centers) has improved. In brain tumors, such as in other solid tumors, we have entered an era of immune-oncology. Immunotherapy seems to have an acceptable safety and tolerability profile in the recurrent setting and is under investigation in clinical trials in newly diagnosed glioblastoma patients. This review focuses on novel targeted therapies recently developed for the management of newly diagnosed and recurrent glioblastomas.
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