Concurrent treatment with temozolomide and radiotherapy followed by maintenance temozolomide is the standard of care for patients with newly diagnosed glioblastoma. Bevacizumab, a humanized ...monoclonal antibody against vascular endothelial growth factor A, is currently approved for recurrent glioblastoma. Whether the addition of bevacizumab would improve survival among patients with newly diagnosed glioblastoma is not known.
In this randomized, double-blind, placebo-controlled trial, we treated adults who had centrally confirmed glioblastoma with radiotherapy (60 Gy) and daily temozolomide. Treatment with bevacizumab or placebo began during week 4 of radiotherapy and was continued for up to 12 cycles of maintenance chemotherapy. At disease progression, the assigned treatment was revealed, and bevacizumab therapy could be initiated or continued. The trial was designed to detect a 25% reduction in the risk of death and a 30% reduction in the risk of progression or death, the two coprimary end points, with the addition of bevacizumab.
A total of 978 patients were registered, and 637 underwent randomization. There was no significant difference in the duration of overall survival between the bevacizumab group and the placebo group (median, 15.7 and 16.1 months, respectively; hazard ratio for death in the bevacizumab group, 1.13). Progression-free survival was longer in the bevacizumab group (10.7 months vs. 7.3 months; hazard ratio for progression or death, 0.79). There were modest increases in rates of hypertension, thromboembolic events, intestinal perforation, and neutropenia in the bevacizumab group. Over time, an increased symptom burden, a worse quality of life, and a decline in neurocognitive function were more frequent in the bevacizumab group.
First-line use of bevacizumab did not improve overall survival in patients with newly diagnosed glioblastoma. Progression-free survival was prolonged but did not reach the prespecified improvement target. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00884741.).
Radiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM). O(6)-methylguanine-DNA methyltransferase (MGMT) methylation status may be an ...important determinant of treatment response. Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM.
This phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of ≥ 60 with adequate tissue. Stratification included clinical factors and tumor MGMT methylation status. Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles. The primary end point was OS. Secondary analyses evaluated the impact of MGMT status.
A total of 833 patients were randomly assigned to either arm 1 or arm 2 (1,173 registered). No statistically significant difference was observed between arms for median OS (16.6 v 14.9 months, respectively; hazard ratio HR, 1.03; P = .63) or median PFS (5.5 v 6.7 months; HR, 0.87; P = .06). Efficacy did not differ by methylation status. MGMT methylation was associated with improved OS (21.2 v 14 months; HR, 1.74; P < .001), PFS (8.7 v 5.7 months; HR, 1.63; P < .001), and response (P = .012). There was increased grade ≥ 3 toxicity in arm 2 (34% v 53%; P < .001), mostly lymphopenia and fatigue.
This study did not demonstrate improved efficacy for DD temozolomide for newly diagnosed GBM, regardless of methylation status. However, it did confirm the prognostic significance of MGMT methylation. Feasibility of large-scale accrual, prospective tumor collection, and molecular stratification was demonstrated.
Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment for cancer. These agents, transforming the field of oncology, are not devoid of toxicity and cause immune-related side ...effects which can involve any organ including the nervous system. In this study, we present 9 patients (7 men and 2 women) with neurologic complications secondary to ICPI treatment. These included meningoencephalitis, limbic encephalitis, polyradiculitis, cranial polyneuropathy, myasthenic syndrome and myositis. Four patients received dual ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte associated protein-4 blocking antibodies. Median time to onset of neurologic adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5 days–19 weeks). In all patients ICPIs were stopped and corticosteroids were initiated, resulting in a marked improvement in seven out of nine patients. Two patients, one with myositis and one with myasthenic syndrome, died. In two patients ICPI therapy was resumed after resolution of the neurological adverse event with no additional neurologic complications. This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.
Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma Mellinghoff, Ingo K; van den Bent, Martin J; Blumenthal, Deborah T ...
The New England journal of medicine,
08/2023, Letnik:
389, Številka:
7
Journal Article
Recenzirano
Isocitrate dehydrogenase (IDH)-mutant grade 2 gliomas are malignant brain tumors that cause considerable disability and premature death. Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 ...and IDH2 enzymes, showed preliminary activity in IDH-mutant gliomas.
In a double-blind, phase 3 trial, we randomly assigned patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery to receive either oral vorasidenib (40 mg once daily) or matched placebo in 28-day cycles. The primary end point was imaging-based progression-free survival according to blinded assessment by an independent review committee. The key secondary end point was the time to the next anticancer intervention. Crossover to vorasidenib from placebo was permitted on confirmation of imaging-based disease progression. Safety was also assessed.
A total of 331 patients were assigned to receive vorasidenib (168 patients) or placebo (163 patients). At a median follow-up of 14.2 months, 226 patients (68.3%) were continuing to receive vorasidenib or placebo. Progression-free survival was significantly improved in the vorasidenib group as compared with the placebo group (median progression-free survival, 27.7 months vs. 11.1 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval CI, 0.27 to 0.56; P<0.001). The time to the next intervention was significantly improved in the vorasidenib group as compared with the placebo group (hazard ratio, 0.26; 95% CI, 0.15 to 0.43; P<0.001). Adverse events of grade 3 or higher occurred in 22.8% of the patients who received vorasidenib and in 13.5% of those who received placebo. An increased alanine aminotransferase level of grade 3 or higher occurred in 9.6% of the patients who received vorasidenib and in no patients who received placebo.
In patients with grade 2 IDH-mutant glioma, vorasidenib significantly improved progression-free survival and delayed the time to the next intervention. (Funded by Servier; INDIGO ClinicalTrials.gov number, NCT04164901.).
Patients with progressive primary brain tumors (PBT) are attracted to promising new treatments, even prior to convincing data. Anti-PD1 immunotherapies have been in the spotlight since publication of ...groundbreaking results for metastatic melanoma with pembrolizumab (PBL). Our objective was to report on the response and toxicity of PBL in patients with advanced PBT. We retrospectively reviewed the charts of 22 patients (17 adults and 5 children) with recurrent central nervous system tumors treated with PBL. We analyzed prior antineoplastic therapies, steroid usage, and outcomes. Patients received a median of two neoplastic therapies prior to PBL, and a median of three infusions of PBL in adults and four in children. Twelve patients (9 adults and 3 children) started PBL on steroids (median dose in adults 4 mg; range 2–8, and in children 1.5 mg, range 0.5–4) and five patients received steroids later during PBL treatment. Twelve patients (10 adults and 2 children) received concomitant bevacizumab with PBL. Side effects were minimal. All patients showed progressive tumor growth during therapy. Median OS from the start of PBL was 2.6 months in adults and 3.2 months in children. Two GB patients underwent tumor resection following treatment with PBL. Tumor-lymphocytic response in these cases was unremarkable, and PD-L1 immuno-staining was negative. In this series of 22 patients with recurrent primary brain tumors, PBL showed no clinical or histologic efficacy. We do not recommend further use of PBL for recurrent PBT unless convincing prospective clinical trial data are published.
Radiation with concurrent and adjuvant (6 cycles) temozolomide (TMZ) is the established standard of postsurgical care for newly diagnosed glioblastoma (GBM). This regimen has been adopted with ...variations, including extending TMZ beyond 6 cycles. The optimal duration of maintenance therapy remains controversial.
We performed pooled analysis of individual patient data from 4 randomized trials for newly diagnosed GBM. All patients who were progression free 28 days after cycle 6 were included. The decision to continue TMZ was per local practice and standards, and at the discretion of the treating physician. Patients were grouped into those treated with 6 cycles and those who continued beyond 6 cycles. Progression-free and overall survival were compared, adjusted by age, performance status, resection extent, and MGMT methylation.
A total of 2214 GBM patients were included in the 4 trials. Of these, 624 qualified for analysis 291 continued maintenance TMZ until progression or up to 12 cycles, while 333 discontinued TMZ after 6 cycles. Adjusted for prognostic factors, treatment with more than 6 cycles of TMZ was associated with a somewhat improved progression-free survival (hazard ratio HR 0.80 0.65-0.98, P = .03), in particular for patients with methylated MGMT (n = 342, HR 0.65 0.50-0.85, P < .01). However, overall survival was not affected by the number of TMZ cycles (HR = 0.92 0.71-1.19, P = .52), including the MGMT methylated subgroup (HR = 0.89 0.63-1.26, P = .51).
Continuing TMZ beyond 6 cycles was not shown to increase overall survival for newly diagnosed GBM.
Purpose
Low-grade gliomas (LGG) are classified into three distinct groups based on their IDH1 mutation and 1p/19q codeletion status, each of which is associated with a different clinical expression. ...The genomic sub-classification of LGG requires tumor sampling via neurosurgical procedures. The aim of this study was to evaluate the radiomics approach for noninvasive classification of patients with LGG and IDH mutation, based on their 1p/19q codeletion status, by testing different classifiers and assessing the contribution of the different MR contrasts.
Methods
Preoperative MRI scans of 47 patients diagnosed with LGG with IDH1-mutated tumors and a genetic analysis for 1p/19q deletion status were included in this study. A total of 152 features, including size, location and texture, were extracted from fluid-attenuated inversion recovery images,
T
2
-weighted images (WI) and post-contrast
T
1
WI
. Classification was performed using 17 machine learning classifiers. Results were evaluated by a fivefold cross-validation analysis.
Results
Radiomic analysis differentiated tumors with 1p/19q intact (
n
=
21
; astrocytomas) from those with 1p/19q codeleted (
n
=
26
; oligodendrogliomas). Best classification was obtained using the Ensemble Bagged Trees classifier, with sensitivity
=
92%, specificity
=
83% and accuracy
=
87%, and with area under the curve
=
0.87. Tumors with 1p/19q intact were larger than those with 1p/19q codeleted (
46.2
±
30.0
vs.
30.8
±
16.8
cc, respectively;
p
=
0.03
) and predominantly located to the left insula (
p
=
0.04
).
Conclusion
The proposed method yielded good discrimination between LGG with and without 1p/19q codeletion. Results from this study demonstrate the great potential of this method to aid decision-making in the clinical management of patients with LGG.
Background
High‐grade gliomas (HGGs) induce both vasogenic edema and extensive infiltration of tumor cells, both of which present with similar appearance on conventional MRI. Using current ...radiological criteria, differentiation between these tumoral and nontumoral areas within the nonenhancing lesion area remains challenging.
Purpose
To use radiomics patch‐based analysis, based on conventional MRI, for the classification of the nonenhancing lesion area in patients with HGG into tumoral and nontumoral components.
Study Type
Prospective.
Subjects
In all, 179 MRI scans were obtained from 102 patients: 67 patients with HGG and 35 patients with brain metastases. A subgroup of 15 patients with HGG were scanned before and following administration of bevacizumab.
Field Strength/Sequence
Pre and postcontrast agent T1‐weighted‐imaging (WI), T2WI, FLAIR, diffusion‐tensor‐imaging (DTI), and dynamic‐contrast‐enhanced (DCE)‐MRI at 3T.
Assessment
A total of 225 histograms and gray‐level‐co‐occurrence matrix‐based features were extracted from the nonenhancing lesion area. Tumoral volumes of interest (VOIs) were defined at the peritumoral area in patients with HGG; nontumoral VOIs were defined in patients with brain metastasis. Twenty machine‐learning algorithms including support‐vector‐machine (SVM), k‐nearest neighbor, decision‐trees, and ensemble classifiers were tested. The best classifier was trained on the entire labeled data, and was used to classify the entire data.
Statistical Tests
Dimensional reduction was performed on the 225 features using principal component analysis. Classification results were evaluated based on the sensitivity, specificity, and accuracy of each of the 20 classifiers, first based on a training and testing dataset (80% of the labeled data) in a 5‐fold manner, and next by applying the best classifier to the validation data (the remaining 20% of the labeled data). Results were additionally evaluated by assessing differences in dynamic‐contrast‐enhanced plasma‐volume (vp) and volume‐transfer‐constant (ktrans) values between the two components using Mann–Whitney U‐test/t‐test.
Results
The best classification into tumoral and nontumoral lesion components was obtained using a linear SVM classifier, with average accuracy of 87%, sensitivity 86%, and specificity of 89% (for the training and testing data). Significantly higher vp and ktrans values (P < 0.0001) were detected in the tumoral compared to the nontumoral component. Preliminary classification results in a subgroup of patients treated with bevacizumab demonstrated a reduction mainly in the nontumoral component following administration of bevacizumab, enabling early assessment of disease progression in some patients.
Data Conclusion
A radiomics patch‐based analysis enables classification of the nonenhancing lesion area in patients with HGG. Preliminary results were promising and the proposed method has the potential to assist in clinical decision‐making and to improve therapy response assessment in patients with HGG.
Level of Evidence: 1
Technical Efficacy Stage 4
J. Magn. Reson. Imaging 2018;48:729–736.
Glioblastoma (GBM) is the most common primary malignant brain tumor. Nomograms are often used for individualized estimation of prognosis. This study aimed to build and independently validate a ...nomogram to estimate individualized survival probabilities for patients with newly diagnosed GBM, using data from 2 independent NRG Oncology Radiation Therapy Oncology Group (RTOG) clinical trials.
This analysis included information on 799 (RTOG 0525) and 555 (RTOG 0825) eligible and randomized patients with newly diagnosed GBM and contained the following variables: age at diagnosis, race, gender, Karnofsky performance status (KPS), extent of resection, O6-methylguanine-DNA methyltransferase (MGMT) methylation status, and survival (in months). Survival was assessed using Cox proportional hazards regression, random survival forests, and recursive partitioning analysis, with adjustment for known prognostic factors. The models were developed using the 0525 data and were independently validated using the 0825 data. Models were internally validated using 10-fold cross-validation, and individually predicted 6-, 12-, and 24-month survival probabilities were generated to measure the predictive accuracy and calibration against the actual survival status.
A final nomogram was built using the Cox proportional hazards model. Factors that increased the probability of shorter survival included greater age at diagnosis, male gender, lower KPS, not having total resection, and unmethylated MGMT status.
A nomogram that assesses individualized survival probabilities (6-, 12-, and 24-mo) for patients with newly diagnosed GBM could be useful to health care providers for counseling patients regarding treatment decisions and optimizing therapeutic approaches. Free software for implementing this nomogram is provided: http://cancer4.case.edu/rCalculator/rCalculator.html.