181 research outputs found
Biomarker and Histopathology Evaluation of Patients with Recurrent Glioblastoma Treated with Galunisertib, Lomustine, or the Combination of Galunisertib and Lomustine
Galunisertib, a Transforming growth factor-βRI (TGF-βRI) kinase inhibitor,
blocks TGF-β-mediated tumor growth in glioblastoma. In a three-arm study of
galunisertib (300 mg/day) monotherapy (intermittent dosing; each cycle =14
days on/14 days off), lomustine monotherapy, and galunisertib plus lomustine
therapy, baseline tumor tissue was evaluated to identify markers associated
with tumor stage (e.g., histopathology, Ki67, glial fibrillary acidic protein)
and TGF-β-related signaling (e.g., pSMAD2). Other pharmacodynamic assessments
included chemokine, cytokine, and T cell subsets alterations. 158 patients
were randomized to galunisertib plus lomustine (n = 79), galunisertib (n = 39)
and placebo+lomustine (n = 40). In 127 of these patients, tissue was adequate
for central pathology review and biomarker work. Isocitrate dehydrogenase
(IDH1) negative glioblastoma patients with baseline pSMAD2+ in cytoplasm had
median overall survival (OS) 9.5 months vs. 6.9 months for patients with no
tumor pSMAD2 expression (p = 0.4574). Eight patients were IDH1 R132H+ and had
a median OS of 10.4 months compared to 6.9 months for patients with negative
IDH1 R132H (p = 0.5452). IDH1 status was associated with numerically higher
plasma macrophage-derived chemokine (MDC/CCL22), higher whole blood FOXP3, and
reduced tumor CD3+ T cell counts. Compared to the baseline, treatment with
galunisertib monotherapy preserved CD4+ T cell counts, eosinophils,
lymphocytes, and the CD4/CD8 ratio. The T-regulatory cell compartment was
associated with better OS with MDC/CCL22 as a prominent prognostic marker.
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Who Is In Charge, and Who Should Be? The Disciplinary Role of the Commander in Military Justice Systems
BackgroundStandard therapy for newly diagnosed glioblastoma is radiotherapy plus temozolomide. In this phase 3 study, we evaluated the effect of the addition of bevacizumab to radiotherapy-temozolomide for the treatment of newly diagnosed glioblastoma. MethodsWe randomly assigned patients with supratentorial glioblastoma to receive intravenous bevacizumab (10 mg per kilogram of body weight every 2 weeks) or placebo, plus radiotherapy (2 Gy 5 days a week; maximum, 60 Gy) and oral temozolomide (75 mg per square meter of body-surface area per day) for 6 weeks. After a 28-day treatment break, maintenance bevacizumab (10 mg per kilogram intravenously every 2 weeks) or placebo, plus temozolomide (150 to 200 mg per square meter per day for 5 days), was continued for six 4-week cycles, followed by bevacizumab monotherapy (15 mg per kilogram intravenously every 3 weeks) or placebo until the disease progressed or unacceptable toxic effects developed. The coprimary end points were investigator-assessed progression-free survival and overall survival. ResultsA total of 458 patients were assigned to the bevacizumab group, and 463 patients to the placebo group. The median progression-free survival was longer in the bevacizumab group than in the placebo group (10.6 months vs. 6.2 months; stratified hazard ratio for progression or death, 0.64; 95% confidence interval [CI], 0.55 to 0.74; P<0.001). The benefit with respect to progression-free survival was observed across subgroups. Overall survival did not differ significantly between groups (stratified hazard ratio for death, 0.88; 95% CI, 0.76 to 1.02; P=0.10). The respective overall survival rates with bevacizumab and placebo were 72.4% and 66.3% at 1 year (P=0.049) and 33.9% and 30.1% at 2 years (P=0.24). Baseline health-related quality of life and performance status were maintained longer in the bevacizumab group, and the glucocorticoid requirement was lower. More patients in the bevacizumab group than in the placebo group had grade 3 or higher adverse events (66.8% vs. 51.3%) and grade 3 or higher adverse events often associated with bevacizumab (32.5% vs. 15.8%). ConclusionsThe addition of bevacizumab to radiotherapy-temozolomide did not improve survival in patients with glioblastoma. Improved progression-free survival and maintenance of baseline quality of life and performance status were observed with bevacizumab; however, the rate of adverse events was higher with bevacizumab than with placebo.
Validation of the American Joint Committee on Cancer new prognostic stage groups for HER2-positive breast cancer patients treated with adjuvant chemotherapy and trastuzumab in the prospective ShortHER trial
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Fotemustine as second-line treatment for recurrent or progressive glioblastoma after concomitant and/or adjuvant temozolomide: a phase II trial of Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO)
Thrombocytopenia limits the feasibility of salvage lomustine chemotherapy in recurrent glioblastoma: a secondary analysis of EORTC 26101
BACKGROUND
Thrombocytopenia represents the main cause of stopping alkylating chemotherapy for toxicity. Here, we explored the incidence, and the consequences for treatment exposure and survival, of thrombocytopenia induced by lomustine in recurrent glioblastoma.
METHODS
We performed a retrospective analysis of the associations of thrombocytopenia with treatment delivery and outcome in EORTC 26101, a randomised trial designed to define the role of lomustine versus bevacizumab versus their combination in recurrent glioblastoma.
RESULTS
A total of 225 patients were treated with lomustine alone (median 1 cycle) (group 1) and 283 patients were treated with lomustine plus bevacizumab (median 3 lomustine cycles) (group 2). Among cycle delays and dose reductions of lomustine for toxicity, thrombocytopenia was the leading cause. Among 129 patients (57%) of group 1 and 187 patients (66%) of group 2 experiencing at least one episode of thrombocytopenia, 36 patients (16%) in group 1 and 93 (33%) in group 2 had their treatment modified because of thrombocytopenia. Lomustine was discontinued for thrombocytopenia in 16 patients (7.1%) in group 1 and in 38 patients (13.4%) in group 2. On adjusted analysis accounting for major prognostic factors, dose modification induced by thrombocytopenia was associated with inferior progression-free survival in patients with MGMT promoter-methylated tumours in groups 1 and 2. This effect was noted for overall survival, too, but only for group 2 patients.
CONCLUSION
Drug-induced thrombocytopenia is a major limitation to adequate exposure to lomustine chemotherapy in recurrent glioblastoma. Mitigating thrombocytopenia to enhance lomustine exposure might improve outcome in patients with MGMT promoter-methylated tumours
PIK3CA MUTATIONS IN HER2-POSITIVE BREAST CANCER PATIENTS ENROLLED IN THE ADJUVANT RANDOMIZED SHORT-HER STUDY.
Prognostic Markers of DNA Methylation and Next-Generation Sequencing in Progressive Glioblastoma from the EORTC-26101 Trial
PURPOSE: The EORTC-26101 study was a randomized phase II and III clinical trial of bevacizumab in combination with lomustine versus lomustine alone in progressive glioblastoma. Other than for progression-free survival (PFS), there was no benefit from addition of bevacizumab for overall survival (OS). However, molecular data allow for the rare opportunity to assess prognostic biomarkers from primary surgery for their impact in progressive glioblastoma. EXPERIMENTAL DESIGN: We analyzed DNA methylation array data and panel sequencing from 170 genes of 380 tumor samples of the EORTC-26101 study. These patients were comparable with the overall study cohort in regard to baseline characteristics, study treatment, and survival.RESULTS: Of patients' samples, 295/380 (78%) were classified into one of the main glioblastoma groups, receptor tyrosine kinase (RTK)1, RTK2 and mesenchymal. There were 10 patients (2.6%) with isocitrate dehydrogenase mutant tumors in the biomarker cohort. Patients with RTK1 and RTK2 classified tumors had lower median OS compared with mesenchymal (7.6 vs. 9.2 vs. 10.5 months). O6-methylguanine DNA-methyltransferase (MGMT) promoter methylation was prognostic for PFS and OS. Neurofibromin (NF)1 mutations were predictive of response to bevacizumab treatment.CONCLUSIONS: Thorough molecular classification is important for brain tumor clinical trial inclusion and evaluation. MGMT promoter methylation and RTK1 classifier assignment were prognostic in progressive glioblastoma. NF1 mutation may be a predictive biomarker for bevacizumab treatment.</p
European Organization for Research and Treatment of Cancer (EORTC) open label phase II study on glufosfamide administered as a 60-minute infusion every 3 weeks in recurrent glioblastoma multiforme
BACKGROUND: Glufosfamide is a new alkylating agent in which the active
metabolite of isophosphoramide mustard is covalently linked to
beta-D-glucose to target the glucose transporter system and increase
intracellular uptake in tumor cells. We investigated this drug in a
multicenter prospective phase II trial in recurrent glioblastoma
multiforme (GBM). PATIENTS AND METHODS: Eligible patients had recurrent
GBM following surgery, radiotherapy and no more than one prior line of
chemotherapy. Patients were treated with glufosfamide 5000 mg/m(2)
administered as a 1-h intravenous infusion. Treatment success was defined
as patients with either an objective response according to Macdonald's
criteria or 6 months progression-free survival. Toxicity was assessed with
the Common Toxicity Criteria (CTC) version 2.0. RESULTS: Thirty-one
eligible patients were included. Toxicity was modest, the main clinically
relevant toxicities being leukopenia (CTC grade >3 in five patients) and
hepatotoxicity (in three patients). No responses were observed; one
patient (3%; 95% confidence interval 0 to 17%) was free from progression
at 6 months. Pharmacokinetic analysis showed a 15% decrease in area under
the curve and glufosfamide clearance in patients treated with
enzyme-inducing antiepileptic drugs, but no effect of these drugs on
maximum concentration and plasma half-life. CONCLUSION: Glufosfamide did
not show significant clinical antitumor activity in patients with
recurrent GBM
PIK3CA Mutation in the ShortHER Randomized Adjuvant Trial for Patients with Early HER2\ufe Breast Cancer: Association with Prognosis and Integration with PAM50 Subtype.
Purpose: We explored the prognostic effect of PIK3CA mutation
in HER2\ufe patients enrolled in the ShortHER trial.
Patients and Methods: The ShortHER trial randomized 1,253
patients with HER2\ufe breast cancer to 9 weeks or 1 year of adjuvant
trastuzumab combined with chemotherapy. PIK3CA hotspot mutations in exon 9 and 20 were analyzed by pyrosequencing. Expression
of 60 genes, including PAM50 genes was measured using the
nCounter platform.
Results: A mutation of the PIK3CA gene was detected in
21.7% of the 803 genotyped tumors. At a median follow-up of
7.7 years, 5-year disease-free survival (DFS) rates were 90.6%
for PIK3CA mutated and 86.2% for PIK3CA wild-type tumors
[HR, 0.84; 95% confidence interval (CI), 0.56\u20131.27; P \ubc 0.417].
PIK3CA mutation showed a favorable prognostic impact in
the PAM50 HER2-enriched subtype (n \ubc 232): 5-year DFS
91.8% versus 76.1% (log-rank P \ubc 0.049; HR, 0.46; 95% CI,
0.21\u20131.02). HER2-enriched/PIK3CA mutated versus wild-type
tumors showed numerically higher tumor-infiltrating lymphocytes (TIL) and significant upregulation of immune-related
genes (including CD8A, CD274, PDCD1, and MYBL2, a proliferation gene involved in immune processes). High TILs as well
as the upregulation of PDCD1 and MYBL2 were associated with
a significant DFS improvement within the HER2-enriched subtype (HR, 0.82; 95% CI, 0.68\u20130.99; P \ubc 0.039 for 10% TILs
increment; HR, 0.81; 95% CI, 0.65\u20130.99; P \ubc 0.049 for PDCD1
expression; HR, 0.72; 95% CI, 0.53\u20130.99; P \ubc 0.042 for MYBL2
expression).
Conclusions: PIK3CA mutation showed no prognostic impact in
the ShortHER trial. Within the HER2-enriched molecular subtype,
patients with PIK3CA mutated tumors showed better DFS versus
PIK3CA wild-type, which may be partly explained by upregulation
of immune-related genes
Pazopanib plus weekly paclitaxel versus weekly paclitaxel alone for platinum-resistant or platinum-refractory advanced ovarian cancer (MITO 11): A randomised, open-label, phase 2 trial
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