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Dexamethasone exerts profound immunologic interference on treatment efficacy for recurrent glioblastoma.

ABSTRACT: Patients with recurrent glioblastoma have a poor outcome. Data from the phase III registration trial comparing tumour-treating alternating electric fields (TTFields) vs chemotherapy provided a unique opportunity to study dexamethasone effects on patient outcome unencumbered by the confounding immune and myeloablative side effects of chemotherapy.Using an unsupervised binary partitioning algorithm, we segregated both cohorts of the trial based on the dexamethasone dose that yielded the greatest statistical difference in overall survival (OS). The results were validated in a separate cohort treated in a single institution with TTFields and their T lymphocytes were correlated with OS.Patients who used dexamethasone doses >4.1?mg per day had a significant reduction in OS when compared with those who used ?4.1?mg per day, 4.8 vs 11.0 months respectively (?(2)=34.6, P<0.0001) in the TTField-treated cohort and 6.0 vs 8.9 months respectively (?(2)=10.0, P<0.0015) in the chemotherapy-treated cohort. In a single institution validation cohort treated with TTFields, the median OS of patients who used dexamethasone >4.1?mg per day was 3.2 months compared with those who used ?4.1?mg per day was 8.7 months (?(2)=11.1, P=0.0009). There was a significant correlation between OS and T-lymphocyte counts.Dexamethasone exerted profound effects on both TTFields and chemotherapy efficacy resulting in lower patient OS. Therefore, global immunosuppression by dexamethasone likely interferes with immune functions that are necessary for the treatment of glioblastoma.

SUBMITTER: Wong ET

PROVIDER: S-EPMC4506397 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Dexamethasone exerts profound immunologic interference on treatment efficacy for recurrent glioblastoma.

Wong E T ET Lok E E Gautam S S Swanson K D KD

British journal of cancer 20150630 2

<h4>Background</h4>Patients with recurrent glioblastoma have a poor outcome. Data from the phase III registration trial comparing tumour-treating alternating electric fields (TTFields) vs chemotherapy provided a unique opportunity to study dexamethasone effects on patient outcome unencumbered by the confounding immune and myeloablative side effects of chemotherapy.<h4>Methods</h4>Using an unsupervised binary partitioning algorithm, we segregated both cohorts of the trial based on the dexamethaso ...[more]

PMID: 26125449

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Project description:BackgroundWe assessed the efficacy and safety of bevacizumab (BEV) through multiple lines in patients with recurrent glioblastoma who had progressed after first-line treatment with radiotherapy, temozolomide, and BEV.Patients and methodsTAMIGA (NCT01860638) was a phase II, randomized, double-blind, placebo-controlled, multicenter trial in adult patients with glioblastoma. Following surgery, patients with newly diagnosed glioblastoma received first-line treatment consisting of radiotherapy plus temozolomide and BEV, followed by six cycles of temozolomide and BEV, then BEV monotherapy until disease progression (PD1). Randomization occurred at PD1 (second line), and patients received lomustine (CCNU) plus BEV (CCNU + BEV) or CCNU plus placebo (CCNU + placebo) until further disease progression (PD2). At PD2 (third line), patients continued BEV or placebo with chemotherapy (investigator's choice). The primary endpoint was survival from randomization. Secondary endpoints were progression-free survival in the second and third lines (PFS2 and PFS3) and safety.ResultsOf the 296 patients enrolled, 123 were randomized at PD1 (CCNU + BEV, n = 61; CCNU + placebo, n = 62). The study was terminated prematurely because of the high drop-out rate during first-line treatment, implying underpowered inferential testing. The proportion of patients receiving corticosteroids at randomization was similar (BEV 33%, placebo 31%). For the CCNU + BEV and CCNU + placebo groups, respectively, median survival from randomization was 6.4 versus 5.5 months (stratified hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.69-1.59), median PFS2 was 2.3 versus 1.8 months (stratified HR, 0.70; 95% CI, 0.48-1.00), median PFS3 was 2.0 versus 2.2 months (stratified HR, 0.70; 95% CI, 0.37-1.33), and median time from randomization to a deterioration in health-related quality of life was 1.4 versus 1.3 months (stratified HR, 0.76; 95% CI, 0.52-1.12). The incidence of treatment-related grade 3 to 4 adverse events was 19% (CCNU + BEV) versus 15% (CCNU + placebo).ConclusionThere was no survival benefit and no detriment observed with continuing BEV through multiple lines in patients with recurrent glioblastoma.Implications for practicePrevious research suggested that there may be value in continuing bevacizumab (BEV) beyond progression through multiple lines of therapy. No survival benefit was observed with the use of BEV through multiple lines in patients with glioblastoma who had progressed after first-line treatment (radiotherapy + temozolomide + BEV). No new safety concerns arose from the use of BEV through multiple lines of therapy.

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Dexamethasone exerts profound immunologic interference on treatment efficacy for recurrent glioblastoma.

Publications

Dexamethasone exerts profound immunologic interference on treatment efficacy for recurrent glioblastoma.

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