Sex-Dependent Analysis of Temozolomide-Induced Myelosuppression and Effects on Survival in a Large Real-life Cohort of Patients With Glioma

Zeiner, Pia S.; Filipski, Katharina; Filmann, Natalie; Forster, Marie-Thérèse; Voss, Martin H.; Fokas, Emmanouil; Herrlinger, Ulrich; Harter, Patrick N.; Steinbach, Joachim P.; Ronellenfitsch, Michael

doi:10.1212/wnl.0000000000200254

Cited by 2 publications

(3 citation statements)

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“…We also evaluated the prediction of hematotoxicity employing previously published baseline factors found to be predictive in glioma patients receiving TMZ chemotherapy [7,8]. Logistic regression analysis confirmed the known higher risk among older and female patients [14], while treatment arm was not predictive. Analyzing treatment arms separately, no significant predictors were found, probably due to limited sample size and event rate.…”

Section: Discussionmentioning

confidence: 96%

“…The association of female gender and increased risk of HAE has been reported for temozolomide in glioma treatment [ 7 , 14 , 15 ], but also for other chemotherapeutics agents employed in a variety of cancers [ 16 ]. Indeed, sex differences in pharmacologic response and adverse drug reactions are increasingly observed and female sex is associated with a greater risk of adverse events [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…These observations are attributed to differences in pharmacokinetics and pharmacodynamics [ 18 ]. Females have a higher percentage of body fat, affecting distribution volumes, but obesity and body fat content were not correlated with myelosuppression [ 14 ]. Other potential mechanisms underlying the sex-dependently increased HAE risk include a lower glomerular filtration rate and activity of hepatic enzymes and drug transporters, which may affect drug clearance [ 16 , 17 ].…”

Section: Discussionmentioning

confidence: 99%

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Patterns, predictors and prognostic relevance of high-grade hematotoxicity after temozolomide or temozolomide-lomustine in the CeTeG/NOA-09 trial

et al. 2023

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Purpose In the randomized phase III trial CeTeG/NOA-09, temozolomide (TMZ)/lomustine (CCNU) combination therapy was superior to TMZ in newly diagnosed MGMT methylated glioblastoma, albeit reporting more frequent hematotoxicity. Here, we analyze high grade hematotoxicity and its prognostic relevance in the trial population. Methods Descriptive and comparative analysis of hematotoxicity adverse events ≥ grade 3 (HAE) according to the Common Terminology of Clinical Adverse Events, version 4.0 was performed. The association of HAE with survival was assessed in a landmark analysis. Logistic regression analysis was performed to predict HAE during the concomitant phase of chemotherapy. Results HAE occurred in 36.4% and 28.6% of patients under CCNU/TMZ and TMZ treatment, respectively. The median onset of the first HAE was during concomitant chemotherapy (i.e. first CCNU/TMZ course or daily TMZ therapy), and 42.9% of patients with HAE receiving further courses experienced repeat HAE. Median HAE duration was similar between treatment arms (CCNU/TMZ 11.5; TMZ 13 days). Chemotherapy was more often discontinued due to HAE in CCNU/TMZ than in TMZ (19.7 vs. 6.3%, p = 0.036). The occurrence of HAE was not associated with survival differences (p = 0.76). Regression analysis confirmed older age (OR 1.08) and female sex (OR 2.47), but not treatment arm, as predictors of HAE. Conclusion Older age and female sex are associated with higher incidence of HAE. Although occurrence of HAE was not associated with shorter survival, reliable prediction of patients at risk might be beneficial to allow optimal management of therapy and allocation of supportive measures. Trial registration NCT01149109.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Patterns, predictors and prognostic relevance of high-grade hematotoxicity after temozolomide or temozolomide-lomustine in the CeTeG/NOA-09 trial

et al. 2023

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Mammalian target of rapamycin inhibition protects glioma cells from temozolomide-induced cell death

Sauer,

Lorenz,

Divé

et al. 2024

Cell Death Discov.

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Glioblastoma is an incurable brain tumor with a median survival below two years. Trials investigating targeted therapy with inhibitors of the kinase mTOR have produced ambiguous results. Especially combination of mTOR inhibition with standard temozolomide radiochemotherapy has resulted in reduced survival in a phase II clinical trial. To date, this phenomenon is only poorly understood. To recreate the therapeutic setting in vitro, we exposed glioblastoma cell lines to co-treatment with rapamycin and temozolomide and assessed cell viability, DNA damage and reactive oxygen species. Additionally, we employed a novel translatomic based mass spectrometry approach (“mePROD”) to analyze acute changes in translated proteins. mTOR inhibition with rapamycin protected glioblastoma cells from temozolomide toxicity. Following co-treatment of temozolomide with rapamycin, an increased translation of reactive oxygen species (ROS)-detoxifying proteins was detected by mass spectrometry. This was accompanied by improved ROS-homeostasis and reduced DNA damage. Additionally, rapamycin induced the expression of the DNA repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT) in glioblastoma cells with an unmethylated MGMT gene promotor. Inhibition of mTOR antagonized the cytotoxic effects of temozolomide in vitro. The induction of antioxidant defences and MGMT are two underlying candidate mechanisms. Further functional experiments in vitro and in vivo are warranted to characterize this effect that appears relevant for combinatorial therapeutic strategies.

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Sex-Dependent Analysis of Temozolomide-Induced Myelosuppression and Effects on Survival in a Large Real-life Cohort of Patients With Glioma

Cited by 2 publications

References 28 publications

Patterns, predictors and prognostic relevance of high-grade hematotoxicity after temozolomide or temozolomide-lomustine in the CeTeG/NOA-09 trial

Patterns, predictors and prognostic relevance of high-grade hematotoxicity after temozolomide or temozolomide-lomustine in the CeTeG/NOA-09 trial

Mammalian target of rapamycin inhibition protects glioma cells from temozolomide-induced cell death

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