Temozolomide chronotherapy in patients with glioblastoma: a retrospective single-institute study

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Abstract

Background

Chronotherapy is an innovative approach to improving survival through timed delivery of anti-cancer treatments according to patient daily rhythms. Temozolomide (TMZ) is a standard-of-care chemotherapeutic agent for glioblastoma (GBM). Whether timing of TMZ administration affects GBM patient outcome has not previously been studied. We sought to evaluate maintenance TMZ chronotherapy on GBM patient survival.

Methods

This retrospective study reviewed patients with newly diagnosed GBM from January 1, 2010 to December 31, 2018 at Washington University School of Medicine who had surgery, chemoradiation, and were prescribed TMZ to be taken in the morning or evening. The Kaplan–Meier method and Cox regression model were used for overall survival (OS) analyses. The propensity score method accounted for potential observational study biases. The restricted mean survival time (RMST) method was performed where the proportional hazard assumption was violated.

Results

We analyzed 166 eligible GBM patients with a median follow-up of 5.07 years. Patients taking morning TMZ exhibited longer OS compared to evening (median OS, 95% confidence interval [CI] = 1.43, 1.12–1.92 vs 1.13, 0.84–1.58 years) with a significant year 1 RMST difference (−0.09, 95% CI: −0.16 to −0.018). Among MGMT-methylated patients, median OS was 6 months longer for AM patients with significant RMST differences at years 1 (−0.13, 95% CI = −0.24 to −0.019) to 2.5 (−0.43, 95% CI = −0.84 to −0.028). Superiority of morning TMZ at years 1, 2, and 5 (all P < .05) among all patients was supported by RMST difference regression after adjusting for confounders.

Conclusions

Our study presents preliminary evidence for the benefit of TMZ chronotherapy to GBM patient survival. This impact is more pronounced in MGMT-methylated patients.

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Most cited references 47

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Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma

Roger Stupp, Warren P Mason, Martin J van den Bent … (2005)

Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, given concomitantly with and after radiotherapy, in terms of efficacy and safety. Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients. The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity. Copyright 2005 Massachusetts Medical Society.

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MGMT gene silencing and benefit from temozolomide in glioblastoma.

Monika E Hegi, Annie-Claire Diserens, Thierry Gorlia … (2005)

Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit. Copyright 2005 Massachusetts Medical Society.

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CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2012–2016

Quinn Ostrom, Gino Cioffi, Haley Gittleman … (2019)

The Central Brain Tumor Registry of the United States (CBTRUS), in collaboration with the Centers for Disease Control and Prevention and National Cancer Institute, is the largest population-based registry focused exclusively on primary brain and other central nervous system (CNS) tumors in the United States (US) and represents the entire US population. This report contains the most up-to-date population-based data on primary brain tumors available and supersedes all previous reports in terms of completeness and accuracy. All rates are age-adjusted using the 2000 US standard population and presented per 100,000 population. The average annual age-adjusted incidence rate (AAAIR) of all malignant and non-malignant brain and other CNS tumors was 23.41 (Malignant AAAIR = 7.08, non-Malignant AAAIR = 16.33). This rate was higher in females compared to males (25.84 versus 20.82), Whites compared to Blacks (23.50 versus 23.34), and non-Hispanics compared to Hispanics (23.84 versus 21.28). The most commonly occurring malignant brain and other CNS tumor was glioblastoma (14.6% of all tumors), and the most common non-malignant tumor was meningioma (37.6% of all tumors). Glioblastoma was more common in males, and meningioma was more common in females. In children and adolescents (age 0–19 years), the incidence rate of all primary brain and other CNS tumors was 6.06. An estimated 86,010 new cases of malignant and non-malignant brain and other CNS tumors are expected to be diagnosed in the US in 2019 (25,510 malignant and 60,490 non-malignant). There were 79,718 deaths attributed to malignant brain and other CNS tumors between 2012 and 2016. This represents an average annual mortality rate of 4.42. The five-year relative survival rate following diagnosis of a malignant brain and other CNS tumor was 35.8%, and the five-year relative survival rate following diagnosis of a non-malignant brain and other CNS tumors was 91.5%.

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Author and article information

Journal

Journal ID (nlm-ta): Neurooncol Adv

Journal ID (iso-abbrev): Neurooncol Adv

Journal ID (publisher-id): noa

Title: Neuro-oncology Advances

Publisher: Oxford University Press (US )

ISSN (Electronic): 2632-2498

Publication date Collection: Jan-Dec 2021

Publication date (Electronic): 02 March 2021

Publication date PMC-release: 02 March 2021

Volume: 3

Issue: 1

Electronic Location Identifier: vdab041

Affiliations

[1 ] Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine , St. Louis, Missouri, USA

[2 ] Siteman Cancer Center Biostatistics Core, Washington University School of Medicine , St. Louis, Missouri, USA

[3 ] Department of Biology, Washington University , St Louis, Missouri, USA

[4 ] Division of Oncology, Department of Medicine, Washington University School of Medicine , St Louis, Missouri, USA

[5 ] Department of Pediatrics, Washington University School of Medicine , St Louis, Missouri, USA

[6 ] Department of Neuroscience, Washington University School of Medicine , St Louis, Missouri, USA

Author notes

Corresponding Authors: Jian L. Campian, MD, PhD, Division of Oncology, Washington University School of Medicine, Campus Box 8056, 660 South Euclid Ave, St Louis, MO, 63110, USA ( campian.jian@ 123456wustl.edu ); Erik D. Herzog, PhD, Departments of Biology and Neuroscience, Washington University in St. Louis, Campus Box 1137, 1 Brookings Dr, St. Louis, MO, 63130, USA ( herzog@ 123456wustl.edu ).

These authors contributed equally to this work.

Author information

Anna R Damato https://orcid.org/0000-0003-3283-3958

Jingqin Luo https://orcid.org/0000-0003-2759-3072

Joshua B Rubin https://orcid.org/0000-0002-7395-1937

Erik D Herzog https://orcid.org/0000-0001-7209-5174

Jian L Campian https://orcid.org/0000-0002-5317-8481

Article

Publisher ID: vdab041

DOI: 10.1093/noajnl/vdab041

PMC ID: 8086242

PubMed ID: 33959716

SO-VID: 66cfd760-ed44-4695-8481-13b22a348d82

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

History

Date: 30 April 2021

Page count

Pages: 11

Funding

Funded by: Foundation for Barnes-Jewish Hospital and the Barnard Trust;

Funded by: Children's Discovery Institute, DOI 10.13039/100009340;

Funded by: National Institutes of Health, DOI 10.13039/100000002;

Funded by: National Cancer Institute, DOI 10.13039/100000054;

Award ID: P30CA091842

Award ID: F31CA250161

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Temozolomide chronotherapy in patients with glioblastoma: a retrospective single-institute study

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Most cited references 47

Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma

MGMT gene silencing and benefit from temozolomide in glioblastoma.

CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2012–2016

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