A randomized feasibility study evaluating temozolomide circadian medicine in patients with glioma.

Background: Gliomas are the most common primary brain tumor in adults. Current treatments involve surgery, radiation, and temozolomide (TMZ) chemotherapy; however, prognosis remains poor and new approaches are required. Circadian medicine aims to maximize treatment efficacy and/or minimize toxicity by timed delivery of medications in accordance with the daily rhythms of the patient. We published a retrospective study showing greater anti-tumor efficacy for the morning, relative to the evening, administration of TMZ in patients with glioblastoma. We conducted this prospective randomized trial to determine the feasibility, and potential clinical impact, of TMZ chronotherapy in patients with gliomas (NCT02781792). Methods: Adult patients with gliomas (WHO grade II-IV) were enrolled prior to initiation of monthly TMZ therapy and were randomized to receive TMZ either in the morning (AM) before 10 am or in the evening (PM) after 8 pm. Pill diaries were recorded to measure compliance and FACT-Br quality of life (QoL) surveys were completed throughout treatment. Study compliance, adverse events (AE), and overall survival were compared between the two arms. Results: A total of 35 evaluable patients, including 21 with GBM, were analyzed (18 AM patients and 17 PM patients). Compliance data demonstrated the feasibility of timed TMZ dosing. There were no significant differences in AEs, QoL, or survival between the arms. Conclusions: Chronotherapy with TMZ is feasible. A larger study is needed to validate the effect of chronotherapy on clinical efficacy.

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

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.

The predictive value of absolute lymphocyte counts on tumor progression and pseudoprogression in patients with glioblastoma.

BACKGROUND: Differentiating true glioblastoma multiforme (GBM) from pseudoprogression (PsP) remains a challenge with current standard magnetic resonance imaging (MRI). The objective of this study was to explore whether patients' absolute lymphocyte count (ALC) levels can be utilized to predict true tumor progression and PsP. METHODS: Patients were considered eligible for the study if they had 1) GBM diagnosis, 2) a series of blood cell counts and clinical follow-ups, and 3) tumor progression documented by both MRI and pathology. Data analysis results include descriptive statistics, median (IQR) for continuous variables and count (%) for categorical variables, p values from Wilcoxon rank sum test or Fisher's exact test for comparison, respectively, and Kaplan-Meier analysis for overall survival (OS). OS was defined as the time from patients' second surgery to their time of death or last follow up if patients were still alive. RESULTS: 78 patients were included in this study. The median age was 56 years. Median ALC dropped 34.5% from baseline 1400 cells/mm3 to 917 cells/mm3 after completion of radiation therapy (RT) and temozolomide (TMZ). All study patients had undergone surgical biopsy upon MRI-documented progression. 37 had true tumor progression (47.44%) and 41 had pseudoprogression (52.56%). ALC before RT/TMZ, post RT/TMZ and at the time of MRI-documented progression did not show significant difference between patients with true progression and PsP. Although not statistically significant, this study found that patients with true progression had worse OS compared to those with PsP (Hazard Ratio [HR] 1.44, 95% CI 0.86-2.43, P = 0.178). This study also found that patients with high ALC (dichotomized by median) post-radiation had longer OS. CONCLUSION: Our results indicate that ALC level in GBM patients before or after treatment does not have predictive value for true disease progression or pseudoprogression. Patients with true progression had worse OS compared to those who had pseudoprogression. A larger sample size that includes CD4 cell counts may be needed to evaluate the PsP predictive value of peripheral blood biomarkers.

Cancer in Youth Living With HIV (YLWHIV): A Narrative Review of the Access to Oncological Services Among YLWHIV and the Role of Economic Strengthening in Child Health.

Youth Living with HIV/AIDS (YLWHIV) have a higher risk of developing immunodeficiency related illnesses including certain cancers than their general population counterparts of the same age. This narrative review of current available literature describes factors associated with pediatric access to oncological services, and the role economic strengthening could play in improving health outcomes for this vulnerable population. Findings suggest that both HIV-infected and -uninfected children living in low and middle-income countries struggle with access and adherence to cancer treatment and care. Cost of treatment is a major barrier to access and adherence. Asset-building savings programs may increase financial security and subsequently result in better health outcomes although they have not been utilized to improve access to cancer treatment.

Suubi4Cancer: A protocol for an innovative combination intervention to improve access to pediatric cancer services and treatment adherence among children living with HIV/AIDS in Uganda.

Youth Living with HIV (YLWHIV) are at high risk for cancer. Sub-Saharan Africa (SSA) has some of the worst pediatric cancer survival rates due to barriers to accessing cancer services and treatment adherence. This protocol describes a study that aims at: 1) Identifying confirmed and suspected cancer cases in a cohort of >3000 HIV positive youth; 2) Examining the short-term preliminary outcomes of an evidence-based Economic Empowerment (EE) intervention, Suubi ("hope" in a local Ugandan language), on access to pediatric cancer diagnosis and care, and treatment adherence among YLWHIV with suspected cancers in Uganda; and 3) Exploring multi-level factors impacting intervention participation and experiences. The proposed Suubi4Cancer intervention combines savings-led EE through family development accounts (FDA) with financial literacy and management (FLM) and cancer education (CE). The study will review medical charts in 39 clinics in Southwest Uganda to identify confirmed and suspected cancer cases. Subsequently, Suubi4Cancer will be evaluated via a randomized-controlled trial design (FDA + FLM + CE versus Usual Care) targeting a total of 78 youth ages 10-to-24 and their caregivers. Assessments at baseline and 9 months will examine change in cancer treatment access; cancer treatment adherence; and knowledge, attitudes, and beliefs about cancer and cancer treatment. Semi-structured interviews with the intervention group will explore their intervention experiences. To our knowledge, Suubi4Cancer will be the first study to test the preliminary impact and acceptability of a combination intervention to increase access to cancer diagnosis and treatment services for YLWHIV. TRIAL REGISTRATION: Clinical Trials NCT03916783 (Registered: 04/16/19).