Use of metformin and outcome of patients with newly diagnosed glioblastoma: Pooled analysis

Metformin has been linked to improve survival of patients with various cancers. There is little information on survival of glioblastoma patients after use of metformin. We assessed the association between metformin use and survival in a pooled analysis of patient data from 1,731 individuals from the randomized AVAglio, CENTRIC and CORE trials. We performed multivariate Cox analyses for overall survival (OS) and progression-free survival (PFS) comparing patients' use of metformin at baseline and/or during concomitant radiochemotherapy (TMZ/RT). Further exploratory analyses investigated the effect of metformin with a history of diabetes and nonfasting glucose levels in relation to OS or PFS of glioblastoma patients. Metformin alone or in any combination was not significantly associated with OS or PFS (at baseline, hazard ratio [HR] for OS = 0.87; 95% confidence interval [CI] = 0.65-1.16; HR for PFS = 0.84; 95% CI = 0.64-1.10; during TMZ/RT HR for OS = 0.97; 95% CI = 0.68-1.38; HR for PFS = 1.02; 95% CI = 0.74-1.41). We found a statistically nonsignificant association of metformin monotherapy with glioblastoma survival at baseline (HR for OS = 0.68; 95% CI = 0.42-1.10; HR for PFS = 0.57; 95% CI = 0.36-0.91), but not during the TMZ/RT period (HR for OS = 0.90; 95% CI = 0.51-1.56; HR for PFS = 1.05; 95% CI = 0.64-1.73). Diabetes mellitus or increased nonfasting glucose levels were not associated with a difference in OS or PFS in our selected study population. Metformin did not prolong survival of patients with newly diagnosed glioblastoma in our analysis. Additional studies may identify patients with specific tumor characteristics that are associated with potential benefit from treatment with metformin, possibly due to metabolic vulnerabilities

Diabetes, use of antidiabetic drugs, and the risk of glioma

Prior epidemiologic studies suggest inverse relations between diabetes and glioma risk, but the underlying mechanisms, including use of antidiabetic drugs, are unknown.; We therefore performed a matched case-control analysis using the Clinical Practice Research Datalink (CPRD). We identified incident glioma cases diagnosed between 1995 and 2012 and matched each case with 10 controls on age, gender, calendar time, general practice, and years of active history in the CPRD. We performed conditional logistic regression to estimate odds ratios (ORs) with 95% CIs, adjusted for body mass index and smoking.; We identified 2005 cases and 20 050 controls. Diabetes was associated with decreased risk of glioma (OR = 0.74; 95% CI = 0.60-0.93), particularly glioblastoma (OR = 0.69; 95% CI = 0.51-0.94). Glioblastoma risk reduction was markedly pronounced among diabetic men (OR = 0.60; 95% CI = 0.40-0.90), most apparently for those with diabetes of long-term duration (OR for >5 vs 0 y = 0.46; 95% CI = 0.26-0.82) or poor glycemic control (OR for HbA1c ≥8 vs <6.5% = 0.20; 95% CI = 0.06-0.70). In contrast, the effect of diabetes on glioblastoma risk was absent among women (OR = 0.85; 95% CI = 0.53-1.36). No significant associations with glioma were found for use of metformin (OR for ≥30 vs 0 prescriptions = 0.72; 95% CI = 0.38-1.39), sulfonylureas (OR = 0.71; 95% CI = 0.39-1.30), or insulin (OR = 0.79; 95% CI = 0.37-1.69).; Antidiabetic treatment appears to be unrelated to glioma, but long-term diabetes duration and increased HbA1c both show decreased glioma risk. Stronger findings in men than women suggest low androgen levels concurrent with diabetes as a biologic mechanism

Association of antidepressant drug use with outcome of patients with glioblastoma

Depressive symptoms are common among patients with glioblastoma, but patients are often not treated with antidepressants. There is only limited evidence on the association of antidepressant drug use with survival in glioblastoma. We performed a pooled analysis of patients treated within the CENTRIC, CORE, AVAglio and ACT‐IV trials to explore the relation of antidepressant drug use with progression‐free (PFS) and overall survival (OS) at baseline, at the start of maintenance therapy and at the start of maintenance cycle 4. We further assessed the association of antidepressant drugs with seizure, cognition, fatigue and a diagnosis of depression. Among more than 1700 patients, we found no significant association between the use of antidepressants at baseline or at the start of maintenance therapy and PFS or OS. However, we found OS, but not PFS, to be significantly worse in patients using antidepressants at the start of maintenance cycle 4. After adjustment for antiepileptic drug use and despite showing a trend for increased risk, seizures were not significantly associated with antidepressant drug use, nor was there a change in mini mental state examination (MMSE) scores or fatigue by antidepressant drug use at baseline. However, there was a significant positive association between antidepressant use at the start of maintenance treatment and fatigue during maintenance treatment. The association of antidepressant use at the start of maintenance cycle 4 with inferior OS of glioblastoma patients requires independent confirmation and further study. Further prospective trials should evaluate efficacy, side effects and associations with outcome of antidepressants in glioblastoma

Autoimmune diseases and immunosuppressive therapy in relation to the risk of glioma

Effectors from the immune system can modulate the course and possibly the early development of gliomas. We, therefore, hypothesized that autoimmune diseases associated with increased immune-surveillance may also modulate the risk of human glioma. To test this hypothesis, we used data from the well-validated Clinical Practice Research Datalink (CPRD) GOLD from the UK to analyze the association of immune-related disorders or use of immunosuppressive drugs and the risk of glioma. We identified 3112 incident glioma cases diagnosed between 1995 and 2017. We randomly selected up to 10 controls, matching them to glioma cases on age, sex, index date, general practice, and number of years of active history in the database prior to the index date. We performed conditional logistic regression analyses to estimate Odds Ratios (ORs) of glioma among those exposed to allergies, autoimmune diseases, and immunosuppressive drugs. Overall, we found no materially altered association between a history of any autoimmune disease (OR 0.98, 95% CI 0.86-1.11), allergy (OR 0.97, 95% CI 0.89-1.05), or use of immunosuppressive drugs and the risk of glioma. However, subgroup analyses among younger patients found a statistically significant increased risk of glioma in patients with a history of inflammatory bowel disease (IBD) (OR 2.59, 95% CI 1.31-5.12). There was also an inverse association between asthma and risk of glioma in patients with longer survival (OR 0.73, 95% CI 0.58-0.91) and between long-term duration diabetes and risk of glioma (OR 0.71, 95% CI 0.53-0.96)

Suicide risk and mortality among patients with cancer

Despite substantial progress in cancer therapy in recent decades, patients with cancer remain at high suicide risk. Data from individual studies have not been comprehensively quantified and specific risk factors are ill-defined. We assessed suicide mortality risk according to cancer prognosis, stage, time since diagnosis, gender, ethnicity, marital status, year of recruitment and geographic region. We searched EMBASE, MEDLINE, PsycINFO, Web of Science, CINAHL and Google Scholar for relevant articles up to February 2021. We used a random effects model, performed meta-regression meta-analysis and assessed heterogeneity and publication bias using I², funnel plots and Egger’s and Begg’s tests. We performed a systematic review including 62 studies and 46,952,813 patients. To avoid patient sample overlap, the meta-analysis was performed on 28 studies, involving 22,407,690 patients with cancer. Suicide mortality was significantly increased compared with the general population (standardized mortality ratio = 1.85, 95% confidence interval = 1.55–2.20). Risk was strongly related to cancer prognosis, cancer stage, time since diagnosis and geographic region. Patients with cancer, particularly those with specific risk factors, should be closely monitored for suicidality and need specialized care to reduce short- and long-term risks of suicide

Author Correction: Suicide risk and mortality among patients with cancer.

Correction to: Nature Medicine https://doi.org/10.1038/s41591-022-01745-y. Published online 28 March 2022. In the version of this article initially published, refs. 12 and 16 were duplicated as refs. 21 and 22, which have now been removed and the list renumbered. There were typographical errors in the Supplementary Information which are reflected in descriptions of the meta-analysis in the main text, as follows: the review included 47,035,065 patients with cancer (not 46,952,813, as stated previously), the number of whom died by suicide is 69,401 (not 69,298 as reported previously), encompassing 107,961,345 person-years of follow-up (not 107,691,796, as noted previously); the “Study population” section of the Results now reports 30 studies performed in the USA and 25 in Europe (not 31 and 24, respectively, as stated previously). The abstract and the “Study population,” “Sensitivity analyses using all 62 eligible studies” and “Assessment of publication bias” sections of the Results have been amended. The typographical errors in the Supplementary Information were corrected as follows: pages 6 and 12, Turaga et al., end-time of recruitment updated from 2015 to 2005; page 7, Patasius et al., standardized mortality ratio updated from 1.01 to 1.10; page 7, Levi et al., follow-up in person-years updated from 57,614 to 57,164; page 8, Alanee et al., number of suicide cases updated from 30 to 33; page 9, Osazuwa-Peters et al., study population count updated from 205,658 to 287,901; pages 7 and 11, Kaceniene et al., country of study updated from USA to Lithuania. The results of the metadata analysis remain unchanged. Updates have now been made in the HTML and PDF versions of the full text, Extended Data Figures 2, 4 and 5 and the Supplementary Information

Diabetes, use of metformin, and the risk of meningioma

Background Metformin is a commonly used oral antidiabetic agent that has been associated with decreased cancer risk. However, data regarding the association between metformin use and the risk of meningioma are unavailable. Methods We conducted a matched case-control analysis using data from the U. K.-based Clinical Practice Research Datalink (CPRD) to analyse diabetes status, duration of diabetes, glycemic control, and use of metformin, sulfonylureas, and insulin in relation to the risk of meningioma. We conducted conditional logistic regression analyses to determine relative risks, estimated as odds ratios (ORs) with 95% confidence intervals (CIs) and adjusted for body mass index, smoking, history of arterial hypertension, myocardial infarction, and use of estrogens (among women). Results We identified 2,027 meningioma cases and 20,269 controls. For diabetes there was the suggestion of an inverse association with meningioma (OR = 0.89; 95% CI = 0.74 - 1.07), which was driven by an inverse relation among women (OR = 0.78; 95% CI = 0.62 - 0.98), in whom we also noted a suggestive inverse association with duration of diabetes (p-value for trend = 0.071). For metformin there was a suggestive positive relation, particularly after matching on duration of diabetes and HbA1c level (OR = 1.64; 95% CI = 0.89 - 3.04). Sulfonylureas showed no clear association (OR = 0.91; 95% CI = 0.46 - 1.80). For insulin there was the suggestion of an inverse relation, in particular when comparing a high vs. low number of prescriptions (OR = 0.58; 95% CI = 0.18 - 1.83). Conclusion Further studies are needed to solidify a possible inverse association between diabetes and meningioma risk and to clarify the role of antidiabetics in this context

Antimicrobial drug use and the risk of glioma: A case–control study

Background The use of antibiotics has been associated with increased risks of various cancers. Comprehensive information on the association of antibiotic use with the risk of glioma is lacking. Methods We performed a large case–control study based on the Clinical Practice Research Datalink (CPRD) GOLD from the United Kingdom. We identified 4423 glioma cases recorded between 1995 and 2020 and matched them to controls (1:10) on the date of diagnosis (i.e., the index date), age, sex, general practice, and number of years of medical history in the database prior to the index date. We conducted conditional logistic regression analyses to calculate odds ratios (ORs) with 95% confidence intervals (CIs). The exposures of interest were the use of antimicrobial drugs, including antibacterial, antiviral, antifungal, antiprotozoal, and anthelmintic drugs with specific subclasses, where possible. Results We found no substantially increased risk of glioma after ever-use of antibiotics (OR 1.13, 95% CI 1.03–1.24). The risk did not increase with the increasing number of prescriptions received or with increasing time from first use to cancer diagnosis. The use of polyenes was associated with a weakly decreased risk of glioma (OR 0.81, 95% CI 0.67–0.96)

Targeted therapies in patients with newly diagnosed glioblastoma - a systematic meta-analysis of randomized clinical trials

Glioblastoma (GB) is the most common malignant primary brain tumor in adults. The standard of care for newly diagnosed GB involves surgical resection followed by radiochemotherapy with temozolomide, with or without tumor-treating fields. In recent years, various efforts have been made to identify suitable molecularly targeted treatment options for malignant brain tumors. This meta-analysis provides an overview of recently published randomized controlled trials (RCTs) with and without molecular stratification, analyzing targeted agents in patients with newly diagnosed GB. The Cochrane Library, MEDLINE (Ovid), ClinicalTrials.gov, WHO's International Clinical Trials Registry Platform, and Google Scholar were searched for RCTs on targeted therapies in patients with newly diagnosed glioblastoma. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were extracted and pooled in a random-effects meta-analysis. Twelve RCTs (n=3,941 patients) involving protein kinase inhibitors, proteasome and histone deacetylase inhibitors, anti-angiogenic approaches, and poly (ADP-ribose) polymerase (PARP) inhibitors were included in the meta-analysis. None of the targeted agents achieved a significant benefit with regard to OS (HR=0.98 [95% Confidence Interval (CI) 0.86-1.11, p=0.7731]. By comparison, targeted therapy showed a benefit for PFS (HR=0.83 [95% CI 0.74-0.94, p=0.0037], especially for patients with an unmethylated O6-Methylguanin-DNA-methyltransferase (MGMT) promoter (0.75 [95% CI 0.56-0.99, p=0.0440]). Prolongation of PFS was largely driven by VEGF inhibition with bevacizumab (HR=0.70 [95% CI 0.61-0.80, p=0.0000]). VEGF inhibition with bevacizumab prolonged PFS in patients with newly diagnosed glioblastoma compared with standard care. However, no improvement in OS was observed with any of the targeted agents

Targeted agents in patients with progressive glioblastoma—A systematic meta‐analysis of randomized clinical trials

Background Glioblastoma (GB) is the most common malignant primary brain tumor in adults and is associated with a poor prognosis. Current treatment guidelines outline the standard of care for patients with newly diagnosed GB; however, there is currently no well-established consensus for the treatment of progressive GB. With this systematic meta-analysis of recently published randomized controlled trials (RCTs), we aim to establish evidence on targeted agents in the treatment of patients with progressive GB. Material and Methods We conducted searches across the Cochrane Library, Pubmed, MEDLINE (Ovid), ClinicalTrials.gov, WHO‘s International Clinical Trials Registry Platform and Google Scholar, encompassing the time span from 1954 to 2022, aiming to identify RCTs evaluating targeted therapies in patients with progressive GB. In order to perform a random-effects meta-analysis, we extracted hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS). Results We included 16 RCTs (n = 3025 patients) in the systematic meta-analysis. Formally, regorafenib (RR 0.50; 95% CI 0.33–0.75), Depatux-M + TMZ (RR 0.66; 95% CI 0.47–0.93) and rindopepimut + bevacizumab (RR 0.53; 95% CI 0.32–0.88) were associated with an improved OS compared to the control arm. The combination of bevacizumab + CCNU (RR = 0.49; 95% CI 0.35–0.69) and regorafenib (RR 0.65; 95% CI 0.44–0.95) were formally associated with improved PFS. Conclusions The aim of this systematic meta-analysis was to establish evidence for the use of targeted therapies in progressive GB. While some studies demonstrated benefits for OS and/or PFS, those results have to be interpreted with caution as most studies had major methodological weaknesses, including potential differences in sample size, trial design, or the initial distribution of prognostic factors