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Translational Oncology Feb 2016This systematic review and meta-analysis evaluated anti-programmed cell death (PD)-1 immunotherapy (nivolumab or pembrolizumab) for overall efficacy, safety, and...
This systematic review and meta-analysis evaluated anti-programmed cell death (PD)-1 immunotherapy (nivolumab or pembrolizumab) for overall efficacy, safety, and effective dose relative to standard chemotherapy or other conventional drugs in the treatment of malignant tumors. We searched the following databases, PubMed, Medline, Embase, Cochrane, Wangfang Data, Weipu, and China National Knowledge Infrastructure, and the reference lists of the selected articles for randomized controlled trials (RCTs) of anti-PD-1 therapies in humans. The outcome measures were overall survival, treatment response, and adverse events. Only four randomized controlled trials met our inclusion criteria. Three of these evaluated responses to nivolumab, whereas one tested pembrolizumab. The result of our analysis suggested that nivolumab may improve the overall response rate in treating melanoma relative to chemotherapy and has few associated adverse events. Similarly, in metastatic melanoma patients, nivolumab had a significant advantage over dacarbazine in terms of 1-year survival, progression-free survival, and objective response rate. Regarding dose levels of nivolumab for patients with metastatic renal cell carcinoma, the outcomes in response to 2 and 10 mg/kg were similar, but both had significant advantages over 0.3 mg/kg. In addition, pembrolizumab showed similar outcomes in response to 2- and 10-mg/kg treatment. Anti-PD-1 immunotherapy appears to be safe and effective for patients with melanoma or metastatic renal cell carcinoma. Our meta-analysis is limited, but additional clinical trials are warranted to verify this preliminary evidence of positive outcomes and before anti-PD-1 therapy can be recommended for routine clinical use.
PubMed: 26947879
DOI: 10.1016/j.tranon.2015.11.010 -
Scientific Reports Jul 2020Translation of survival benefits observed in glioblastoma clinical trials to populations and to longer-term survival remains uncertain. We aimed to assess if... (Comparative Study)
Comparative Study Meta-Analysis
Translation of survival benefits observed in glioblastoma clinical trials to populations and to longer-term survival remains uncertain. We aimed to assess if ≥ 2-year survival has changed in relation to the trial of radiotherapy plus concomitant and adjuvant temozolomide published in 2005. We searched MEDLINE and Embase for population-based studies with ≥ 50 patients published after 2002 reporting survival at ≥ 2 years following glioblastoma diagnosis. Primary endpoints were survival at 2-, 3- and 5-years stratified by recruitment period. We meta-analysed survival estimates using a random effects model stratified according to whether recruitment ended before 2005 (earlier) or started during or after 2005 (later). PROSPERO registration number CRD42019130035. Twenty-three populations from 63 potentially eligible studies contributed to the meta-analyses. Pooled 2-year overall survival estimates for the earlier and later study periods were 9% (95% confidence interval [CI] 6-12%; n/N = 1,488/17,507) and 18% (95% CI 14-22%; n/N = 5,670/32,390), respectively. Similarly, pooled 3-year survival estimates increased from 4% (95% CI 2-6%; n/N = 325/10,556) to 11% (95% CI 9-14%; n/N = 1900/16,397). One study with a within-population comparison showed similar improvement in survival among the older population. Pooled 5-year survival estimates were 3% (95% CI 1-5%; n/N = 401/14,919) and 4% (95% CI 2-5%; n/N = 1,291/28,748) for the earlier and later periods, respectively. Meta-analyses of real-world data suggested a doubling of 2- and 3-year survival in glioblastoma patients since 2005. However, 5-year survival remains poor with no apparent improvement. Detailed clinically annotated population-based data and further molecular characterization of longer-term survivors may explain the unchanged survival beyond 5 years.
Topics: Brain Neoplasms; Cancer Survivors; Chemotherapy, Adjuvant; Disease-Free Survival; Glioblastoma; Humans; Risk; Temozolomide; Time Factors; Treatment Outcome
PubMed: 32669604
DOI: 10.1038/s41598-020-68011-4 -
BMC Cancer Feb 2024Recent advances in the management of pancreatic neuroendocrine tumors (pNETs) highlight the potential benefits of temozolomide, an alkylating agent, for these patients.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Recent advances in the management of pancreatic neuroendocrine tumors (pNETs) highlight the potential benefits of temozolomide, an alkylating agent, for these patients. In this meta-analysis, we aimed to assess the outcome of temozolomide, alone or in combination with other anticancer medications in patients with advanced pNET.
METHODS
Online databases of PubMed, Web of Science, Embase, the Cochrane Library, and ClinicalTrials.gov were searched systematically for clinical trials that reported the efficacy and safety of temozolomide in patients with advanced pNET. Random-effect model was utilized to estimate pooled rates of outcomes based on Response Evaluation Criteria in Solid Tumors criteria, biochemical response, and adverse events (AEs).
RESULTS
A total of 14 studies, providing details of 441 individuals with advanced pNET, were included. The quantitative analyses showed a pooled objective response rate (ORR) of 41.2% (95% confidence interval, CI, of 32.4%-50.6%), disease control rate (DCR) of 85.3% (95% CI of 74.9%-91.9%), and a more than 50% decrease from baseline chromogranin A levels of 44.9% (95% CI of 31.6%-49.0%). Regarding safety, the results showed that the pooled rates of nonserious AEs and serious AEs were 93.8% (95% CI of 88.3%-96.8%) and 23.7% (95% CI of 12.0%-41.5%), respectively. The main severe AEs encompassed hematological toxicities.
CONCLUSIONS
In conclusion, our meta-analysis suggests that treatment with temozolomide, either as a monotherapy or in combination with other anticancer treatments might be an effective and relatively safe option for patients with advanced locally unresectable and metastatic pNET. However, additional clinical trials are required to further strengthen these findings. This study has been registered in PROSPERO (CRD42023409280).
Topics: Humans; Temozolomide; Neuroendocrine Tumors; Response Evaluation Criteria in Solid Tumors; Pancreatic Neoplasms; Neuroectodermal Tumors, Primitive
PubMed: 38347461
DOI: 10.1186/s12885-024-11926-2 -
The Cochrane Database of Systematic... Mar 2021Glioblastoma is an aggressive form of brain cancer. Approximately five in 100 people with glioblastoma survive for five years past diagnosis. Glioblastomas that have a... (Meta-Analysis)
Meta-Analysis
Prognostic value of test(s) for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation for predicting overall survival in people with glioblastoma treated with temozolomide.
BACKGROUND
Glioblastoma is an aggressive form of brain cancer. Approximately five in 100 people with glioblastoma survive for five years past diagnosis. Glioblastomas that have a particular modification to their DNA (called methylation) in a particular region (the O-methylguanine-DNA methyltransferase (MGMT) promoter) respond better to treatment with chemotherapy using a drug called temozolomide.
OBJECTIVES
To determine which method for assessing MGMT methylation status best predicts overall survival in people diagnosed with glioblastoma who are treated with temozolomide.
SEARCH METHODS
We searched MEDLINE, Embase, BIOSIS, Web of Science Conference Proceedings Citation Index to December 2018, and examined reference lists. For economic evaluation studies, we additionally searched NHS Economic Evaluation Database (EED) up to December 2014.
SELECTION CRITERIA
Eligible studies were longitudinal (cohort) studies of adults with diagnosed glioblastoma treated with temozolomide with/without radiotherapy/surgery. Studies had to have related MGMT status in tumour tissue (assessed by one or more method) with overall survival and presented results as hazard ratios or with sufficient information (e.g. Kaplan-Meier curves) for us to estimate hazard ratios. We focused mainly on studies comparing two or more methods, and listed brief details of articles that examined a single method of measuring MGMT promoter methylation. We also sought economic evaluations conducted alongside trials, modelling studies and cost analysis.
DATA COLLECTION AND ANALYSIS
Two review authors independently undertook all steps of the identification and data extraction process for multiple-method studies. We assessed risk of bias and applicability using our own modified and extended version of the QUality In Prognosis Studies (QUIPS) tool. We compared different techniques, exact promoter regions (5'-cytosine-phosphate-guanine-3' (CpG) sites) and thresholds for interpretation within studies by examining hazard ratios. We performed meta-analyses for comparisons of the three most commonly examined methods (immunohistochemistry (IHC), methylation-specific polymerase chain reaction (MSP) and pyrosequencing (PSQ)), with ratios of hazard ratios (RHR), using an imputed value of the correlation between results based on the same individuals.
MAIN RESULTS
We included 32 independent cohorts involving 3474 people that compared two or more methods. We found evidence that MSP (CpG sites 76 to 80 and 84 to 87) is more prognostic than IHC for MGMT protein at varying thresholds (RHR 1.31, 95% confidence interval (CI) 1.01 to 1.71). We also found evidence that PSQ is more prognostic than IHC for MGMT protein at various thresholds (RHR 1.36, 95% CI 1.01 to 1.84). The data suggest that PSQ (mainly at CpG sites 74 to 78, using various thresholds) is slightly more prognostic than MSP at sites 76 to 80 and 84 to 87 (RHR 1.14, 95% CI 0.87 to 1.48). Many variants of PSQ have been compared, although we did not see any strong and consistent messages from the results. Targeting multiple CpG sites is likely to be more prognostic than targeting just one. In addition, we identified and summarised 190 articles describing a single method for measuring MGMT promoter methylation status.
AUTHORS' CONCLUSIONS
PSQ and MSP appear more prognostic for overall survival than IHC. Strong evidence is not available to draw conclusions with confidence about the best CpG sites or thresholds for quantitative methods. MSP has been studied mainly for CpG sites 76 to 80 and 84 to 87 and PSQ at CpG sites ranging from 72 to 95. A threshold of 9% for CpG sites 74 to 78 performed better than higher thresholds of 28% or 29% in two of three good-quality studies making such comparisons.
Topics: Adult; Antineoplastic Agents, Alkylating; Bias; Brain Neoplasms; Cohort Studies; CpG Islands; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Glioblastoma; High-Throughput Nucleotide Sequencing; Humans; Immunohistochemistry; Polymerase Chain Reaction; Predictive Value of Tests; Prognosis; Promoter Regions, Genetic; Temozolomide; Tumor Suppressor Proteins
PubMed: 33710615
DOI: 10.1002/14651858.CD013316.pub2 -
Neuro-oncology Sep 2021The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) causes resistance of tumor cells to alkylating agents. It is a predictive biomarker in high-grade... (Meta-Analysis)
Meta-Analysis
MGMT promoter methylation testing to predict overall survival in people with glioblastoma treated with temozolomide: a comprehensive meta-analysis based on a Cochrane Systematic Review.
BACKGROUND
The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) causes resistance of tumor cells to alkylating agents. It is a predictive biomarker in high-grade gliomas treated with temozolomide, however, there is no consensus on which test method, methylation sites, and cutoff values to use.
METHODS
We performed a Cochrane Review to examine studies using different techniques to measure MGMT and predict survival in glioblastoma patients treated with temozolomide. Eligible longitudinal studies included (i) adults with glioblastoma treated with temozolomide with or without radiotherapy, or surgery; (ii) where MGMT status was determined in tumor tissue, and assessed by 1 or more technique; and (iii) where overall survival was an outcome parameter, with sufficient information to estimate hazard ratios (HRs). Two or more methods were compared in 32 independent cohorts with 3474 patients.
RESULTS
Methylation-specific PCR (MSP) and pyrosequencing (PSQ) techniques were more prognostic than immunohistochemistry for MGMT protein, and PSQ is a slightly better predictor than MSP.
CONCLUSIONS
We cannot draw strong conclusions about use of frozen tissue vs formalin-fixed paraffin-embedded in MSP and PSQ. Also, our meta-analysis does not provide strong evidence about the best CpG sites or threshold. MSP has been studied mainly for CpG sites 76-80 and 84-87 and PSQ at CpG sites ranging from 72 to 95. A cutoff threshold of 9% for CpG sites 74-78 performed better than higher thresholds of 28% or 29% in 2 of the 3 good-quality studies. About 190 studies were identified presenting HRs from survival analysis in patients in which MGMT methylation was measured by 1 technique only.
Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Glioblastoma; Glioma; Humans; Methylation; Promoter Regions, Genetic; Temozolomide; Tumor Suppressor Proteins
PubMed: 34467991
DOI: 10.1093/neuonc/noab105 -
BMC Cancer Nov 2021Malignant glioma cell line models are integral to pre-clinical testing of novel potential therapies. Accurate prediction of likely efficacy in the clinic requires that...
BACKGROUND
Malignant glioma cell line models are integral to pre-clinical testing of novel potential therapies. Accurate prediction of likely efficacy in the clinic requires that these models are reliable and consistent. We assessed this by examining the reporting of experimental conditions and sensitivity to temozolomide in glioma cells lines.
METHODS
We searched Medline and Embase (Jan 1994-Jan 2021) for studies evaluating the effect of temozolomide monotherapy on cell viability of at least one malignant glioma cell line. Key data items included type of cell lines, temozolomide exposure duration in hours (hr), and cell viability measure (IC).
RESULTS
We included 212 studies from 2789 non-duplicate records that reported 248 distinct cell lines. The commonest cell line was U87 (60.4%). Only 10.4% studies used a patient-derived cell line. The proportion of studies not reporting each experimental condition ranged from 8.0-27.4%, including base medium (8.0%), serum supplementation (9.9%) and number of replicates (27.4%). In studies reporting IC, the median value for U87 at 24 h, 48 h and 72 h was 123.9 μM (IQR 75.3-277.7 μM), 223.1 μM (IQR 92.0-590.1 μM) and 230.0 μM (IQR 34.1-650.0 μM), respectively. The median IC at 72 h for patient-derived cell lines was 220 μM (IQR 81.1-800.0 μM).
CONCLUSION
Temozolomide sensitivity reported in comparable studies was not consistent between or within malignant glioma cell lines. Drug discovery science performed on these models cannot reliably inform clinical translation. A consensus model of reporting can maximise reproducibility and consistency among in vitro studies.
Topics: Animals; Antineoplastic Agents, Alkylating; Bias; Brain Neoplasms; Cell Line, Tumor; Cell Survival; Glioma; Humans; In Vitro Techniques; Mice; Temozolomide
PubMed: 34794398
DOI: 10.1186/s12885-021-08972-5 -
Medicine Nov 2019Glioblastoma (GB) is one of the most common malignancies with limited standard therapies such as surgery, radiotherapy (RT) plus temozolomide (TMZ). Molecularly targeted... (Comparative Study)
Comparative Study
BACKGROUND
Glioblastoma (GB) is one of the most common malignancies with limited standard therapies such as surgery, radiotherapy (RT) plus temozolomide (TMZ). Molecularly targeted drugs have been investigated among various clinical trials and are expected to develop in the field of tumor therapy, while the efficacy remains uncertain due to limited previous results. Thus, we focus on the evaluation of molecularly targeted drugs to clarify its overall effectiveness in terms of treating newly diagnosed GB.
METHODS
Electronic databases were searched for eligible literatures updated to April 2018. Randomized-controlled trials were included to assess the efficacy and safety of molecularly targeted drugs in patients with newly diagnosed GB. The main outcomes were further calculated including the following parameters: PFS (progression-free survival), OS (overall survival) as well as AEs (adverse events). All data were pooled along with their 95% confidence interval using RevMan software. Sensitivity analyses and heterogeneity were evaluated quantitatively.
RESULTS
The combination of molecularly targeted drugs with TMZ + RT had no significant effects on OS (OR = 0.96, 95%CI = 0.89-1.04, P = .36). Meanwhile, the combination regimen significantly improved the PFS of patients with newly diagnosed GB (OR = 0.86 ,95% CI 0.75-0.98, P = .02). The rate of AEs (OR = 1.68,95%CI = 1.44-1.97, P < .00001) was higher in patients receiving molecularly targeted drugs, which was comparable to the contemporary group.
CONCLUSION
Longer PFS and a higher rate of AEs were observed with the addition of molecularly targeted drugs to standard chemoradiation in patients harboring newly diagnosed GB. Nevertheless, compared with the control arm, the regimen did not significantly prolong OS.
Topics: Brain Neoplasms; Chemoradiotherapy; Female; Glioblastoma; Humans; Male; Molecular Targeted Therapy; Prognosis; Randomized Controlled Trials as Topic; Survival Analysis; Temozolomide; Treatment Outcome
PubMed: 31702627
DOI: 10.1097/MD.0000000000017759