Summary Hazard Ratios Research Articles

Association between Body Mass Index and All-Cause Mortality in Hypertensive Adults: Results from the China Stroke Primary Prevention Trial (CSPPT).

The association between elevated body mass index (BMI) and risk of death has been reported in many studies. However, the association between BMI and all-cause mortality for hypertensive Chinese adults remains unclear. We conducted a post-hoc analysis using data from the China Stroke Primary Prevention Trial (CSPPT). Cox regression analysis was performed to determine the significance of the association of BMI with all-cause mortality. During a mean follow-up duration of 4.5 years, 622 deaths (3.0%) occurred among the 20,694 participants aged 45–75 years. A reversed J-shaped relationship was observed between BMI and all-cause mortality. The hazard ratios (HRs) for underweight (<18.5 kg/m2), overweight (24.0–27.9 kg/m2), and obesity (≥28.0 kg/m2) were calculated relative to normal weight (18.5–23.9 kg/m2). The summary HRs were 1.56 (95% CI, 1.11–2.18) for underweight, 0.78 (95% CI 0.64–0.95) for overweight and 0.64 (95% CI, 0.48–0.85) for obesity. In sex-age-specific analyses, participants over 60 years of age had optimal BMI in the obesity classification and the results were consistent in both males and females. Relative to normal weight, underweight was associated with significantly higher mortality. Excessive weight was not associated with increased risk of mortality. Chinese hypertensive adults had the lowest mortality in grade 1 obesity.

Clinical and prognostic value of preoperative hydronephrosis in upper tract urothelial carcinoma: a systematic review and meta-analysis

Background. Epidemiological studies have reported various results relating preoperative hydronephrosis to upper tract urothelial carcinoma (UTUC). However, the clinical significance and prognostic value of preoperative hydronephrosis in UTUC remains controversial. The aim of this study was to provide a comprehensive meta-analysis of the extent of the possible association between preoperative hydronephrosis and the risk of UTUC.Methods. We searched PubMed, ISI Web of Knowledge, and Embase to identify eligible studies written in English. Summary odds ratios (ORs) or hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using fixed-effects or random-effects models. Results. Nineteen relevant studies, which had a total of 5,782 UTUC patients enrolled, were selected for statistical analysis. The clinicopathological and prognostic relevance of preoperative hydronephrosis was evaluated in the UTUC patients. The results showed that all tumor stages, lymph node status and tumor location, as well as the risk of cancer-specific survival (CSS), overall survival (OS), recurrence-free survival (RFS) and metastasis-free survival (MFS) were significantly different between UTUC patients with elevated preoperative hydronephrosis and those with low preoperative hydronephrosis. High preoperative hydronephrosis indicated a poor prognosis. Additionally, significant correlations between preoperative hydronephrosis and tumor grade (high grade vs. low grade) were observed in UTUC patients; however, no significant difference was observed for tumor grading (G1 vs. G2 + G3 and G1 + G2 vs. G3). In contrast, no such correlations were evident for recurrence status or gender in UTUC patients.Conclusions. The results of this meta-analysis suggest that preoperative hydronephrosis is associated with increased risk and poor survival in UTUC patients. The presence of preoperative hydronephrosis plays an important role in the carcinogenesis and prognosis of UTUC.

The Prognostic Value of Tumor-Infiltrating Lymphocytes in Breast Cancer: A Systematic Review and Meta-Analysis.

BackgroundThe prognostic values of tumor-infiltrating lymphocytes (TILs) and TILs subsets in breast cancer (BC) are uncertain.MethodsA systematic literature search (MEDLINE, Web of Science, EMBASE, and the Cochrane Library to August 2014) was conducted for studies which met the eligibility criteria. The primary clinical outcome was defined as disease-free survival (DFS), overall survival (OS), and BC-specific survival (BCSS). Random or fixed-effects model was adopted to estimate the summary hazard ratio (HR).ResultsTwenty-five published studies comprising 22,964 patients were reviewed. Pooled analysis indicated that TILs were not prognostic markers for DFS and OS in overall population, but related to improved DFS (HR, 0.82; 95% CI, 0.76–0.88) and OS (HR, 0.79; 95% CI, 0.71–0.87) in triple negative breast cancer (TNBC) patients. For TILs subsets, CD8+ lymphocytes were associated with improved DFS (HR, 0.69; 95% CI, 0.56–0.84) and BCSS (HR, 0.78; 95% CI, 0.71–0.86) in overall population, while FOXP3+ lymphocytes were associated with reduced DFS (HR, 1.47; 95% CI, 1.01–2.05) and OS (HR, 1.50; 95% CI, 1.15–1.97). In estrogen receptor (ER) negative patients, CD8+ lymphocytes was also related to better BCSS. In addition, the high density of CD20+, CD3+ or low level of PD-1+ or γδ T lymphocytes indicated increased OS in limited studies.ConclusionTILs and TILs subsets are promising prognostic biomarkers in breast cancer, especially in TNBC.

HbA1c and Risks of All-Cause and Cause-Specific Death in Subjects without Known Diabetes: A Dose-Response Meta-Analysis of Prospective Cohort Studies.

Whether HbA1c levels are associated with mortality in subjects without known diabetes remains controversial. Moreover, the shape of the dose–response relationship on this topic is unclear. Therefore, a dose–response meta-analysis was conducted. PubMed and EMBASE were searched. Summary hazard ratios (HRs) were calculated using a random-effects model. Twelve studies were included. The summary HR per 1% increase in HbA1c level was 1.03 [95% confidence interval (CI) = 1.01–1.04] for all-cause mortality, 1.05 [95% CI = 1.02–1.07) for cardiovascular disease (CVD) mortality, and 1.02 (95% CI = 0.99–1.07) for cancer mortality. After excluding subjects with undiagnosed diabetes, the aforementioned associations remained significant for CVD mortality only. After further excluding subjects with prediabetes, all aforementioned associations presented non-significance. Evidence of a non-linear association between HbA1c and mortality from all causes, CVD and cancer was found (all Pnon-linearity < 0.05). The dose–response curves were relatively flat for HbA1c less than around 5.7%, and rose steeply thereafter. In conclusion, higher HbA1c level is associated with increased mortality from all causes and CVD among subjects without known diabetes. However, this association is driven by those with undiagnosed diabetes or prediabetes. The results regarding cancer mortality should be treated with caution due to limited studies.

Effect of Body Mass Index on Overall Survival of Pancreatic Cancer: A Meta-Analysis.

Although obesity has been identified as a risk factor for pancreatic cancer, the important question of whether obesity influences the prognosis of pancreatic cancer has not been explicated thoroughly. We therefore performed a meta-analysis to investigate the association between body mass index (BMI) and survival outcomes of patients with pancreatic cancer.Studies that described the relationship between BMI and overall survival (OS) of pancreatic cancer were searched in PubMed, Embase, Ovid, and Cochrane Library Databases from the earliest available date to May 12, 2015. Hazard ratios (HRs) for OS in each BMI category from individual studies were extracted and pooled by a random-effect model. Dose–response meta-analysis was also performed to estimate summary HR and 95% confidence interval (CI) for every 5-unit increment. Publication bias was evaluated by Begg funnel plot and Egger linear regression test.Ten relevant studies involving 6801 patients were finally included in the meta-analysis. Results showed that obesity in adulthood significantly shortened OS of pancreatic cancer patients (HR: 1.29, 95% CI: 1.17–1.41), whereas obesity at diagnosis was not associated with any increased risk of death (HR: 1.10, 95% CI: 0.78–1.42). For every 5-kg/m2 increment in adult BMI, the summary HR was 1.11 (95% CI: 1.05–1.18) for death risk of pancreatic cancer. However, no dose–response relationship was found in the BMI at diagnosis. Egger regression test and Begg funnel plot both revealed no obvious risk of publication bias.In conclusion, increased adult BMI is associated with increased risk of death for pancreatic cancer patients, which suggested that obesity in adulthood may be an important prognostic factor that indicates an abbreviated survival from pancreatic cancer. More studies are needed to validate this finding, and the mechanism behind the observation should be evaluated in further studies.

Prognostic Effect of the Nocturnal Blood Pressure Fall in Hypertensive Patients: The Ambulatory Blood Pressure Collaboration in Patients With Hypertension (ABC-H) Meta-Analysis.

The prognostic importance of the nocturnal systolic blood pressure (SBP) fall, adjusted for average 24-hour SBP levels, is unclear. The Ambulatory Blood Pressure Collaboration in Patients With Hypertension (ABC-H) examined this issue in a meta-analysis of 17 312 hypertensives from 3 continents. Risks were computed for the systolic night-to-day ratio and for different dipping patterns (extreme, reduced, and reverse dippers) relative to normal dippers. ABC-H investigators provided multivariate adjusted hazard ratios (HRs), with and without adjustment for 24-hour SBP, for total cardiovascular events (CVEs), coronary events, strokes, cardiovascular mortality, and total mortality. Average 24-hour SBP varied from 131 to 140 mm Hg and systolic night-to-day ratio from 0.88 to 0.93. There were 1769 total CVEs, 916 coronary events, 698 strokes, 450 cardiovascular deaths, and 903 total deaths. After adjustment for 24-hour SBP, the systolic night-to-day ratio predicted all outcomes: from a 1-SD increase, summary HRs were 1.12 to 1.23. Reverse dipping also predicted all end points: HRs were 1.57 to 1.89. Reduced dippers, relative to normal dippers, had a significant 27% higher risk for total CVEs. Risks for extreme dippers were significantly influenced by antihypertensive treatment (P<0.001): untreated patients had increased risk of total CVEs (HR, 1.92), whereas treated patients had borderline lower risk (HR, 0.72) than normal dippers. For CVEs, heterogeneity was low for systolic night-to-day ratio and reverse/reduced dipping and moderate for extreme dippers. Quality of included studies was moderate to high, and publication bias was undetectable. In conclusion, in this largest meta-analysis of hypertensive patients, the nocturnal BP fall provided substantial prognostic information, independent of 24-hour SBP levels.

Burden of cancer associated with type 2 diabetes mellitus in Japan, 2010-2030.

Diabetes mellitus constitutes a major disease burden globally, and the prevalence of diabetes continues to increase worldwide. We aimed to estimate the burden of cancer associated with type 2 diabetes mellitus in Japan between 2010 and 2030. In this study, we estimated the population attributable fraction of cancer risk associated with type 2 diabetes in 2010 and 2030 using the prevalence estimates of type 2 diabetes in Japan from 1990 to 2030, summary hazard ratios of diabetes and cancer risk from a pooled analysis of eight large‐scale Japanese cohort studies, observed incidence/mortality of cancer in 2010 and predicted incidence/mortality for 2030 derived from the age–period–cohort model. Our results showed that between 2010 and 2030, the total numbers of cancer incidence and mortality were predicted to increase by 38.9% and 10.5% in adults aged above 20 years, respectively. In the number of excess incident cancer cases associated with type 2 diabetes, an increase of 26.5% in men and 53.2% in women is expected between 2010 and 2030. The age‐specific analysis showed that the population attributable fraction of cancer will increase in adults aged >60 years over time, but will not change in adults aged 20–59 years. In conclusion, this study suggests a modest but steady increase in cancers associated with type 2 diabetes.

The prognostic value of the miR-200 family in ovarian cancer: a meta-analysis.

To assess the association between miR-200 family expression and overall survival/progression-free survival in women with ovarian cancer. A systematic literature search, up to September 2015, in PubMed, EMBASE and Cochrane Library was performed to identify articles that assessed the association between miR-200 family expression and the survival of women with ovarian cancer. Summary hazard ratios and 95% confidence interval were calculated to estimate the effect. A total of seven articles, consisting of 553 women, were included in this meta-analysis. Overall, significantly improved overall survival/progression-free survival were observed with higher expression of the miR-200 family in women with ovarian cancer (overall survival, hazard ratio = 0.34, 95% confidence interval 0.20-0.58; progression-free survival, hazard ratio = 0.64, 95% confidence interval 0.50-0.82). Subgroup analysis revealed that there was a significant association between enhanced expression of the miR-200c and improved overall survival (hazard ratio = 0.20, 95% confidence interval 0.10-0.42) and progression-free survival (hazard ratio = 0.30, 95% confidence interval 0.11-0.81). Moreover, in the Asian population, a significant association was found between higher expression of the miR-200 family and improved overall survival (hazard ratio = 0.20, 95% confidence interval 0.09-0.45). High expression of miR-200c may predict improved survival in women with ovarian cancer and high expression of the miR-200 family significantly improves overall survival for Asian women.

Use of beta-blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers and breast cancer survival: Systematic review and meta-analysis.

Breast cancer (BC) is the second leading cause of cancer death among women in Western Countries. Beta-blocker (BB) drugs, angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) were suggested to have a favorable role in the development and progression of BC. We have performed a meta-analysis to clarify the potential benefits of these drugs on BC survival. A total number of 46 265 BC patients from eleven papers were included, ten independent studies on BB use and seven on ACEi/ARB use. The summary hazard ratio (SHR) was estimated by pooling the study-specific estimates with random effects models and maximum likelihood estimation. We assessed the homogeneity of the effects across studies and evaluated between-study heterogeneity by meta-regression and sensitivity analyses. We found a significant improvement in BC specific survival for patients treated with BB drugs at the time of BC diagnosis (SHR: 0.44; 95%CI: 0.26-0.73 with I(2) = 78%). We also observed a borderline significant improvement in disease free survival for subjects treated with BB (SHR: 0.71, 95%CI: 0.19-1.03). No association of ACEi/ARB use with disease free and overall survival was found. In conclusion, we report epidemiological evidence that BB improve BC-specific survival. Clinical trials addressing this hypothesis are warranted.

Age at Menarche, Level of Education, Parity and the Risk of Hysterectomy: A Systematic Review and Meta-Analyses of Population-Based Observational Studies.

BackgroundAlthough rates have declined, hysterectomy is still a frequent gynaecological procedure. To date, there has been no systematic quantification of the relationships between early/mid-life exposures and hysterectomy. We performed a systematic review and meta-analyses to quantify the associations between age at menarche, education level, parity and hysterectomy.MethodsEligible studies were identified by searches in PubMed and Embase through March 2015. Study-specific estimates were summarised using random effects meta-analysis. Heterogeneity was explored using sub-group analysis and meta-regression.ResultsThirty-two study populations were identified for inclusion in at least one meta-analysis. Each year older at menarche was associated with lower risk of hysterectomy—summary hazard ratio 0.86 (95% confidence interval: 0.78, 0.95; I2 = 0%); summary odds ratio 0.88 (95% confidence interval: 0.82, 0.94; I2 = 61%). Low education levels conferred a higher risk of hysterectomy in the lowest versus highest level meta-analysis (summary hazard ratio 1.87 (95% confidence interval: 1.25, 2.80; I2 = 86%), summary odds ratio 1.51 (95% confidence interval: 1.35, 1.69; I2 = 90%)) and dose-response meta-analysis (summary odds ratio 1.17 (95% confidence interval: 1.12, 1.23; I2 = 85%) per each level lower of education). Sub-group analysis showed that the birth cohort category of study participants, the reference category used for level of education, the year the included article was published, quality of the study (as assessed by the authors) and control for the key variables accounted for the high heterogeneity between studies in the education level meta-analyses. In the meta-analyses of studies of parity and hysterectomy the results were not statistically significant.ConclusionsThe present meta-analyses suggest that the early life factors of age at menarche and lower education level are associated with hysterectomy, although this evidence should be interpreted with some caution due to variance across the included studies.

Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: A systematic review and meta-analysis.

Immune checkpoint inhibitors (ICIs) rely on the presence of ongoing immune response to exert their antitumor effect. Little is known whether an age-related decline in immune function negatively influences antitumor response and in so doing diminishes the efficacy of ICIs in elderly subjects. We performed a meta-analysis to compare the efficacy of ICIs between younger and older patients. PubMed and the ASCO databases were searched up to September 2015. We included randomized controlled trials (RCTs) of ICIs (ipilimumab, tremelimumab, nivolumab and pembrolizumab) reporting subgroup comparison of overall survival (OS) and/or progression-free survival (PFS) based on age cutoffs. The summary hazard ratio (HR) and 95% confidence interval (CI) were calculated. A total of 5265 patients from nine RCTs of ICI were included. When patients are dichotomized into younger and older groups with an age cut-off of 65-70 years, ICIs improved OS in both younger (HR, 0.75; 95% CI, 0.68-0.82) and older (HR, 0.73; 95% CI, 0.62-0.87) groups. An improvement in PFS was observed in younger (HR, 0.58; 95% CI, 0.40-0.84) and older (HR, 0.77; 95% CI, 0.58-1.01) patients. Subgroup analyses according to ICI and tumor type showed a consistent survival benefit in both younger and older groups except for the subgroup of older patients treated in 4 trials of anti-programmed cell death protein-1 (PD-1) monoclonal antibody (HR, 0.86; 95% CI, 0.41-1.83). A benefit in OS with ICIs was significant in both younger and older patients with a cut-off age of 65-70 years.

Abstract PD1-01: Impact of statin use on cancer recurrence and mortality in patients with breast cancer: A systematic review and meta-analysis

Abstract Background: Statins have been described as having an association with a decreased risk of breast cancer. They have also shown antineoplastic properties in preclinical studies. Statins inhibit the enzyme 'HMG CoA reductase' and the expression of this enzyme in cancer cells has been implicated as an adverse prognostic factor in patients with breast cancer. Methods: We performed a systemic review of literature through April 2015 and utilized PubMed and Embase to identify studies that described an association between statin use and survival in breast cancer. Studies which did not report a comparison of survival using Kaplan-Meier curves were excluded. Summary hazard ratio (HR) with 95% confidence intervals (CI) was estimated using the random effects model, and heterogeneity was measured using the inconsistency index (I2). Results: After reviewing 637 abstracts, 12 studies which included a total of 87951 patients were identified and data was extracted. 8 studies provided a summary statistic for the association of statins with recurrence-free survival (RFS) in patients with breast cancer and were included in a meta-analysis. Statin use was associated with improved RFS (N= 29729 patients, HR 0.66; 95% CI 0.53- 0.84) with moderate heterogeneity (I2= 48%). Furthermore, this survival benefit appeared to be confined to use of lipophilic statins (3 studies, HR 0.72; 95% CI 0.59- 0.89) as hydrophilic statin use was not associated with improvement in RFS (3 studies, HR 0.80; 95% CI 0.44- 1.46). A meta-analysis of 5 studies showed no significant association between the use of statins on breast cancer-specific survival (CSS) (N= 60686 patients, HR 0.71; 95% CI 0.49- 1.03, I2= 84%). We also found no association between statin use and overall survival (OS) (5 studies and 22283 patients, HR 0.83; 95% CI 0.58- 1.19, I2= 62%). Conclusions: Statin use, or more specifically, lipophilic statin use is associated with an improved recurrence-free survival for patients with breast cancer. However, there was no effect of statin use on either cancer-specific survival or overall survival. These benefits need to be assessed in a prospective randomized cohort and the choice of statin, dose and biomarkers that may predict the efficacy of these drugs will need to be identified. Characteristics of included studiesNameYearCountryImpact on RFSImpact on CSSImpact on OSSample SizeMedian follow-up (in years)Desai2015USANA0.59 [0.32, 1.06]NA7,88311.5Cardwell2015UKNA0.84 [0.68, 1.04]0.84 [0.72, 0.97]17,8805.7Murtola2014FinlandNA0.46 [0.38, 0.55]NA31,1143.25Boudreau2014USA0.78 [0.56, 1.08]NANA4,2166.3Sendur2014TurkeyP 0.004P 0.005P = 0.0051,1724Brewer2013USA0.49 [0.28-0.84]0.85 [0.46, 1.57]0.80 [0.43, 1.49]724NANickels2013Germany0.83 [0.54,1.24]0.89 [0.52, 1.49]1.21 [0.87, 1.69]3,085*5.3Zeichner2013USA1.42 [0.42, 4.81]NA1.5 [0.07, 32.02]3003.5Chae2011USA0.40 [0.24, 0.67]NANA7034.5Ceacareanu2011USA0.27 [0.10, 0.71]NA0.23 [0.08, 0.66]2942.5Ahern2011Denmark0.80 [0.64, 1.00]NANA18,7696.8Kwan2008USA0.67 [0.39, 1.13]NANA1,8115*= sample size for RFS: 2912, Abbreviations: RFS: recurrence-free survival, CSS: cancer-specific survival, OS: overall survival (expressed in hazard ratio and 95% confidence intervals) Citation Format: Manthravadi S, Shrestha A, Madhusudhana S. Impact of statin use on cancer recurrence and mortality in patients with breast cancer: A systematic review and meta-analysis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD1-01.

Irinotecan chemotherapy combined with fluoropyrimidines versus irinotecan alone for overall survival and progression-free survival in patients with advanced and/or metastatic colorectal cancer.

Chemotherapy is the treatment of choice in patients with advanced or metastatic colorectal cancer (CRC) where surgical resection of metastases is not an option. Both irinotecan (IRI) and fluoropyrimidines are often included in first- or second- line chemotherapy treatment regimens in such patients. However, it is not clear whether combining these agents is superior to irinotecan alone. To compare the efficacy and safety of two chemotherapeutic regimens, irinotecan monotherapy or irinotecan in combination with fluoropyrimidines, for patients with advanced CRC when administered in the first or second-line settings. We searched the following electronic databases to identify randomized controlled trials: Cochrane Colorectal Cancer Group Specialised Register (January 13, 2016), Cochrane Central Register of Controlled Trials (CENTRAL)(The Cochrane Library Issue 12, 2016), Ovid MEDLINE (1950 to January 13, 2016), Ovid EMBASE (1974 to January 13, 2016), registers of controlled trials in progress, references cited in relevant publications and conference proceedings in related fields (BioMed Central and Medscape's Conference). The key authors or investigators of all eligible studies, and professionals in the field were contacted when necessary. The search from January 2016 identified one eligible study, an ongoing trial currently presented as an abstract, to be considered in an update of this review. Randomized controlled trials (RCTs) investigating the efficacy and safety of IRI chemotherapy combined with fluoropyrimidine compared with IRI alone for the treatment of patients with advanced CRC, regardless of treatment line settings. Study eligibility and methodological quality were assessed independently by the two authors, and any disagreement was solved by a third author. The data collected from the studies were reviewed qualitatively and quantitatively using the Cochrane Collaboration statistical software RevMan 5.3. Five studies were included in this review with a total of 1,726 patients. The top-up search resulted in an additional ongoing trial, the results of which have not been incorporated in this review. Among five included studies, no reduction in all-cause mortality was observed in the combination arm, with a summary hazard ratio (HR) of 0.91 (95% CI: 0.81-1.02). Longer progression-free survival was observed in those treated with the combination chemotherapy (HR: 0.68, 95% CI: 0.53-0.87), however, this result may have been driven by findings from the single first-line treatment setting study.The quality of evidence for overall survival was low and for progression-free survival was moderate, mainly due to study limitation from the lack of information on randomisation methods and allocation concealment.There were higher risks of toxicity outcomes grade 3 or 4 diarrhoea and grade 1 or 2 alopecia, and a lower risk of grade 3 or 4 neutropenia in controls compared to the invervention group. Evidence for toxicity has been assessed to be low to moderate quality. There was no overall survival benefit of the irinotecan and fluoropyrimidine treatment over irinotecan alone, thus both regimens remain reasonable options in treating patients with advanced or metastatic CRC. Given the low and moderate quality of the evidence, future studies with sufficient numbers of patients in each treatment arms are needed to clarify the benefit observed in progression-free survival with combination irinotecan and fluoropyrimidines.

The Efficacy of Single-Agent Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Biologically Selected Patients with Non-Small-Cell Lung Cancer: A Meta-Analysis of 19 Randomized Controlled Trials

Objective: To determine the efficacy of first-generation single-agent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in advanced non-small-cell lung cancer patients with known EGFR mutation status, we undertook this pooled analysis. Method: We searched for randomized controlled trials (RCTs) in Medline, Embase, the Cochrane Controlled Trials Register, the Science Citation Index, and the American Society of Clinical Oncology annual meetings. Results: Out of 2,129 retrieved articles, 19 RCTs enrolling 2,016 patients with wild-type EGFR tumors and 1,034 patients with mutant EGFR tumors were identified. For these EGFR mutant patients, single-agent EGFR-TKI therapy improved progression-free survival (PFS) over chemotherapy: the summary hazard ratios (HRs) were 0.41 (p < 0.001) for the first-line setting and 0.46 (p = 0.02) for the second-/third-line setting. For those EGFR wild-type patients, single-agent EGFR-TKI therapy did not do as well as chemotherapy in the first-line setting (HR = 1.65, p = 0.03) and in the second-/third-line setting (HR = 1.27, p = 0.006). No statistically significant difference was observed in terms of overall survival (OS). Using platinum-based doublet chemotherapy as a common comparator, indirect comparison showed the superior efficacy of single-agent EGFR-TKI therapy over EGFR-TKIs added to chemotherapy in PFS [HR = 1.35 (1.03, 1.77), p = 0.03]. Additionally, a marginal trend towards the same direction was found in the OS analysis [HR = 1.16 (0.99, 1.35), p = 0.06]. Interestingly, for those EGFR wild-type tumors, single-agent EGFR-TKI therapy was inferior to EGFR-TKIs added to chemotherapy in PFS [HR = 0.38 (0.33, 0.44), p < 0.001] and OS [HR = 0.83 (0.71, 0.97), p = 0.02]. Conclusions: For these EGFR mutant patients, single-agent EGFR-TKI therapy prolonged PFS over chemotherapy. However, single-agent EGFR-TKI therapy was inferior to chemotherapy in PFS for those EGFR wild-type patients. Single-agent EGFR-TKI therapy could improve PFS over the combination of EGFR-TKIs and chemotherapy in these EGFR mutant patients. However, EGFR-TKIs combined with chemotherapy could provide additive PFS and OS benefit over single-agent EGFR-TKI therapy in those EGFR wild-type patients.

Thalidomide-based Regimens for Elderly and/or Transplant Ineligible Patients with Multiple Myeloma: A Meta-analysis.

Background:Thalidomide is an immunomodulatory and anti-angiogenic drug that has shown promise in patients with myeloma. Trials comparing efficacy of standard melphalan and prednisone (MP) therapy with MP plus thalidomide (MPT) in transplant-ineligible or elderly patients with multiple myeloma (MM) have provided conflicting evidence. This meta-analysis aimed to determine the efficacy and toxicity of thalidomide in previously untreated elderly patients with myeloma.Methods:Medline, the Cochrane Controlled Trials register, conference proceedings of the American Society of Hematology (1995–2014), the American Society of Clinical Oncology (1995–2014), and CBM, VIP, and CNKI databases were searched for randomized control trials with the use of the medical subject headings “MM” and “thalidomide”. Trials were assessed by two reviewers for eligibility. Meta-analysis was conducted using a fixed effects model. Sensitivity analysis was performed to test the robustness of the findings.Results:Overall, seven trials were identified, covering a total of 1821 subjects. The summary hazard ratio (thalidomide vs. control) was 0.82 (95% confidence interval [CI]: 0.72–0.94) for overall survival (OS), and 0.65 (95% CI: 0.58–0.73) for progression-free survival, in favor of thalidomide treated group. The risk ratio of complete response with induction thalidomide was 3.48 (95% CI: 2.24–5.41). A higher rate of III/IV adverse events were observed in MPT arm compared with the MP arm. However, analysis of sub-groups administering anticoagulation as venous thromboembolism prophylaxis suggested no difference in relative risk of thrombotic events between two arms (RR = 1.47, 95% CI: 0.43–5.07, P = 0.54). Further analysis of trials on the treatment effects of MPT versus MP on adverse events-related mortality showed no statistical difference between two arms (RR = 1.24, 95% CI: [0.95–1.63], P = 0.120).Conclusion:Thalidomide appears to improve the OS of elderly and/or transplant-ineligible patients with MM when it is added to standard MP therapy.

Increased intake of vegetables, but not fruits, may be associated with reduced risk of hip fracture: A meta-analysis.

Association between dietary intake of vegetables and fruits and risk of hip fracture has been reported for many years. However, the findings remain inconclusive. We conducted a meta-analysis to evaluate the relationship between intake of vegetables and fruits, and risk of hip fracture. Literature search for relevant studies was performed on PubMed and Embase databases. Five observational studies were included in the meta-analysis. Summary hazard ratio (HR) with corresponding 95% confidence interval (CI) was calculated from pooled data using the random-effects model irrespective of heterogeneity. Sensitivity and subgroup analysis were performed to explore possible reasons for heterogeneity. The summary HR for hip fracture in relation to high intake vs. low intake of only vegetables, only fruits, and combined intake of fruits and vegetables, was 0.75 (95% CI, 0.61–0.92), 0.87 (95% CI, 0.74–1.04), and 0.79 (95% CI, 0.61–1.03), respectively. Subgroup analyses based on study design, geographical location, number of cases, and gender showed similar results. Increased intake of vegetables, but not fruits, was found to be associated with a lower risk of hip fracture. Large prospective clinical trials with robust methodology are required to confirm our findings.

Factors associated with the time to the first wheezing episode in infants: a cross-sectional study from the International Study of Wheezing in Infants (EISL).

Male gender, asthmatic heredity, perinatal tobacco smoke exposure and respiratory infections have been associated with wheeze in the first years of life, among other risk factors. However, information about what factors modify the time to the first episode of wheeze in infants is lacking. The present study analyses which factors are associated with shorter time to the first episode of wheeze in infants. Parents of 11- to 24-month-old children were surveyed when attending their health-care centres for a control visit. They answered a questionnaire including the age in months when a first wheeze episode (if any) had occurred (outcome variable). The study was performed in 14 centres in Latin America (LA) and in 8 centres in Europe (EU) (at least 1,000 infants per centre). Factors known to be associated with wheezing in the cohort were included in a survival analysis (Cox proportional hazards model). Summary hazard ratios adjusted for all risk factors (aHR) were calculated using the meta-analysis approach with random effects. A total of 15,067 infants had experienced wheezing at least once, out of 35,049 surveyed. Male gender in LA (aHR 1.05, 95% confidence interval (CI) 1.00–1.10, P=0.047), parental asthma in LA and EU (aHR 1.05, 95% CI 1.00–1.11, P=0.037), infant eczema in EU (aHR 1.25, 95% CI 1.12–1.39, P<0.001) and having a cold during the first 3 months in LA and EU (aHR 1.97, 95% CI 1.90–2.04, P<0.001), in LA (aHR 1.98, 95% CI 1.90–2.06, P<0.001) and in EU (aHR 1.91, 95% CI 1.75–2.09, P<0.001) were associated with a shorter period of time to the first episode. Breast feeding for at least 3 months was associated with a longer period, only in LA (aHR 0.91, 95% CI 0.86–0.96, P<0.001). Cold symptoms during the first 3 months is the most consistent factor shortening the time to the first episode of wheezing; breast feeding for ⩾3 months delays it only in LA, whereas eczema shortens it only in EU. Avoiding a common cold in the first months of life could be a good strategy to delay the first wheeze episode; however, cohort studies will help to elucidate this association.

Body mass index and mortality in prostate cancer patients: a dose-response meta-analysis.

Previous studies concerning the association between body mass index (BMI) and mortality in prostate cancer yielded mixed results. We investigated the association by performing a meta-analysis of all available studies. Relevant studies were identified by searching PubMed and EMBASE to August 2015. We calculated the summary hazard ratio (HR) and 95% confidence interval (CI) using random-effects models. We estimated combined HRs associated with defined increments of BMI, using random-effects meta-analysis and dose-response meta-regression models. Thirty-seven cohort studies and one case-control study involving 27 38 000 patients of prostate cancer were selected for meta-analysis. The summary results indicated higher prediagnosis BMI but not postdiagnosis BMI was associated with increased risk of death from prostate cancer. An increment of every 5 kg/m(2) in prediagnosis BMI was associated with a 15% higher prostate cancer-specific mortality (HR=1.15, 95% CI: 1.07-1.23, P<0.01). Prediagnosis or postdiagnosis BMI showed no effect on all-cause mortality in prostate cancer patients. In conclusion, higher prediagnosis BMI is associated with a higher risk of death from prostate cancer. Considering the significant heterogeneity among included studies, these findings require confirmation in future studies.

Abstract A159: Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: A meta-analysis of randomized controlled trials

Abstract Background: Immune checkpoint inhibitors (ICIs) that block inhibitory receptors such as cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), programmed death-1 (PD-1) and its ligand PD-L1 have been a cornerstone of immunotherapy in oncology. Four ICIs are currently approved by the United States Food and Drug Administration (FDA): anti-CTLA-4 monoclonal antibodies (ipilimumab and tremelimumab) and anti-PD1 monoclonal antibodies (nivolumab and pembrolizumab). Immunosenescence, a phenomenon of decreased immune function as a result of age-associated alterations to the immune system, has been described. However, it is still unclear to what extent immunosenescence may affect efficacy of ICIs. We performed a systematic review and meta-analysis to compare efficacy of ICIs between younger and older patients. Methods: We conducted a review of PubMed from January 1966 to May 2015. We limited our search to ICIs approved by the FDA. Search keywords were: ‘‘ipilimumab’’, ‘‘tremelimumab’’, ‘‘nivolumab’’,‘‘pembrolizumab’’. The search was limited to randomized clinical trials (RCTs) published in English. We also searched abstracts and virtual meeting presentations utilizing the same search terms from the American Society of Clinical Oncology (ASCO) conferences held up to May 2015 to identify relevant trials. Clinical trials that met the following criteria were included: (1) phase II and III trials in patients with cancers; (2) random assignment of participants to treatment with ICIs or control (chemotherapy, placebo or best supportive care); and (3) subgroup comparison of overall survival based on age using hazard ratio (HR). A general variance-based method was used to estimate the summary HRs, and their 95% confidence intervals. Statistical heterogeneity in results between trials included in the meta-analysis was examined using Cochrane's Q statistic, and inconsistency was quantified with I2 statistic. The assumption of homogeneity was considered invalid for P values less than 0.10. Summary HRs were calculated using random-effects or fixed-effects models depending on the heterogeneity of included studies. Statistical analyses were performed by using Comprehensive Meta-Analysis software, version 2 (Biostat, Englewood, NJ, USA). Results: A total of 3,322 patients from six phase III RCTs of ICI were included in the analysis with three ipilimumab trials, two nivolumab trials and one tremelimumab trial. The underlying malignancies included were melanoma (4 trials), prostate cancer (1 trial) and non–small-cell lung cancer (1 trial). Five trials used 65 years and one trial used 70 years as an age cut-off to conduct subgroup analyses. For 2,078 younger patients, the pooled HR for OS showed significant difference between ICIs and controls (HR, 0.73; 95% CI, 0.66–0.81; P &amp;lt;0.001). The fixed-effects model was used because there was no significant heterogeneity (Q = 9.86; P = 0.13; I2 = 39.17). For 1,244 older patients, ICIs also significantly improved OS (HR, 0.72; 95% CI, 0.58–0.90; P = 0.004) in comparison with controls. The test for heterogeneity was significant and a random-effects model was used (Q = 18.43; P = 0.02; I2 = 56.59). There was no statistically significant difference between subgroups of younger and older patients concerning the pooled HR for OS (P = 0.93). Conclusions: In this meta-analysis, immune checkpoint inhibitors significantly improved overall survival compared with controls in both younger and older patients. Our data suggest the survival benefit conferred by ICIs is independent of chronological age if patients are dichotomized into younger and older groups with an age cut-off of 65-70 years. Further research is needed to examine the association between efficacy of ICIs and functional changes in immune system with aging. Citation Format: Tomohiro Funakoshi, Hyman Muss, Stergios Moschos. Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: A meta-analysis of randomized controlled trials. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A159.

Gemcitabine plus S-1: a hopeful frontline treatment for Asian patients with unresectable advanced pancreatic cancer.

Gemcitabine-based chemotherapy is widely used for unresectable advanced pancreatic cancer which contains locally advanced and metastatic pancreatic cancer. We performed meta-analysis to examine whether gemcitabine plus S-1 could improve treatment efficacy as first-line chemotherapy for those patients when compared with gemcitabine alone. STATA was used to estimate the summary hazard ratios or odds ratios and their 95% confidence intervals. Heterogeneity among trials was examined by Cochran's χ(2) test. Publication bias was evaluated by Begg's and Egger's tests. Subgroup analysis based on the extent of disease was performed. Four randomized controlled trials including 878 Asian patients were analyzed. In total meta-analysis, gemcitabine plus S-1 significantly improved overall survival (hazard ratio, 0.82; 95% confidence interval, 0.70-0.96; P = 0.015), progression-free survival (hazard ratio, 0.64; 95% confidence interval, 0.55-0.74; P < 0.001), overall response rate (odds ratio, 3.00; 95% confidence interval, 2.04-4.41; P < 0.001) and disease control rate (odds ratio, 1.78; 95% confidence interval, 1.32 to 2.39; P < 0.001), and was associated with more but manageable hematologic (leukocytopenia, neutropenia, thrombocytopenia) and non-hematologic (diarrhea, stomatitis, nausea, rash) adverse events. In subgroup analysis, gemcitabine plus S-1, comparing with gemcitabine, significantly improved overall survival in locally advanced patients (hazard ratio, 0.69; 95% confidence interval, 0.48 to 0.99; P = 0.022) but not in metastatic patients (hazard ratio, 0.75; 95% confidence interval, 0.46-1.23; P = 0.256). This meta-analysis confirmed the survival benefits of gemcitabine plus S-1 as first-line treatment for unresectable advanced pancreatic cancer at least in Asia, while good Eastern Cooperative Oncology group performance status was warranted. Importantly, we highlighted the significant overall survival benefit of gemcitabine plus S-1 in locally advanced patients but not in metastatic patients.