Confidence Intervals For Overall Survival Research Articles

Ferroptosis is a protective factor for the prognosis of cancer patients: a systematic review and meta-analysis

BackgroundCancer is a leading global cause of death. Conventional cancer treatments like surgery, radiation, and chemotherapy have associated side effects. Ferroptosis, a nonapoptotic and iron-dependent cell death, has been identified and differs from other cell death types. Research has shown that ferroptosis can promote and inhibit tumor growth, which may have prognostic value. Given the unclear role of ferroptosis in cancer biology, this meta-analysis aims to investigate its impact on cancer prognosis.MethodsThis systematic review and meta-analysis conducted searches on PubMed, Embase, and the Cochrane Library databases. Eight retrospective studies were included to compare the impact of ferroptosis inhibition and promotion on cancer patient prognosis. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Studies lacking clear descriptions of hazard ratios (HR) and 95% confidence intervals for OS and PFS were excluded. Random-effects meta-analysis and meta-regression were performed on the included study data to assess prognosis differences between the experimental and control groups. Meta-analysis results included HR and 95% confidence intervals.This study has been registered with PROSPERO, CRD 42023463720 on September 27, 2023.ResultsA total of 2,446 articles were screened, resulting in the inclusion of 5 articles with 938 eligible subjects. Eight studies were included in the meta-analysis after bias exclusion. The meta-analysis, after bias exclusion, demonstrated that promoting ferroptosis could increase cancer patients’ overall survival (HR 0.31, 95% CI 0.21–0.44) and progression-free survival (HR 0.26, 95% CI 0.16–0.44) compared to ferroptosis inhibition. The results showed moderate heterogeneity, suggesting that biological activities promoting cancer cell ferroptosis are beneficial for cancer patient’s prognosis.ConclusionsThis systematic review and meta-analysis demonstrated that the promotion of ferroptosis yields substantial benefits for cancer prognosis. These findings underscore the untapped potential of ferroptosis as an innovative anti-tumor therapeutic strategy, capable of addressing challenges related to drug resistance, limited therapeutic efficacy, and unfavorable prognosis in cancer treatment.RegistrationCRD42023463720.

Clinical Characteristics and Prognostic Factors of Endometrial Cancer Patients With Liver Metastasis: A Surveillance, Epidemiology, and End Results Database (SEER)-Based Study of 1,034 Women.

Background There are several patterns of metastatic spread fromendometrial cancer (EC). Although studies have been conducted to study the EC population with distant metastasis in the bone and lungs, there is still a lack of studies on liver metastasis. This study aims toevaluate and assess the clinical features and prognosticfactors of EC patients with liver metastasis. Methodology We conducted a retrospective cohort study adhering to the guidelines for reporting observational research. We utilized the Surveillance, Epidemiology, and End Results database to gather data on female patients diagnosed with EC and reported liver metastasis. We estimated survival curves using the Kaplan-Meier method and evaluated differences in survival using the log-rank test. We also conducted univariable and multivariable Cox proportional hazards regression analyses to determine the hazard ratios with 95% confidence intervals for overall survival (OS) and identify factors that impact survival. Results We analyzed data from 1,034 EC patients with liver metastasis. Median OS after liver metastasis was six months, and cancer-specific survival was seven months.Univariate Cox regression analysis revealed several factors associated with decreased OS in EC patients. These included age (≥60 years), non-endometrioid and sarcoma histological subtypes, absence of surgery, no chemotherapy, and the presence of distant metastasis to the lung, brain, and bone. Conversely, married marital status and white race were linked to a better prognosis. Subsequent multivariate Cox regression analysis identified age (≥60 years), non-endometrioid histological subtype, absence of surgery, no chemotherapy, and the presence of distant metastasis to lung, brain, and bone remaining as independent risk factors for decreased OS. In contrast, the white race still emerged as an independent prognostic factor for better OS. Conclusions Various risk factors, such as age, race, lung, bone, or brain metastasis, as well as chemotherapy and surgery, may influence the prognosis of individuals with primary EC liver metastases.

Efficacy of PD-1 Inhibitors in First-Line Treatment for Advanced Gastroesophageal Junction and Gastric Cancer by Subgroups: A Systematic Review and Meta-Analysis

Background: PD-1 inhibitors have been approved for the first-line treatment of patients with advanced gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma. However, the results of several clinical trials are not entirely consistent, and the dominant population of first-line immunotherapy for advanced gastric/gastroesophageal junction cancer still needs to be precisely determined. Objective: This objective of this study is to evaluate the efficacy of anti-PD-1/PD-L1 therapy in advanced gastric/gastroesophageal junction adenocarcinoma patients through a systematic review and meta-analysis of relevant clinical trials. Method: The PubMed, Embase, and Cochrane Library electronic databases were searched up to August 1, 2022, for clinical trials of anti-PD-1/PD-L1 immunotherapy for the first-line treatment of advanced gastroesophageal cancer. Hazard ratios and 95% confidence intervals for overall survival, progression-free survival, and objective response rates were extracted and pooled for meta-analysis. Prespecified subgroups included the following: agent type, PD-L1 expression, and high microsatellite instability. Results: This study analyzed 5 RCTs involving 3,355 patients. Compared with the chemotherapy group, the combined immunotherapy group had a significantly higher objective response rate (OR = 0.63, 95% CI: 0.55–0.72, p < 0.00001) and prolonged overall survival (HR = 0.82, 95% CI: 0.76–0.88, p < 0.00001) and progression-free survival (HR = 0.75, 95% CI: 0.69–0.82, p < 0.00001). The combination of immunotherapy and chemotherapy prolonged OS in both MSI-H (HR = 0.38, p = 0.002) and MSS (HR = 0.78, p < 0.00001) populations, but there was a significant difference between groups (p = 0.02). However, in improving ORR, the benefit of ICI combined with chemotherapy in the MSS group and MSI-H group was not significantly different between groups (p = 0.52). Combination therapy with ICIs was more effective than chemotherapy alone in prolonging OS in the subgroup with a high CPS, regardless of the CPS cutoff for PD-L1. However, when the cutoff of CPS was 1, the difference between subgroups did not reach statistical significance (p = 0.12), while the benefit ratio of the MSI-H group was higher when the cutoff was 10 (p = 0.004) than when the cutoff value was 5 (p = 0.002). Conclusions: For first-line treatment of advanced gastroesophageal cancer, an ICI combination strategy is more effective than chemotherapy. The subgroup of patients with a CPS ≥10 has a more significant benefit, and CPS ≥10 has the potential to be used as an accurate marker of the dominant population of immuno-combined therapy.

The prognostic ability of immune scoring system Immunoscore in patients with localized colon cancer: A systematic review and meta-analysis.

2565 Background: Assessment of tumor recurrence risk as well as prognosis in resectable colon cancer are still mainly based on the histopathological criteria of tumor invasion reflected in the TNM classification. Robust data in colorectal tumor research show the value of tumor microenvironment and tumor‐infiltrating lymphocytes (TILs) as novel parameters to predict recurrence and survival. The utility of the derived tumor Immunoscore via digital pathology is now being promoted to refine the prognosis of early colon cancer patients together with the TNM staging to guide treatment decisions, but is not yet a recommendation in international consensus guidelines. This study assessed the prognostic value of this diagnostic tool in predicting clinical outcomes. Methods: A systematic literature search using PubMed, Embase, and Cochrane CENTRAL Library was conducted to identify observational or randomized controlled studies from January 2008 and December 2022 according to pre- specified inclusion and exclusion criteria which examined the relationship between Immunoscore and long-term prognosis (overall survival and disease free survival) in patients with localized colon cancer. Hazard ratios with 95% confidence interval for overall survival (OS) and disease-free survival (DFS) were extracted. Pooled estimates of the prognostic ability of Immunoscore were obtained using bi-variate random effects model. Statistical heterogeneity between studies was evaluated with I2 statistics and explored through sensitivity analysis. Results: A total of 5,718 patients from 11 studies were included in the meta-analysis. Moderate heterogeneity between studies for both DFS (I2= 27%) and OS (I2= 33%) was seen. The pooled analysis indicated that compared to those with high Immunoscore, colon cancer patients with low Immunoscore were associated with shorter disease-free survival (HR 1.75, 95% CI 1.53 - 2.49) and overall survival (HR 1.87 95% CI 1.45 – 2.13). In the subgroup analyses, this association was consistent across geographic regions and maximum time of follow up. Conclusions: A low Immunoscore was significantly associated with poorer clinical outcomes in terms of disease-free survival and overall survival. The use of Immunoscore provides valuable estimate of the risk of recurrence in patients with early colon cancer and has the potential to greatly affect treatment decisions in conjunction with the existing risk assessment system.

The correlation between the influencing factors and efficacy of immune checkpoint inhibitor therapy: an umbrella meta-analysis of randomized controlled trials

Objective We performed an umbrella meta-analysis to explore the factors that influence the efficacy of immune checkpoint inhibitor (ICI) therapy. Materials and methods We systematically searched three databases (PubMed, Web of Science and Embase) up to 20 February 2023. Extracting the effect size and 95% confidence intervals for overall survival (OS), progression-free survival (PFS) and the objective response rate (ORR). Results A total of 65 articles were included. We identified the following factors that benefit ICI therapy: smoking status (PFS: 0.72 [0.62, 0.84], p < .001), chemotherapy (PFS: 0.68 [0.58, 0.79], p < .001), expression of programmed cell death ligand 1(PD-L1) (≥1%, ≥5%, or ≥10%) (≥1%: 0.76 [0.71,0.82], p < .001; ≥5%: 0.62 [0.52, 0.74], p < .001; ≥10%: 0.42 [0.30, 0.59], p < .001). We also identified three adverse factors: epidermal growth factor receptor mutations (OS: 1.57 [1.06, 2.32], p = .02), with liver metastases (OS: 1.16 [1.02,1.32], p = .02) and antibiotics (OS: 3.13 [1.25,7.84], p < .001; PFS: 2.54 [1.38, 4.68], p = .003). Conclusion The results of this umbrella meta-analysis first supported pre-existing understandings of the relationship between beneficial and adverse factors with the efficacy of ICI therapy. In addition, the overexpression of PD-L1 may adversely affect patients.

Long-term Survival After Endoscopic Resection For Gastric Cancer: Real-world Evidence From a Multicenter Prospective Cohort

We aimed to clarify the long-term outcomes of endoscopic resection (ER) for early gastric cancers (EGCs) based on pathological curability in a multicenter prospective cohort study. We analyzed the long-term outcomes of 9054 patients with 10,021 EGCs undergoing ER between July 2010 and June 2012. Primary endpoint was the 5-year overall survival (OS). The hazard ratio for all-cause mortality was calculated using the Cox proportional hazards model. We also compared the 5-year OS with the expected one calculated for the surgically resected patients with EGC. If the lower limit of the 95% confidence interval (CI) of the 5-year OS exceeded the expected 5-year OS minus a margin of 5% (threshold 5-year OS), ER was considered to be effective. Pathological curability was categorized into en bloc resection, negative margins, and negative lymphovascular invasion: differentiated-type, pT1a, ulcer negative, ≤2 cm (Category A1); differentiated-type, pT1a, ulcer negative, >2 cm or ulcer positive, ≤3 cm (Category A2); undifferentiated-type, pT1a, ulcer negative, ≤2 cm (Category A3); differentiated-type, pT1b (SM1), ≤3 cm (Category B); or noncurative resections (Category C). Overall, the 5-year OS was 89.0% (95% CI, 88.3%-89.6%). In a multivariate analysis, no significant differences were observed when the hazard ratio of Categories A2, A3, and B were compared with that of A1. In all the pathological curability categories, the lower limit of the 95% CI for the 5-year OS exceeded the threshold 5-year OS. ER can be recommended as a standard treatment for patients with EGCs fulfilling Category A2, A3, and B, as well as A1 (UMIN Clinical Trial Registry, UMIN000005871).

Clinical outcomes and safety of enzalutamide (ENZA) plus androgen-deprivation therapy (ADT) in metastatic hormone-sensitive prostate cancer (mHSPC) in patients aged &lt; 75 and ≥ 75 years: ARCHES post hoc analysis.

5069 Background: Patients with metastatic prostate cancer aged ≥75 years have a poorer prognosis compared with younger patients. In ARCHES (NCT02677896), ENZA + ADT improved radiographic progression-free survival (rPFS), overall survival (OS), and other key secondary endpoints vs. placebo (PBO) + ADT in patients with mHSPC. Final OS results confirmed a long-term survival benefit with ENZA + ADT. This post hoc analysis of ARCHES data investigated OS and other clinical outcomes in patients aged &lt;75 and ≥75 years. Methods: Patients with mHSPC (n=1150) were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume and prior docetaxel use. Subgroup analysis was performed in patients aged &lt;75 and ≥75 years. Efficacy and safety outcomes were compared across treatment arms. Results: Of the ARCHES population, 339 patients (29.5%) were aged ≥75 years (ENZA + ADT, n=170; PBO + ADT, n=169); PBO patients crossing over to ENZA were aged: &lt;75 years, n=133; ≥75 years, n=47. Some differences in baseline characteristics were observed between age groups, such as higher prior docetaxel use in patients aged &lt;75 years (ENZA + ADT, 21.0%; PBO + ADT, 20.4%) vs. those aged ≥75 years (ENZA + ADT, 10.6%; PBO + ADT, 11.2%). When compared to PBO + ADT, ENZA + ADT improved OS and other secondary efficacy endpoints in both age groups without evidence of statistical heterogeneity (Table); however, 95% confidence intervals for OS and rPFS hazard ratios spanned 1 in the older age group. The safety profile of treatment arms was generally similar in both age groups, with a higher incidence of falls, cognitive impairment, and cardiovascular events among elderly patients receiving ENZA + ADT vs. PBO + ADT. Conclusions: This post hoc analysis of ARCHES data demonstrated that ENZA + ADT provides clinical benefit and is generally well-tolerated in patients with mHSPC aged ≥75 years, supporting the therapeutic role of ENZA in these patients. Clinical trial information: NCT02677896. [Table: see text]

Efficacy of FOLFIRI plus cetuximab vs FOLFIRI plus bevacizumab in 1st-line treatment of older patients with RAS wild-type metastatic colorectal cancer: an analysis of the randomised trial FIRE-3

SummaryBackgroundThe evidence on the efficacy of anticancer therapy is limited in older patients with metastatic colorectal cancer (mCRC). This retrospective analysis of phase III FIRE-3 trial assesses the efficacy of FOLFIRI plus either cetuximab or bevacizumab according to the patients’ age and sidedness of primary tumour.MethodsThe study endpoints overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were compared between younger (<65 years) and older (≥65 years) patients, followed by stratification according to primary tumour sidedness. ORR was compared using Fisher´s exact test, OS and PFS were estimated by the Kaplan–Meier method and compared using the log-rank test. Univariate Cox regression analyses assessed hazard ratios and 95% confidence intervals for OS and PFS.ResultsOverall, older patients with RAS WT tumours had a significantly shorter OS when compared to younger patients (25.9 months vs 29.3 months, HR 1.29; P = 0.02). Also the proportion of right-sided tumours was significantly greater in older patients (27.1% vs 17.9%; P = 0.029). Secondary resection rates were numerically higher in younger patients (25.4% vs. 17.6%, P = 0.068) than in older patients. This was primarily seen in the Cetuximab arm, where older patients underwent less likely resection (13.1% vs. 26%; P = 0.02). Older patients with left-sided tumours showed only a trend towards greater efficacy of cetuximab (HR 0.86; P = 0.38). In patients with right-sided primary tumours, older patients did not appear to benefit from cetuximab in contrast to younger patients (≥65 years: 16.6 months vs 23.6 months, HR 1.1; P = 0.87; <65 years: 21.9 months vs 16.4 months HR 1.5; P = 0.31).ConclusionsIn FIRE-3, OS was generally shorter in older patients in comparison to younger patients. This could be explained by the overrepresentation of right-sided tumours and a lower secondary resection rate in older patients. The efficacy of targeted therapy was dependent on tumour sidedness in older patients with RAS WT mCRC.Clinical trialFIRE-3 (NCT00433927).

Predictive and prognostic value of gene mutations in myelodysplastic syndrome treated with hypomethylating agents: a meta-analysis

Although the effect of gene mutations on overall response rate (ORR) and overall survival (OS) in myelodysplastic syndrome (MDS) treated with hypomethylating agents (HMAs) has been explored, the effect is still controversial. We performed this meta-analysis to investigate the effect. The pooled odds ratio (OR) and 95% confidence interval (CI) for ORR and the pooled hazard ratio (HR) and 95%CI for OS were chosen to estimate the effect. The pooled OR of TET2 was 0.73 (95%CI: 0.59–0.91, p = 0.005) and the pooled OR of ASXL1 was 1.38 (95%CI: 1.12–1.71, p = 0.003). As for prognosis, the pooled HR of RUNX1 was 1.45 (95%CI: 1.15–1.85, p = 0.002). The pooled HR of TP53 was 2.30 (95%CI: 1.83–2.90, p < 0.001) and the pooled HR of U2AF1 was 1.41 (95%CI: 1.15–1.74, p = 0.001). There was no statistical difference shown in other genes. Therefore, TET2 mutation and ASXL1 wild-type were the predictor of better response to HMAs. Mutations of TP53, RUNX1, and U2AF1 were associated with poor prognosis in MDS.

Impact of Treatment with Iron Chelation Therapy in Lower-Risk MDS Patients Participating in the European Leukemianet MDS (EUMDS) Registry

BackgroundIron overload/toxicity due to red blood cell transfusions (RBCT) is associated with morbidity and mortality in various patient groups, including patients with lower-risk myelodysplastic syndrome (LR-MDS). Many studies suggested improved overall survival (OS) after iron chelation therapy (ICT), but most studies suffer from methodological problems. In daily practice, many transfused LR-MDS patients receive ICT according to (inter)national guidelines to counteract the effects of RBCT. The value of ICT in LR-MDS remains unproven. The aim of this study is to assess the effect of ICT on OS in LR-MDS patients.MethodsThe EUMDS registry, prospectively collects observational data on LR-MDS patients from 142 centers in 16 countries in Europe and Israel. Three iron chelators are available in Europe for treatment of secondary iron overload, but availability varies between countries. We first assessed the impact of treatment of the three iron chelators on OS. Secondly, we compared the chelated patients with a contemporary control group within the EUMDS registry. The control group consisted of patients who met the eligibility criteria for using ICT (≥15 RBC units, RBCT intensity of ≥1 RBC unit/month during a six-month period between visits, or serum ferritin ≥1000 µg/L), but who did not receive ICT. A Cox proportional hazards model was used, treating receipt of ICT as an time-varying variable. Finally, all transfused chelated and non-chelated patients were compared with a propensity-score matched model (3:1 nearest matching with replacement) in which more confounding factors could be added to Cox model in order to deal with confounding as adequately as possible.ResultsThe EUMDS registry included 2205 patients as of July 2017. At this point, 205 patients received ICT. Table 1 shows the follow-up duration for all patients. Of the chelated patients, 154 received deferasirox as initial chelator, 39 deferoxamine, and 12 deferiprone. Nineteen patients switched from one chelator to another, but usually the treatment period of the 2nd chelator was short compared to the 1st chelator (data not shown). The median time on chelation for all 205 patients was 13 months (range 3-42). Patients receiving ICT were on average younger, had better performance scores and less comorbidities compared to the control group (table 2).Comparison of three iron chelators The OS from the start of ICT for 154 patients treated with deferasirox is not significantly different compared to deferoxamine (n=39; p=0.058). The Hazard Ratio (HR) and 95% confidence intervals (CI) for OS (deferasirox as reference group) adjusted for age, sex, comorbidity, performance status, and cumulative number of RBCT for deferoxamine was 1.95 (0.85-4.50) and for deferiprone 0.38 (0.04-4.06) (Table 2).Comparison with non-chelated control group The control group consisted of 657 non-chelated patients (table 2). The crude HR and 95% CI for OS for all chelated patients was 0.66 (0.52-0.85) (non-chelated group as reference). After adjusting for age, sex, comorbidity, performance status, RBCT intensity, cumulative number of RBCT, and IPSS-R, the HR was 0.75 (0.50-1.15). When the analysis was restricted to the patients treated with deferasirox, the crude HR was 0.61 (0.46-0.81) and the adjusted HR was 0.79 (0.51-1.22).Propensity-matched model The chelated and non-chelated patients were matched for age, RBCT intensity, ferritin level, comorbidity, and performance status. 128 chelated patients and 223 controls could be matched, the overlap of propensity scores in both groups was good (data not shown). The crude HR and 95% CI for OS for the chelated group (non-chelated group as reference) was 0.77 (0.55-1.07). When correcting for age, sex, comorbidity, performance status, RBCT intensity, cumulative RBCT number, and IPSS-R, the HR was 0.62 (0.39-0.98). When we again restricted the analysis to deferasirox, the crude HR was 0.71 (0.48-1.06) and the adjusted HR was 0.58 (0.33-1.01).ConclusionOS of LR-MDS patients treated with ICT, was better compared to a large, control group and significantly better in a propensity-score matched model. In the absence of randomized, controlled trials proving the survival advantage of ICT, our large, prospective, observational study of clinical practice in Europe and Israel provides sound evidence of a beneficial effect of ICT on OS. [Display omitted] DisclosuresFenaux:Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Sanz:Gamida Cell: Research Funding. skov-Holm:Celgene: Research Funding. Almeida:Alexion: Honoraria; Bristol Meyer Squibb: Honoraria; Servier: Consultancy; Celgene: Consultancy; Novartis: Consultancy. Germing:Novartis: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria, Research Funding. Itzykson:Janssen: Research Funding; Novartis: Research Funding. Guerci-Bresler:BMS: Speakers Bureau; Incyte: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Speakers Bureau.

Prognostic value of pretreatment neutrophil-to-lymphocyte ratio in renal cell carcinoma: a systematic review and meta-analysis

BackgroundNumerous studies show that the pretreatment neutrophil-to-lymphocyte ratio (NLR) is associated with the prognosis of patients with RCC. However, their findings are inconsistent, urging us to explore the prognostic value of NLR in RCC patients.MethodsThis study was pre-registered in PROSPERO (CRD42020167131). Two reviewers independently performed a systematical search of PubMed, Web of Science, EMBASE, and Cochrane Library databases for prospective or retrospective cohort studies investigating the prognostic value of pretreatment NLR. Hazard ratios with 95% confidence intervals for overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), cancer-specific survival (CSS), and other useful clinicopathological features were extracted and analyzed with fixed or random-effect models by using Review Manager 5.3 and Stata 12.0 software. Heterogeneity was estimated on the basis of Cochran’s Q test and I2 value. Sensitivity analyses and subgroup analyses were also performed to explore the potential sources of heterogeneity. Publication bias was assessed with funnel plots and precisely assessed by Egger’s tests. The quality of the evidence was evaluated in accordance with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE).ResultsOverall, 6461 RCC patients from 24 retrospective studies and 1 prospective study were included. In overall population, elevated pretreatment NLR was associated with poorer OS (pooled HR = 1.90, 95% CI = 1.56–2.30, p < 0.001; I2 = 87%), DFS/PFS (pooled HR = 2.09, 95% CI: 1.49–2.94, p < 0.001; I2 = 99%), and CSS (pooled HR = 2.31, 95% CI: 1.61–3.33, p < 0.001; I2 = 14%). Furthermore, this negative association was further confirmed in patients with nonmetastatic and metastatic RCC patients, respectively. We also investigated the predictive role of NLR in metastatic RCC patients treated with immune checkpoint inhibitors (ICIs). The results indicated that the level of NLR was significantly associated with OS (pooled HR = 3.92, 95% CI: 2.00–7.69, p < 0.001; I2 = 0%) and PFS (pooled HR = 2.20, 95% CI: 95% CI: 1.61–3.01, p < 0.001; I2 = 20%).ConclusionsThis study demonstrated that elevated pretreatment NLR was significantly associated with poor prognosis of RCC patients. NLR could be helpful as a potential prognostic biomarker to guide clinical decision-making and select individualized treatment strategies for RCC patients.

NEMESIS: Noninferiority, Individual-Patient Metaanalysis of Selective Internal Radiation Therapy with 90Y Resin Microspheres Versus Sorafenib in Advanced Hepatocellular Carcinoma

In randomized clinical trials, no survival benefit has been observed for selective internal radiation therapy (SIRT) over sorafenib in patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess, through a metaanalysis, whether overall survival (OS) with SIRT, as monotherapy or followed by sorafenib, is noninferior to sorafenib and to compare safety profiles for patients with advanced HCC. Methods: We searched MEDLINE, EMBASE, and the Cochrane Library up to February 2019 to identify randomized clinical trials comparing SIRT, as monotherapy or followed by sorafenib, with sorafenib monotherapy among patients with advanced HCC. The main outcomes were OS and frequency of treatment-related severe adverse events (≥grade 3). The per-protocol population was the primary analysis population. A noninferiority margin of 1.08 in terms of hazard ratio was prespecified for the upper boundary of 95% confidence interval for OS. Prespecified subgroup analyses were performed. Results: Three randomized clinical trials, involving 1,243 patients, comparing sorafenib with SIRT (SIRveNIB and SARAH) or SIRT followed by sorafenib (SORAMIC), were included. After randomization, 411 of 635 (64.7%) patients allocated to SIRT and 522 of 608 (85.8%) allocated to sorafenib completed the studies without major protocol deviations. Median OS with SIRT, whether or not followed by sorafenib, was noninferior to sorafenib (10.2 and 9.2 mo [hazard ratio, 0.91; 95% confidence interval, 0.78-1.05]). Treatment-related severe adverse events were reported in 149 of 515 patients (28.9%) who received SIRT and 249 of 575 (43.3%) who received sorafenib only (P < 0.01). Conclusion: SIRT as initial therapy for advanced HCC is noninferior to sorafenib in terms of OS and offers a better safety profile.

Assessing the Justification, Funding, Success, and Survival Outcomes of Randomized Noninferiority Trials of Cancer Drugs

Noninferiority trials test whether a new intervention is not worse than the comparator by a given margin. To study the characteristics of published randomized noninferiority trials in oncology with overall survival as an end point, to assess the association of justification and success in achieving noninferiority with the funding of these trials, and to evaluate the association of such trials with patient survival. A systematic search of PubMed and Google Scholar databases was conducted in March 2018, with no date restrictions. Randomized noninferiority trials of cancer drug therapies with overall survival as an end point were included. Trials of decision support, supportive care, and nondrug treatment in both arms were excluded. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines for meta-epidemiological studies. Studies were screened for eligibility criteria, and data on criteria for noninferiority, funding, success (achieving noninferiority), and hazard ratios with confidence intervals for overall survival were extracted. Hazard ratios for overall survival were pooled across trials using a random-effects model. Associations of the justification for using a noninferiority design and success in achieving noninferiority with the source of funding were assessed. Overall pooled hazard ratios and confidence intervals for overall survival were calculated. Among 74 noninferiority trials of cancer drug therapies, 23 (31%; enrolling 21 437 patients) used overall survival as the primary end point. The noninferiority margins for the hazard ratio of overall survival ranged from 1.08 to 1.33. Noninferiority design was justified in 14 trials (61%) but not in 9 (39%). Overall, 18 trials (78%) concluded with a finding of noninferiority. Industry funding was associated with lack of justification for noninferiority design (P = .02, assessed using the Fisher exact test) but not with success in proving noninferiority (P = .80, assessed using the Fisher exact test). When the hazard ratios across the trials were pooled, there was no beneficial or detrimental association with overall survival, with a pooled hazard ratio of 0.97 (95% CI, 0.92-1.02). The findings suggest that a substantial fraction of noninferiority trials in oncology, most of which are industry funded, lack justification for such a design. Greater attention to the use of noninferiority designs in randomized clinical trials of cancer drugs from local and national regulators is warranted.

Prognostic role of pretreatment thrombocytosis on survival in patients with cervical cancer: a systematic review and meta-analysis

BackgroundThis meta-analysis summarized the prognostic role of an elevated platelet count before treatment on survival outcomes in patients with cervical cancer.MethodsThe PubMed, Embase, and Cochrane library electronic databases were systematically searched for studies reporting the effect estimates with 95% confidence intervals (CIs) of pretreatment thrombocytosis on survival from the database inceptions to December 2018. The pooled hazard ratios (HRs) with 95% CIs for overall survival (OS), progression-free survival (PFS), and recurrence-free survival (RFS) were calculated using random-effects models.ResultsNineteen retrospective studies that recruited 6521 patients with cervical cancer were eligible for this study. The summary results indicated that an elevated platelet count was significantly associated with a poor OS (HR 1.50; 95% CI 1.19–1.88; P = 0.001), PFS (HR 1.33; 95% CI 1.07–1.64; P = 0.010), and RFS (HR 1.66; 95% CI 1.20–2.28; P = 0.002). Sensitivity analysis indicated that the pooled PFS was variable after sequential exclusion of individual studies. The predictive value of pretreatment thrombocytosis on OS differed according to the publication year (P = 0.039), country (P = 0.013), and sample size (P = 0.029), and the role of pretreatment thrombocytosis on PFS could be affected by the study quality (P = 0.046).ConclusionThe findings of this study indicated that an elevated platelet count before treatment was associated with poor OS, PFS, and RFS. These results require further verification in large-scale prospective studies.

Mutations in the DNA methylation pathway predict clinical efficacy to hypomethylating agents in myelodysplastic syndromes: a meta-analysis

PurposeMyelodysplastic syndromes (MDS) are characterized by variable degrees of clinical outcomes. Until now, hypomethylating agents (HMAs) are the only drugs that have been approved by FDA in remedying this complicated prognosis disease, but without satisfactory outcome. So, biomarkers of better clinical outcome are of great significance. Many studies have already reported the potential prognostic value of DNA methylation pathway related gene (TET2/DNMT3 A/IDH) mutations in demethylation therapy patients, with controversial results. Therefore, a meta-analysis was performed to investigate their prognostic impact on HMAs treated MDS. MethodsDatabases, including PubMed, Embase, web of science and the Cochrane Library, were searched for relevant studies published up to 29 May 2018. Overall response rate (ORR) and overall survival (OS) were selected as endpoints. We extracted odds ratio to evaluate the effect of mutations on ORR, and the corresponding hazard ratios and their 95% confidence intervals for OS. ResultsA total of 13 cohort studies, covering 1398 patients with MDS treated by HMAs were included in the final meta-analysis. Our results indicated that DNMT3 A mutations had a favorable impact (P = 0.008) and TET2 mutations, which showed no significance (P = 0.06) in all included patients, could imply good efficacy in some subgroups on ORR. However, none advantages of mutations on ORR translated into a benefit in overall survival. ConclusionsThis meta-analysis indicates one favorable factor, DNMT3 A mutations, on ORR in MDS patients with HMAs therapy. The identification of mutations in DNMT3 A can improve clinical efficacy and help make treatment decisions.

Pathologic and prognostic impacts of FGFR2 amplification in gastric cancer: a meta-analysis and systemic review.

Fibroblast growth factor receptor-2 (FGFR2) gene is amplified in up to 15% of patients with gastric cancer (GC). However, the prognostic significance of FGFR2 amplification has been controversial. This meta-analysis was conducted to evaluate the clinicopathological impacts of FGFR2 amplification in patients with GC. We performed a systematic computerized search of the electronic databases of PubMed, PMC, EMBASE, Web of Science, and Google Scholar and selected studies assessing the correlation of FGFR2 amplification with pathologic features and/or prognosis in gastric adenocarcinoma. From eight studies, 2,377 patients were included in the pooled analysis of odds ratios (ORs) with 95% confidence intervals (CIs) for pathologic findings and hazard ratios (HRs) with 95% CIs for overall survival. FGFR2 amplification was significantly associated with LN metastasis (OR = 3.93, 95% CI: 2.22-6.96, p < 0.00001) and poorly differentiated adenocarcinoma (OR = 2.36, 95% CI: 1.03-5.39, p = 0.04). In addition, patients with GC harboring FGFR2 amplification showed significantly worse survival (HR = 2.09, 95% CI: 1.68-2.59, p < 0.00001), compared with patients with FGFR2-unamplified GC. In conclusion, this meta-analysis indicates that FGFR2 amplification is an adverse prognostic factor in patients with GC.

Pathological and Prognostic Impacts of FGFR2 Overexpression in Gastric Cancer: A Meta-Analysis.

Fibroblast growth factor receptor-2 (FGFR2) protein expression by immunohistochemistry has been reported in up to 60% of patients with gastric cancer (GC). However, the clicopathological impacts of high FGFR2 expression have not been consistent among studies. We conducted this meta-analysis to evaluate the pathological and prognostic significance of FGFR2 overexpression in patients with GC. A systematic search of the electronic databases including PubMed, PMC, EMBASE, and Google Scholar was performed. From ten studies, 4,294 patients were included in the pooled analyses of odds ratios (ORs) with 95% confidence intervals (CIs) for pathological features and hazard ratios (HRs) with 95% CIs for overall survival according to the FGFR2 expression status. Compared with tumors showing low FGFR2 expression, GCs with FGFR2 overexpression revealed deeper depth of invasion (pT3-4) (OR = 2.63, 95% CI: 1.70-4.06, p < 0.0001), higher rate of lymph node metastasis (OR = 1.87, 95% CI: 1.31-2.67, p < 0.0001), and more advanced stage (III-IV) (OR = 1.78, 95% CI: 1.07-2.96, p = 0.03). In addition, patients with FGFR2-overexpressed GC showed significantly worse survival than those with FGFR2-low tumor (HR = 1.40, 95% CI: 1.25-1.58, p < 0.00001). In conclusion, this meta-analysis indicates that FGFR2 overexpression is associated with poor pathological features and prognosis in patients with GC.

Prognostic Value of mRNA Expression of MAP4K Family in Acute Myeloid Leukemia.

Background:Despite diverse functions in diseases, the prognostic potential of the family of mitogen-activated protein kinase kinase kinase kinase genes in acute myeloid leukemia remains unknown.Methods:The messenger RNA expression of the MAP4K family members in 151 patients with acute myeloid leukemia was extracted from the OncoLnc database. Data for gender, age, cytogenetic, leukocyte count, CD34, FAB classification, RUNX1, and TP53 were provided by the University of California–Santa Cruz Xena platform. Kaplan-Meier analysis and Cox regression model provided an estimate of the hazard ratio with 95% confidence intervals for overall survival.Results:Analysis demonstrated favorable overall survival in patients with acute myeloid leukemia attributing to high expression of MAP4K3, MAP4K4, and MAP4K5 and low expression of MAP4K1 (adjusted P = .005, P = .022, P = .002, and P = .024; adjusted hazard ratio = 0.490, 95% confidence interval = 0.297-0.809, hazard ratio = 0.598, 95% confidence interval = 0.385-0.928, hazard ratio = 0.490, 95% confidence interval = 0.310-0.776, and hazard ratio = 0.615, 95% confidence interval = 0.403-0.938, respectively). Combining the high-expressing MAP4K3, MAP4K4, and MAP4K5 with the low-expressing MAP4K1 in a joint effect analysis predicted a favorable prognosis of overall survival in acute myeloid leukemia.Conclusion:High expression of MAP4K3, MAP4K4, and MAP4K5 combined with low expression of MAP4K1 can serve as a sensitive tool to predict favorable overall survival in patients with acute myeloid leukemia.

Prognostic Role of MicroRNAs in Human Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Background MicroRNAs (miRNAs) have been found to play an important role in the development and outcomes for multiple human cancers. Their role as a prognostic biomarker in non-small-cell lung cancer (NSCLC) remains unclear. This meta-analysis aims to clarify the role of various miRNAs in the survival of NSCLC patients. Materials and Methods All studies were identified through medical database search engines. A meta-analysis was conducted to assess the correlation between miRNAs expressions and overall survival among those NSCLC studies. Relevant data were extracted from each eligible study regarding baseline characteristics and key statistics such as hazard ratio (HR), 95% confidence interval (CI), and P value, which were utilized to calculate a pooled effect size. Result Thirty-two studies were included in the meta-analysis. Using a random effect model, the combined HR and 95% CI for overall survival (OS) was calculated as 1.59 (1.39–1.82), predicting a poor overall survival. Five miRNAs (miR-21, miR-155, miR-let-7, miR-148a, and miR-148b) were found to be of significance for predicting OS in at least two studies, hence, selected for subgroup analysis. Subgroup analysis disclosed that elevated levels of miR-21 and miR-155 in both cancer tissue and blood samples were associated with worse OS. Compared to American studies (I-squared: <0.001% and P value: 0.94), Asian and European studies exhibited greater heterogeneity in miRNA expression and relationship to OS (I-squared, P values were approximately 78.85%, <0.001 and 61.28%, 0.006, respectively). These subgroup analyses also highlighted that elevated expression of miR-21 and miR-155 and low levels of expression of miR-148a, miR-148b, and miR-let-7 were associated with poor prognosis in NSCLC. Conclusion miR-21, miR-155, miR-148a, miR-148b, and miR-let-7 are consistently up- or downregulated in NSCLC and are associated with poor OS. These miRNAs show potential as useful prognostic biomarkers in the diagnosis, treatment, and follow-up of NSCLC.

PS02.074: ENDOSCOPIC TUMOUR MORPHOLOGY AFFECTS SURVIVAL IN OESOPHAGEAL CANCER

Abstract Background Oesophageal carcinoma can present with a variety of endoscopic morphologies. No previous studies have ascertained whether endoscopic tumour morphology impacts survival. This study describes three distinct endoscopic tumour morphologies; ulcerating, exophytic and stenosing, and analyses their impact on survival. Methods This is a retrospective cohort study of 181 patients who underwent diagnostic endoscopy prior to oesophagectomy at St Thomas’ Hospital, London. Univariable and multivariable Cox regression analyses were performed to determine hazard ratios (HR) with 95% confidence intervals for overall survival. Results There were 56 ulcerating, 68 exophytic and 57 stenosing lesions. Median survival was 52.7 months for ulcerating lesions, 46.8 months for exophytic lesions and 33.8 months for stenosing lesions (P = 0.01). When compared to stenosing lesions, exophytic and ulcerating lesions demonstrated a significant survival advantage on univariable analysis (exophytic HR 0.53; 95%CI 0.21–0.95, ulcerating HR 0.37; 95%CI 0.19–0.73). Conclusion This study demonstrates that endoscopic morphology may be an important prognostic factor in oesophageal cancer. Further studies are needed to confirm whether this is an independent prognostic indicator which may help guide future neoadjuvant and surgical treatment strategies. Disclosure All authors have declared no conflicts of interest.