Restricted Mean Survival Time Ratio Research Articles

All-cause mortality and suicide after pediatric traumatic brain injury: a 20-year nationwide study in Finland

ObjectivesTo assess all-cause mortality and suicides after pediatric traumatic brain injury (pTBI). Study designWe conducted population-based historical cohort study using three nationwide registers from 1998 to 2018 in Finland. All patients that were the age of 0–17 at the time of the pTBI were included. The reference group consisted of children with ankle or wrist fractures. We used Kaplan–Meier and restricted mean survival time (RMST) analysis with 95% confidence intervals (CI) to compare all-cause mortality and suicides between groups. ResultsAfter 20 years of follow-up, there were 479 deaths in the pTBI group (0.67% of 71,963) and 306 deaths in the reference group (0.47% of 64,848). In the pTBI group, 28.6% of the deaths occurred after the first follow-up year, compared to 2.6% in the reference group. In all-cause mortality, survival time was slightly less in the pTBI group with age and gender adjustment throughout the follow-up period [20-year RMST ratio: 0.995; CI (0.994–0.996)]. The leading manners of death were suicides (pTBI group = 28.4%; reference group = 45.5%) and traffic collisions (pTBI group = 37.4%; reference group = 20.8%). Age and gender-adjusted survival time was slightly less for those with suicide as a manner of death in the pTBI group [10-year RMST ratio: 0.999; CI (0.999–0.999); 20-year RMST ratio: 0.999; CI (0.998–0.999)]. ConclusionsChildren and adolescents who sustained a TBI have slightly lower long-term survival time for all-cause mortality, most of which occurs during the first year following injury. There is no clinically meaningful difference in deaths by suicide between the two injury groups.

Scaling and interpreting treatment effects in clinical trials using restricted mean survival time.

Restricted mean survival time is the expected duration of survival up to a chosen time of restriction . For comparison studies, the difference in restricted mean survival times between two groups provides a summary measure of the treatment effect that is free of assumptions regarding the relative shape of the two survival curves, such as proportional hazards. However, it can be difficult to judge the magnitude of the effect from a comparison of restricted means due to the truncation of observation at time . In this article, we describe additional ways of expressing the treatment effect based on restricted means that can be helpful in this regard. These include the ratio of restricted means, the ratio of life-years (or time) lost, and the average integrated difference between the survival curves, equal to the difference in restricted means divided by These alternative metrics are straightforward to calculate and provide a means for scaling the effect size as an aid to interpretation. Examples from two randomized, multicenter clinical trials in prostate cancer, NRG/RTOG 0521 and NRG/RTOG 0534, with primary endpoints of overall survival and biochemical/radiological progression-free survival, respectively, are presented to illustrate the ideas. The four effect measures (restricted mean survival time difference, restricted mean survival time ratio, time lost ratio, and average survival rate difference) were 0.45 years, 1.05, 0.81, and 0.038 for RTOG 0521 and 1.36 years, 1.17, 0.56, and 0.12 for RTOG 0534 with = 12 and 11 years, respectively. Thus, for example, the 0.45-year difference in the first trial translates into a 19% reduction in time lost and a 3.8% average absolute difference between the survival curves over the 12-year horizon, a modest effect size, whereas the 1.36-year difference in the second trial corresponds to a 44% reduction in time lost and a 12% absolute survival difference, a rather large effect. In addition to the difference in restricted mean survival times, these alternative measures can be helpful in determining whether the magnitude of the treatment effect is clinically meaningful.

Abstract 14444: Sex-Mismatch in Heart Transplantation Confers No Additional Risk of Postoperative Outcomes Established via Two One-Sided Equivalence Testing on a Propensity-Matched Cohort

Introduction: Donor-recipient sex-mismatch in heart transplantation (HTx) has decreased since the 1990s, possibly due to conflicting findings regarding its risk. Size mismatch is known to confer risk. Hypothesis: Previously observed differences in outcomes between the arms of sex-matched and sex-mismatched patients were due to underlying size mismatch. Sex-mismatch confers no postoperative risks beyond that due to risk beyond those due to size mismatch. Methods: Patients from the UNOS database between October 1, 1987 and December 31, 2022 were analyzed; under 18 years old, multiorgan transplants, and retransplants were excluded. Cohorts were separated into male and female recipients. Propensity score matching on age, transplant year, waitlist status, donor/recipient PHM ratio, preoperative diagnosis, creatinine clearance, total bilirubin, and mechanical circulatory support was performed. Two One-Sided Testing (TOST) was performed to assess between-arm equivalence in postoperative outcomes. Survival differences were measured by the between-arm ratio of Restricted Mean Survival Time (RMST) and binary outcome differences by the Odds Ratio (OR). We set the equivalence bounds per Wellek’s strict a priori bounds of (0.66, 1.50) for OR and (0.95, 1.05) for the between-arm RMST ratio. Results: In the non-propensity matched cohort, there were significant differences in survival at temporal endpoints up to five years for male recipients (p<0.001) but no significant differences in the female recipients at temporal endpoints up to five years (p=0.3). In the propensity matched cohort, we found significant equivalence between arms in both male and female recipients for all outcomes (Table 1). Conclusions: Sex-mismatch in HTx confers no additional risk to postoperative outcomes beyond those present due to size mismatch. Increasing the acceptance of sex-mismatched donors could potentially expand the donor pool and increase female donor utilization.

Assessing surrogacy using restricted mean survival time ratio for overall survival in liver cancer: a narrative review.

The application of immunotherapy in cancers, including liver cancer, has been increasing. However, non-proportional hazard (NPH) is often observed in cancer immunotherapy trials. In presence of violation of proportional hazard (PH) assumption, restricted mean survival time (RMST) ratio was proposed as an alternative to hazard ratio (HR) for evaluating the treatment effects of such trials. To shorten the total study duration, an intermediate endpoint with shorter follow-up such as progressionfree survival (PFS) is used as the primary endpoint. Our aim is to evaluate the applicability of RMST ratio in addition to the HR in assessing the level of PFS serving as a surrogacy of overall survival (OS). Phase II or phase III hepatocellular carcinoma (HCC) immunotherapy studies that were published between January 2013 and August 2022 were identified via the search in PubMed. Weighted leastsquare regression (WLSR) was applied to analyze the trial level data with the sample size of study being set as the weight. The evaluation was conducted twice with RMST ratio and HR being applied in respective evaluation to examine the level of PFS as a surrogacy for OS. Based on the results of eight included trials, the R-square values of WLSR with either HR or RMST ratio being applied were 0.31 and 0.16 separately, indicating a moderate and low correlation between PFS and OS respectively. In this study, our results demonstrated the potential of RMST ratio in addition to HR for evaluating the level of surrogacy in immunotherapy trials. Furthermore, including more large scale and homogeneous studies into the research may help better understand the level of surrogacy in liver cancer.

Time-Dependent Changes in Risk of Progression During Use of Bevacizumab for Ovarian Cancer

Although bevacizumab has been used in the treatment of ovarian cancer, its optimal use is unknown. To investigate time-dependent changes in the outcomes of bevacizumab therapy. This cohort study was conducted using published data from 7 previous randomized phase 3 clinical trials with bevacizumab (ICON7, GOG-0218, BOOST, GOG-0213, OCEANS, AURERIA, and MITO16B) from January 10 to January 31, 2023. From 2 ancillary analyses of the ICON7 trial with individual patient data and tumor gene expression profiles, an ICON7-A cohort was generated comprising 745 cases. From other studies, published Kaplan-Meier curves were graphically analyzed. Bevacizumab treatment vs placebo or no treatment. Restricted mean survival time and relative risk of progression at a given time point between bevacizumab treatment and control groups. In the ICON7-A cohort (n = 745), restricted mean survival analysis showed that bevacizumab treatment (n = 384) had significantly better progression-free survival (PFS) than the control (n = 361) before bevacizumab discontinuation (restricted mean survival time ratio, 1.08; 95% CI, 1.05-1.11; P < .001), but had significantly worse PFS after bevacizumab discontinuation (0.79; 95% CI, 0.69-0.90; P < .001), showing rebound. In a post hoc analysis, the rebound was similarly observed both in homologous recombination deficiency (HRD) (before, 1.05; 95% CI, 1.02-1.09; P < .001; after, 0.79; 95% CI, 0.63-0.98; P = .04) and non-HRD tumors (before, 1.08; 95% CI, 1.03-1.15; P < .001; after, 0.71; 95% CI, 0.56-0.90; P < .001) of the serous subtype, but not in the nonserous subtype (before, 1.11; 95% CI, 1.05-1.18; P < .001; after, 0.94; 95% CI, 0.78-1.15; P = .57). In Kaplan-Meier curve image-based analysis, the trend of rebound effect was consistently observed in the overall ICON7 and GOG-0218 cohorts and their subgroups stratified by prognostic factors, homologous recombination-associated mutations, and chemotherapy sensitivity. In contrast, no such trend was observed in the studies GOG-0213, OCEANS, AURERIA, and MITO16B, in which patients who experienced relapse received bevacizumab until progression. In ovarian cancer, bevacizumab may reduce progression for approximately 1 year after initiation, but discontinuation may increase subsequent progression in the serous subtype regardless of HRD status. The results suggest that in the first-line treatment, bevacizumab may be more beneficial in patients with a shorter prognosis who are less likely to experience the rebound outcome.

Anti-tumor effects of ketogenic diets and their synergism with other treatments in mice: Bayesian evidence synthesis of 1755 individual mouse survival data

BackgroundKetogenic diets (KDs) are high-fat diets with putative anti-tumor effects. The aim of this study was to synthesize the evidence for the anti-tumor effects of KDs in mice, with a focus on their possible synergism with chemotherapy (CT), radiotherapy (RT), or targeted therapies (TT). MethodsRelevant studies were retrieved from a literature search. A total of 43 articles reporting on 65 mouse experiments fulfilled the inclusion criteria, and 1755 individual mouse survival times were collated from the study authors or the publications. The restricted mean survival time ratio (RMSTR) between the KD and control groups served as the effect size. Bayesian evidence synthesis models were used to estimate pooled effect sizes and to assess the impact of putative confounders and synergism between KD and other therapies. ResultsOverall, there was a significant survival-prolonging effect of KD monotherapy (RMSTR = 1.161 ± 0.040), which was confirmed in meta-regression accounting for syngeneic versus xenogeneic models, early versus late KD start and subcutaneous versus other organ growth. Combining the KD with RT or TT, but not CT, was associated with a further 30% (RT) or 21% (TT) prolongation of survival. An analysis accounting for 15 individual tumor entities showed that KDs exerted significant survival-prolonging effects in pancreatic cancer (all treatment combinations), gliomas (KD + RT and KD + TT), head and neck cancer (KD + RT), and stomach cancer (KD+RT and KD + TT). ConclusionsThis analytical study confirmed the overall anti-tumor effects of KDs in a large number of mouse experiments and provides evidence for synergistic effects with RT and TT.

Transcatheter and surgical aortic valve replacement in patients with left ventricular dysfunction

BackgroundPatients with severe aortic stenosis and left ventricular systolic dysfunction have a poor prognosis, and this may result in inferior survival also after aortic valve replacement. The outcomes of transcatheter and surgical aortic valve replacement were investigated in this comparative analysis.MethodsThe retrospective nationwide FinnValve registry included data on patients who underwent transcatheter or surgical aortic valve replacement with a bioprosthesis for severe aortic stenosis. Propensity score matching was performed to adjust the outcomes for baseline covariates of patients with reduced (≤ 50%) left ventricular ejection fraction.ResultsWithin the unselected, consecutive 6463 patients included in the registry, the prevalence of reduced ejection fraction was 20.8% (876 patients) in the surgical cohort and 27.7% (452 patients) in the transcatheter cohort. Reduced left ventricular ejection fraction was associated with decreased survival (adjusted hazards ratio 1.215, 95%CI 1.067–1.385) after a mean follow-up of 3.6 years. Among 255 propensity score matched pairs, 30-day mortality was 3.1% after transcatheter and 7.8% after surgical intervention (p = 0.038). One-year and 4-year survival were 87.5% and 65.9% after transcatheter intervention and 83.9% and 69.6% after surgical intervention (restricted mean survival time ratio, 1.002, 95%CI 0.929–1.080, p = 0.964), respectively.ConclusionsReduced left ventricular ejection fraction was associated with increased morbidity and mortality after surgical and transcatheter aortic valve replacement. Thirty-day mortality was higher after surgery, but intermediate-term survival was comparable to transcatheter intervention.Trial registration The FinnValve registry ClinicalTrials.gov Identifier: NCT03385915.

Comparison of the efficacies of 1.0 and 1.5 mm silicone tubes for the treatment of nasolacrimal duct obstruction

This retrospective observational study analyzed the postoperative outcomes of bicanalicular intubation using different diameters of tube stents for treating postsaccal nasolacrimal duct obstruction. A total of 130 patients diagnosed with postsaccal obstruction who underwent endoscopic-assisted silicone tube intubation were included in the study. Patients intubated with a 1.5-mm large-diameter tube were designated as the LD group, and those with a 1.0-mm normal-diameter tube were designated as the ND group. The patency rates of the two groups at 1 year after tube removal were compared using the Kaplan–Meier curve and restricted mean survival time (RMST) method with τ = 365 days. Results demonstrated that the recurrence rate after tube removal was significantly lower in the LD group as compared with the ND group (p = 0.001). The patency rates at 1 year after removal in the LD and ND group were 85.7% (95% confidence interval [CI]: 75.4, 91.9) and 73.9% (95% CI: 61.7, 82.8), respectively. When comparing the patency rates by the RMST method at τ = 365 days, the RMST difference, RMST ratio, and RMTL ratio were higher in the LD group at p = 0.045, 0.052, and 0.046, respectively.

Assessing surrogacy using restricted mean survival time ratio for overall survival in liver cancer immunotherapy studies.

e16222 Background: Recently, immunotherapy has played a crucial role in treating liver cancer, one of the major cancers that contributes to global cancer burden. Overall survival (OS) is widely applied in cancer trials to evaluate the treatment effects of new therapies. However, it requires more patients and longer follow-up time comparing with progression-free survival (PFS). In addition, while assessing the treatment effects of cancer immunotherapy, proportional hazard (PH) assumption is often violated due to issues such as delayed treatment effects. Restricted Mean Survival Time (RMST) ratio is increasingly used for treatment effect evaluation when the PH assumption is violated. Such change prompts an important question whether the surrogacy value of PFS will be affected when RMST ratio is used to characterize treatment effect. The aim of this study is to examine the feasibility of using PFS as a surrogate endpoint for OS when the treatment effect is measured using hazard ratio (HR) versus RMST ratio. Methods: The surrogacy of PFS on OS was evaluated through examining the association between PFS and OS using HR and RMST ratio. Seven immunotherapy studies published between 2000 and 2021 were included (Table). Information of examined studies such as treatment arms information, OS and PFS were collected. RMST ratio for PFS and OS were calculated based on the Kaplan-Meier plots extracted from each article using WebPlotDigitizer 4.4. The weighted least square regression lines and R^2 between OS and PFS for HR and RMST ratio were calculated. Results: Among 7 immunotherapy studies, 4 gave placebos to the control arms as treatments. 2 provided Sorafenib and 1 assigned the same drug as treatment arm but with different schedule. All 7 studies had OS and PFS as the endpoints. 2 studies violated the PH assumptions. Based on the data extracted from examined articles, a moderate correlation (0.52) between PFS and OS was observed for HR while low correlation (0.10) was observed for RMST ratio. Conclusions: The R^2 values differ greatly depending on whether HR or RMST ratio was used for assessing surrogacy. Our finding may have important implications for the design of future immunotherapy liver cancer trials. For future work, increasing the number of included studies for a more comprehensive analysis is needed. Moreover, trial-level surrogacy analysis should be conducted to complement the study-level investigation.[Table: see text]

Meta-Analysis of Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting for Left Main Narrowing

Randomized controlled trials (RCTs) comparing percutaneous coronary intervention (PCI) with drug-eluting stents and coronary artery bypass grafting (CABG) for patients with left main coronary artery disease (LMCAD) have reported conflicting results. We performed a systematic review up to May 23, 2021, and 1-stage reconstructed individual patient data meta-analysis (IPDMA) to compare outcomes between both groups. The primary outcome was 10-year all-cause mortality. Secondary outcomes included myocardial infarction (MI), stroke, and unplanned revascularization at 5years. We performed individual patient data meta-analysis using published Kaplan-Meier curves to provide individual data points in coordinates and numbers at risk were used to increase the calibration accuracy of the reconstructed data. Shared frailty model or, when proportionality assumptions were not met, a restricted mean survival time model were fitted to compare outcomes between treatment groups. Of 583 articles retrieved, 5 RCTs were included. A total of 4,595 patients from these 5 RCTs were randomly assigned to PCI (n=2,297) or CABG (n=2,298). The cumulative 10-year all-cause mortality after PCI and CABG was 12.0% versus 10.6%, respectively (hazard ratio [HR] 1.093, 95% confidence interval [CI] 0.925 to 1.292; p=0.296). PCI conferred similar time-to-MI (restricted mean survival time ratio 1.006, 95% CI 0.992 to 1.021, p=0.391) and stroke (restricted mean survival time ratio 1.005, 95% CI 0.998 to 1.013, p=0.133) at 5years. Unplanned revascularization was more frequent after PCI than CABG (HR 1.807, 95% CI 1.524 to 2.144, p <0.001) at 5years. This meta-analysis using reconstructed participant-level time-to-event data showed no statistically significant difference in cumulative 10-year all-cause mortality between PCI versus CABG in the treatment of LMCAD.

Assessing surrogacy using restricted mean survival time ratio for overall survival in non-small cell lung cancer immunotherapy studies.

Proportional hazards (PH) assumption is often violated in cancer immunotherapy studies. Restricted mean survival time (RMST) ratio is a valid metric to quantify the size of treatment effect when non-proportional hazard (NPH) is present. This study investigated the use of RMST ratio and hazard ratio (HR) in studying progression-free survival (PFS) as a surrogate endpoint for overall survival (OS) in non-small cell lung cancer immunotherapy trials. Trial level data were collected from 14 phase III trials published between 2012 and 2018. A weighted least-square regression (WLSR) was performed to evaluate the trial-level surrogacy. Surrogacy was evaluated via the association between RMST ratios for PFS and OS and between HRs for PFS and OS. Using data extracted from published articles, low to moderate correlation (0.49) between PFS and OS was observed for HR while low correlation (0.35) was observed for RMST ratio. When trials violating PH in PFS were included, more consistent correlations for both HR (0.43) and RMST ratio (0.44) were observed. In summary, the strength of PFS surrogacy for OS depends on whether HR or RMST ratio are chosen. RMST ratio and additional sensitivity analysis should be considered in addition to HR.

Outcome After Surgery for Acute Type A Aortic Dissection With or Without Primary Tear Resection

BackgroundThe outcome in patients after surgery for acute type A aortic dissection without replacement of the part of the aorta containing the primary tear is undefined. MethodsData of 1122 patients who underwent surgery for acute type A aortic dissection in 8 Nordic centers from January 2005 to December 2014 were retrospectively analyzed. The patients with primary tear location unfound, unknown, not confirmed, or not recorded (n = 243, 21.7%) were excluded from the analysis. The patients were divided into 2 groups according to whether the aortic reconstruction encompassed the portion of the primary tear (tear resected [TR] group, n = 730) or not (tear not resected [TNR] group, n = 149). The restricted mean survival time ratios adjusted for patient characteristics and surgical details between the groups were calculated for all-cause mortality and aortic reoperation–free survival. The median follow-up time was 2.57 (interquartile range, 0.53-5.30) years. ResultsFor the majority of the patients in the TR group, the primary tear was located in the ascending aorta (83.6%). The reconstruction encompassed both the aortic root and the aortic arch in 7.4% in the TR group as compared with 0.7% in the TNR patients (P < .001). There were no significant differences in all-cause mortality (adjusted restricted mean survival time ratio, 1.01; 95% confidence interval, 0.92-1.12; P = .799) or reoperation-free survival (adjusted restricted mean survival time ratio, 0.98; 95% confidence interval, 0.95-1.02; P = .436) between the TR and TNR groups. ConclusionsPrimary tear resection alone does not determine the midterm outcome after surgery for acute type A aortic dissection.

Prognostic Value of Serum Osteoprotegerin Level in Patients With Hepatocellular Carcinoma Following Surgical Resection.

BackgroundMultiple studies have reported that tissue or serum osteoprotegerin (OPG) level is a prognostic factor for patients with cancer. However, little is known about the role of serum OPG in hepatocellular carcinoma (HCC). In this study, we aimed to investigate whether serum OPG concentration has an effect on HCC patients’ prognosis.MethodsA total of 386 eligible HCC patients undergoing radical hepatectomy were enrolled from Shanghai Ninth People’s Hospital and Zhongshan Hospital between 2010 and 2018. Kaplan-Meier curves, Cox regression model, and the restricted mean survival time (RMST) were used to estimate the association of OPG and HCC patients’ survival outcome. In addition, sensitivity analyses were carried out including subgroup analysis and propensity score matching (PSM).ResultsPatients were separated into two groups according to the cut-off value of OPG calculated by X-tile. Multivariate Cox analysis showed that patients with high OPG level had worse overall survival (OS) (HR: 1.93; 95% CI: 1.40–2.66, p<0.001) and disease-free survival (DFS) (HR: 1.85; 95% CI: 1.39–2.47, p<0.001) before matching. On average, RMST ratio between high and low OPG turned out to be 0.797 (95% CI: 0.716–0.887, p<0.001). In the matched population, we found that OPG level was negatively associated with OS (HR: 1.85; 95% CI: 1.25–2.74, p=0.002) and DFS (HR: 1.71; 95% CI: 1.20–2.44, p=0.003). In addition, a similar trend was further confirmed by subgroup analyses.ConclusionIn a word, HCC patients with high OPG level had poorer survival rates compared with HCC patients with low OPG level. This factor could act as a potential prognostic predictor for HCC patients who underwent radical resection in the future.

Anchored matching-adjusted indirect comparison (MAIC) of regorafenib (REG) versus cabozantinib (CAB) in advanced hepatocellular carcinoma (HCC).

e16188 Background: REG and CAB, two therapies for second-line (2L) advanced HCC, have been evaluated vs. placebo (PBO) in randomized phase III trials, RESORCE (NCT01774344) and CELESTIAL (NCT01908426), respectively. In the absence of head-to-head studies, indirect treatment comparison (ITC) is needed to compare the efficacy and safety of REG vs. CAB. Anchored MAIC is an ITC method adjusting for cross-trial heterogeneity using PBO as the common comparator or anchor. Methods: Patient-level data from RESORCE were available to match the inclusion criteria and published baseline characteristics of CELESTIAL. 2L patients with prior sorafenib exposure of &gt;3 months were included in the analyses. Overall survival (OS), progression-free survival (PFS), and Grade 3/4 treatment-emerging adverse events (TEAEs) occurring in &gt; 10% of patients were compared. Matching was conducted for the following covariates, which were either imbalanced across trials or likely treatment effect modifiers (EMs): gender, region, Eastern Cooperative Oncology Group (ECOG), prior sorafenib duration, extrahepatic spread, macrovascular invasion, hepatitis B (HBV), hepatitis C (HCV), alcohol use, and alpha-fetoprotein (AFP) ≥400 ng/mL. Anchored MAIC were used to compare the relative effect of each treatment. To account for violation of the proportional hazards assumption, in addition to hazard ratios (HRs), restricted mean survival time (RMST) was estimated to quantify differences in OS and PFS. For safety, the relative effects were expressed as risk differences (RDs) (REG – CAB). Results: After matching, the effective sample sizes of REG and its PBO arm were 214 and 82, respectively. For OS, REG showed favorable although not statistically significant HR, and 30% longer mean survival with an RMST ratio approaching statistical significance. For PFS, there was no numerical difference in HR and no clinically meaningful difference based on RMST analyses (Table). REG showed lower incidence of diarrhea [RD of -7.1% (NE, NE)] and fatigue [RD of -6.3% (-14.6, 2.0)]. Conclusions: In this anchored MAIC, REG showed favorable OS and safety profile, especially for diarrhea and fatigue. No clinically meaningful difference was observed for PFS. The analysis could be limited by reduced sample size after matching and unobserved or missing EMs that could not be adjusted.[Table: see text]

Quantifying the Survival Benefits of Oncology Drugs With a Focus on Immunotherapy Using Restricted Mean Survival Time.

Restricted mean survival time (RMST) overcomes limitations of current measures of survival benefits because it directly captures information of the entire area under Kaplan-Meier survival curves. Using RMST difference (absolute survival benefit) and RMST ratio (relative survival benefit), we quantified the magnitude of survival benefits of recent oncology drugs and compared immunotherapies with nonimmunotherapies. Kaplan-Meier curves were extracted from phase II/III randomized controlled trials used by the FDA for oncology drug approvals from January 2011 through November 2017 with overall survival (OS) or progression-free survival (PFS) as primary endpoints. RMST differences, ratios, and their 95% confidence intervals were meta-analyzed to estimate absolute and relative survival benefits of contemporary oncology drugs and to compare immunotherapies with nonimmunotherapies. Meta-regression was conducted to adjust for potential confounders. Ninety-four trials with a total of 51,639 patients were included. Overall absolute survival benefits (RMST differences) were 1.55 months for OS (95% CI, 1.32-1.77) and 2.99 months for PFS (95% CI, 2.65-3.33). Overall relative survival benefits (RMST ratios) were 1.11 for OS (95% CI, 1.09-1.13) and 1.42 for PFS (95% CI, 1.36-1.48). Immunotherapy absolute PFS benefit was less than that of nonimmunotherapy (1.56 vs 3.23 months), whereas immunotherapy absolute OS benefit was larger than that of nonimmunotherapy by 0.59 months (2.02 vs 1.43 months). Adjusted OS RMST difference was 0.91 months greater for immunotherapy than for nonimmunotherapy after adjusting for confounders. Absolute survival benefits of recent oncology drugs are modest. Survival benefits of immunotherapies are not dramatically superior to those of nonimmunotherapies. Routine reporting and use of RMST may help patients, physicians, and payers make more informed and responsible decisions regarding the care of patients with cancer.

Long-Term Survival Analysis of Adjuvant Chemotherapy with or without Trastuzumab in Patients with T1, Node-Negative HER2-Positive Breast Cancer.

Adjuvant therapy for small, node-negative HER2-positive breast cancer (HER2+ BC) is controversial. We aimed to identify the subgroup that would benefit most from adjuvant chemotherapy and trastuzumab. We reviewed records of patients with pT1N0M0 HER2+ BC treated at our institution from January 1, 1998, through October 31, 2009. We compared three groups: A, no adjuvant chemotherapy; B, adjuvant chemotherapy only; and C, adjuvant chemotherapy with trastuzumab. We evaluated disease-free survival (DFS), overall survival (OS), distant recurrence-free survival (DRFS), and breast cancer-specific survival (BCSS) in each group. We reviewed 587 consecutive patients with a median follow-up of 123.0 months. The 10-year DFS rate was 81.0%, 65.4%, and 97.3% in groups A, B, and C, respectively (P < 0.001). The restricted mean survival time ratio did not differ between groups A and B [ratio = 0.982; 95% confidence interval (CI), 0.930-1.036; P = 0.498). Cox regression showed that adjuvant chemotherapy with trastuzumab was associated with better DFS compared with no adjuvant chemotherapy [hazard ratio (HR), 0.071; 95% CI, 0.025-0.204; P < 0.001). Larger tumor size was associated with short DFS (HR, 2.384; 95% CI, 1.549-3.056; P < 0.001); improvements in DFS, OS, DRFS, and BCSS were observed with adjuvant chemotherapy plus trastuzumab in patients with tumors ≥0.8-cm diameter. Receiving adjuvant chemotherapy with trastuzumab was not associated with improved DFS, OS, or DRFS for tumors <0.8 cm. Adjuvant chemotherapy plus trastuzumab should be recommended for patients with pT1N0M0 HER2+ BC ≥0.8 cm in diameter; adjuvant therapy may not be necessary for tumors <0.8 cm.

Pembrolizumab alone or with chemotherapy for PD-L1 positive NSCLC: A network meta-analysis of randomized trials.

9087 Background: Pembrolizumab (P) has replaced chemotherapy (C) as first-line treatment for advanced non-small cell lung cancer (NSCLC) with tumor PD-L1 expression &gt; / = 50%. Among PD-L1 unselected patients, P+C is superior to C alone. This network meta-analysis compared P alone with P+C in patients with &gt; / = 50% PD-L1 positive NSCLC. Methods: An indirect network was constructed to compare P and P+C through the control arms of the Keynote 024, 189 and 407 (PD-L1 &gt; / = 50% subgroup) trials. Baseline characteristics and chemotherapy outcomes were examined for heterogeneity. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and toxicities including immune-related adverse events (irAE) were extracted from trial results. Toxicity results were unavailable for the PD-L1 &gt; / = 50% subgroups of KN 189 &amp; 407, so overall study results were used. Survival outcomes are expressed as hazard ratios (HRs) or restricted mean survival time (RMST) ratios, and toxicity and ORR as risk difference (RD). Results: 507 patients were included: 154 on P, 430 on C and 483 on P+C. Patient characteristics across trials were similar in age, sex, performance status and smoking history. All trials had similar chemotherapy outcomes (PFS 6, 4.9, 4.8 mos) suggesting similar populations. Network meta-analysis showed no difference between P+C and C alone in OS (HR 0.85, 95%CI 0.45-1.59, p = 0.60) or PFS (HR 0.73, 95%CI 0.48-1.1, p = 0.13), but P+C was associated with higher ORR (+16.9%, 95%CI 0.7-33%, p = 0.04). RMST analysis suggested fewer early PFS events with P+C (0-6 mo RMST ratio 1.25, RMST difference 1.02 mo, p = 0.002), with the difference disappearing at 1 year (0-12 mo RMST ratio 1.16, p = 0.07). No difference in RMST for OS was found. Overall toxicities, hematologic and grade 3-5 toxicities were higher with P+C compared with P alone (table). Conclusions: Among patients with &gt; / = 50% PD-L1 positive NSCLC, P+C did not improve OS or PFS compared with P alone, but was associated with higher ORR. RMST analysis suggested fewer early progression events using P+C. [Table: see text]

Correlation of Milestone Restricted Mean Survival Time Ratio With Overall Survival Hazard Ratio in Randomized Clinical Trials of Immune Checkpoint Inhibitors

Immune checkpoint inhibitors (ICIs) have unique patterns of response and survival that differ from conventional chemotherapies. Novel intermediate end points are urgently required to detect the early signals of ICI activity. To evaluate milestone rate (Kaplan-Meier estimates of survival probabilities at given time points) and milestone restricted mean survival time (RMST, the area under survival curves up to given time points) as potential intermediate end points for ICI trials. Electronic databases (pre-MEDLINE, MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials) were searched for randomized clinical trials published between January 1, 2000, and December 31, 2017. Phase 2 and phase 3 randomized clinical trials evaluating ICIs in advanced solid tumors. Two investigators extracted the data and reconstructed individual patient data to estimate the milestone rate or milestone RMST from the published Kaplan-Meier curves. Trial-level milestone rates or milestone RMSTs were estimated for 6-month and 9-month progression-free survival (PFS) and 9-month and 12-month overall survival (OS). A weighted linear regression model evaluated the correlations of ratios of milestone rates or milestone RMSTs with OS hazard ratios (HRs). Twenty-six trials examining 8 different tumor types were identified, including 12 892 patients. Overall survival HR was correlated with the ratio of 9-month OS milestone rate (R2 = 0.45; 95% CI, 0.27-0.74), and with the ratio of 12-month OS milestone rate (R2 = 0.40; 95% CI, 0.22-0.70). The ratio of 9-month OS milestone RMST (R2 = 0.60; 95% CI, 0.28-0.74) and ratio of 12-month OS milestone RMST were correlated with OS HR (R2 = 0.64; 95% CI, 0.42-0.78). No correlations were observed between OS HR and the ratio of 6-month or 9-month PFS milestone rates or milestone RMSTs. Ratios of OS milestone RMSTs had a stronger correlation with OS HRs than ratios of OS milestone rates, whereas ratios of PFS milestone rates and ratios of PFS milestone RMSTs were not correlated with OS HRs. The OS milestone RMST could be further studied as an intermediate end point in future ICI trials.

Application of Bayesian evidence synthesis to modelling the effect of ketogenic therapy on survival of high grade glioma patients

BackgroundKetogenic therapy in the form of ketogenic diets or calorie restriction has been proposed as a metabolic treatment of high grade glioma (HGG) brain tumors based on mechanistic reasoning obtained mainly from animal experiments. Given the paucity of clinical studies of this relatively new approach, our goal is to extrapolate evidence from the greater number of animal studies and synthesize it with the available human data in order to estimate the expected effects of ketogenic therapy on survival in HGG patients. At the same time we are using this analysis as an example for demonstrating how Bayesianism can be applied in the spirit of a circular view of evidence.ResultsA Bayesian hierarchical model was developed. Data from three human cohort studies and 17 animal experiments were included to estimate the effects of four ketogenic interventions (calorie restriction/ketogenic diets as monotherapy/combination therapy) on the restricted mean survival time ratio in humans using various assumptions for the relationships between humans, rats and mice. The impact of different biological assumptions about the relevance of animal data for humans as well as external information based on mechanistic reasoning or case studies was evaluated by specifying appropriate priors. We provide statistical and philosophical arguments for why our approach is an improvement over existing (frequentist) methods for evidence synthesis as it is able to utilize evidence from a variety of sources. Depending on the prior assumptions, a 30–70% restricted mean survival time prolongation in HGG patients was predicted by the models. The highest probability of a benefit (> 90%) for all four ketogenic interventions was obtained when adopting an enthusiastic prior based on previous case reports together with assuming synergism between ketogenic therapies with other forms of treatment. Combinations with other treatments were generally found more effective than ketogenic monotherapy.ConclusionsCombining evidence from both human and animal studies is statistically possible using a Bayesian approach. We found an overall survival-prolonging effect of ketogenic therapy in HGG patients. Our approach is best compatible with a circular instead of hierarchical view of evidence and easy to update once more data become available.

Prescription Drug Coverage and Outcomes of Myeloma Therapy Among Medicare Beneficiaries.

Novel parenteral (bortezomib) and oral (lenalidomide) therapies have improved survival in myeloma, but the standard Medicare benefit covers only parenteral drugs. We examined the association between prescription drug coverage, receipt of therapy, and survival among Medicare beneficiaries with myeloma. Using SEER-Medicare data, we identified enrollment in a Medicare Part D plan (PDP) or other creditable prescription drug coverage (OCC) among 9,755 beneficiaries who were diagnosed with myeloma in 2006 to 2011. We examined the receipt of active myeloma therapy and that of classic cytotoxic agents or bortezomib as first-line regimen and overall survival. We report relative risk (RR) for binary outcome comparisons and 3-year restricted mean survival time (RMST) ratios, with 95% CI, adjusting for baseline patient- and disease-related characteristics. Beneficiaries with diffuse large B-cell lymphoma, a cancer that is uniformly treated with parenteral chemotherapy, served as a comparison cohort. Compared with beneficiaries without prescription drug coverage, PDP or OCC enrollees were more likely to receive active myeloma care, and PDP enrollees were less frequently treated with parenteral agents (adjusted RR, 0.86; 95% CI, 0.80 to 0.93) or classic cytotoxic agents in particular (RR, 0.62; 95% CI, 0.51 to 0.76). Overall survival was significantly better for beneficiaries with PDP coverage (adjusted RMST ratio, 1.16; 95% CI, 1.11 to 1.20) or OCC (RMST ratio, 1.16; 95% CI, 1.12 to 1.21). In contrast, we observed no survival differences by prescription drug coverage status in the control cohort with lymphoma. Prescription drug coverage is associated with decreased use of classic cytotoxic chemotherapy and better survival among Medicare beneficiaries with myeloma, which suggests improved access to all existing treatment options. As oral targeted agents increasingly replace parenteral chemotherapy in oncology, adjustments in coverage policy are needed to ensure access to optimal treatment.