Difference In Restricted Mean Survival Time Research Articles

Survival outcomes of population-wide colonoscopy screening: reanalysis of the NordICC data

BackgroundColonoscopy as a common screening practice to prevent colorectal cancer lacks strong evidence. NordICC, the first randomized trial of colonoscopy screening, reported no clear clinical benefit for colonoscopy in the intention-to-screen population with suggested benefit in the risk of colorectal incidence and cancer-specific mortality in the per-protocol analyses. However, although the study was designed to perform survival analysis, no survival outcomes were reported since the underlying assumption for hazard ratio was not valid. We aimed to assess whether colonoscopy screening is associated with improved survival outcomes compared with usual care.MethodsWe reconstructed patient-level data from the Kaplan-Meier estimator of the primary endpoints reported in NordICC for the intention-to-screen and adjusted per-protocol populations. The restricted-mean survival time difference (RMST-D) and restricted-mean time loss ratio (RMTL-R), which are robust alternatives to the hazard ratio without specific model assumptions, were calculated for colorectal cancer incidence and death.ResultsIn this study, no significant difference in colorectal cancer incidence over 10 years was found in the intention-to-screen population (RMST-D: -0.68 days, 95% CI -3.9–2.6; RMTL-R: 1.04, 95% CI 0.88–1.22) or in the per-protocol analysis population (RMST-D: -2.9 days, 95% CI -6.5–0.67; RMTL-R: 1.15, 95% CI 0.97–1.35). In the intention-to-screen population, inviting individuals to colonoscopy did not improve colorectal-cancer death (RMST-D: -0.29 days, 95% CI -1.6–1.0; RMTL-R: 1.07, 95% CI 0.78–1.48). Over 10 years, in the per-protocol analysis, individuals who underwent colonoscopy survived an average of 1.1 more days free of colorectal cancer, but this difference was not statistically significant (RMST-D: 95% CI -0.13–2.3; RMTL-R: 0.72, 95% CI 0.49–1.07).ConclusionsIn this reanalysis of the NordICC data, no evidence of improvement in survival outcomes for participants invited to undergo colonoscopy compared to usual care was identified, even when assuming that all invited participants did undergo colonoscopy. Thus, our results do not support the use of colonoscopy as a population-wide screening test as a mean to decrease colorectal cancer incidence or death.RegistryNot applicable.

Eight-Year Outcomes of Cardiosphere-Derived Cells in Single Ventricle Congenital Heart Disease.

Cardiosphere-derived cell (CDC) infusion was associated with better clinical outcomes at 2 years in patients with single ventricle heart disease. The current study investigates time-to-event outcomes at 8 years. This cohort enrolled patients with single ventricles who underwent stage 2 or stage 3 palliation from January 2011 to January 2015 at 8 centers in Japan. The primary outcomes were time-dependent CDC treatment effects on death and late complications during 8 years of follow-up, assessed by restricted mean survival time. Among 93 patients enrolled (mean age, 2.3±1.3 years; 56% men), 40 received CDC infusion. Overall survival for CDC-treated versus control patients did not differ at 8 years (hazard ratio [HR], 0.60 [95% CI, 0.21-1.77]; P=0.35). Treatment effect had nonproportional hazards for death favoring CDCs at 4 years (restricted mean survival time difference +0.33 years [95% CI, 0.01-0.66]; P=0.043). In patients with heart failure with reduced ejection fraction, CDC treatment effect on survival was greater over 8 years (restricted mean survival time difference +1.58 years [95% CI, 0.05-3.12]; P=0.043). Compared with control participants, CDC-treated patients showed lower incidences of late failure (HR, 0.45 [95% CI, 0.21-0.93]; P=0.027) and adverse events (subdistribution HR, 0.50 [95% CI, 0.27-0.94]; P=0.036) at 8 years. By 8 years, CDC infusion was associated with lower hazards of late failure and adverse events in single ventricle heart disease. CDC treatment effect on survival was notable by 4 years and showed a durable clinical benefit in patients with heart failure with reduced ejection fraction over 8 years. URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01273857 and NCT01829750.

Condiciones geriátricas y estrategia invasiva en pacientes frágiles con IAMSEST. Análisis de subgrupos de un ensayo clínico aleatorizado

Introduction and objectives Invasive management in frail patients with non–ST-segment elevation myocardial infarction (NSTEMI) remains controversial. We investigated the impact of various geriatric conditions.Methods The MOSCA-FRAIL trial included 167 adults aged ≥ 70 years with frailty (Clinical Frailty Scale [CFS] ≥ 4 points) and NSTEMI, who were randomized to either an invasive (n = 84) or conservative (n = 83) strategy. In addition to frailty, we measured activities of daily living (Barthel index), cognitive impairment (Pfeiffer test), and comorbidities (Charlson index). The primary endpoint was the difference (invasive minus conservative) in restricted mean survival time (RMST) for all-cause mortality at a median follow-up of 3.9 years.Results A total of 93 patients died. The RMST difference favored invasive management at the CFS 25th percentile (CFS = 4; 157 days, 95%CI, 18-295; P = .027), which changed to a nonsignificant effect at the 50th and 75th percentiles. The RMST difference remained nonsignificant, irrespective of the severity of other geriatric assessments. In time-to-event analysis, invasive management was associated with an initially lower life expectancy, peaking at around 1 year, among all subgroups. However, patients with CFS = 4 experienced a benefit at the end of follow-up (181 days, 95%CI, 19-343), whereas those with CFS > 4 did not (−16 days, 95%CI, −217 to 186; interaction P = .16). Subgroups defined by other geriatric markers showed a similar time-dependent trend, albeit with weaker statistical interaction.Conclusions Among adults with frailty and NSTEMI, the CFS might be useful for evaluating the relative risks and benefits of invasive management. A CFS > 4 could serve as a valuable threshold for decision-making.

Causal effect estimation in survival analysis with high dimensional confounders.

With the ever advancing of modern technologies, it has become increasingly common that the number of collected confounders exceeds the number of subjects in a data set. However, matching based methods for estimating causal treatment effect in their original forms are not capable of handling high-dimensional confounders, and their various modified versions lack statistical support and valid inference tools. In this article, we propose a new approach for estimating causal treatment effect, defined as the difference of the restricted mean survival time (RMST) under different treatments in high-dimensional setting for survival data. We combine the factor model and the sufficient dimension reduction techniques to construct propensity score and prognostic score. Based on these scores, we develop a kernel based doubly robust estimator of the RMST difference. We demonstrate its link to matching and establish the consistency and asymptotic normality of the estimator. We illustrate our method by analyzing a dataset from a study aimed at comparing the effects of two alternative treatments on the RMST of patients with diffuse large B cell lymphoma.

Bayesian pairwise meta-analysis of time-to-event outcomes in the presence of non-proportional hazards: A simulation study of flexible parametric, piecewise exponential and fractional polynomial models.

Traditionally, meta-analysis of time-to-event outcomes reports a single pooled hazard ratio assuming proportional hazards (PH). For health technology assessment evaluations, hazard ratios are frequently extrapolated across a lifetime horizon. However, when treatment effects vary over time, an assumption of PH is not always valid. The Royston-Parmar (RP), piecewise exponential (PE), and fractional polynomial (FP) models can accommodate non-PH and provide plausible extrapolations of survival curves beyond observed data. Simulation study to assess and compare the performance of RP, PE, and FP models in a Bayesian framework estimating restricted mean survival time difference (RMSTD) at 50 years from a pairwise meta-analysis with evidence of non-PH. Individual patient data were generated from a mixture Weibull distribution. Twelve scenarios were considered varying the amount of follow-up data, number of trials in a meta-analysis, non-PH interaction coefficient, and prior distributions. Performance was assessed through bias and mean squared error. Models were applied to a metastatic breast cancer example. FP models performed best when the non-PH interaction coefficient was 0.2. RP models performed best in scenarios with complete follow-up data. PE models performed well on average across all scenarios. In the metastatic breast cancer example, RMSTD at 50-years ranged from -14.6 to 8.48 months. Synthesis of time-to-event outcomes and estimation of RMSTD in the presence of non-PH can be challenging and computationally intensive. Different approaches make different assumptions regarding extrapolation and sensitivity analyses varying key assumptions are essential to check the robustness of conclusions to different assumptions for the underlying survival function.

Geriatric conditions and invasive management in frail patients with NSTEMI. A subgroup analysis of a randomized clinical trial

Introduction and objectivesInvasive management in frail patients with non–ST-segment elevation myocardial infarction (NSTEMI) remains controversial. We investigated the impact of various geriatric conditions. MethodsThe MOSCA-FRAIL trial included 167 adults aged ≥ 70 years with frailty (Clinical Frailty Scale [CFS] ≥ 4 points) and NSTEMI, who were randomized to either an invasive (n=84) or conservative (n=83) strategy. In addition to frailty, we measured activities of daily living (Barthel index), cognitive impairment (Pfeiffer test), and comorbidities (Charlson index). The primary endpoint was the difference (invasive minus conservative) in restricted mean survival time (RMST) for all-cause mortality at a median follow-up of 3.9 years. ResultsA total of 93 patients died. The RMST difference favored invasive management at the CFS 25th percentile (CFS=4; 157 days, 95%CI, 18-295; P=.027), which changed to a nonsignificant effect at the 50th and 75th percentiles. The RMST difference remained nonsignificant, irrespective of the severity of other geriatric assessments. In time-to-event analysis, invasive management was associated with an initially lower life expectancy, peaking at around 1 year, among all subgroups. However, patients with CFS=4 experienced a benefit at the end of follow-up (181 days, 95%CI, 19-343), whereas those with CFS >4 did not (−16 days, 95%CI, −217 to 186; interaction P=.16). Subgroups defined by other geriatric markers showed a similar time-dependent trend, albeit with weaker statistical interaction. ConclusionsAmong adults with frailty and NSTEMI, the CFS might be useful for evaluating the relative risks and benefits of invasive management. A CFS >4 could serve as a valuable threshold for decision-making.

Comparative analysis among therapeutic modalities in ruptured hepatocellular carcinoma and identification of imaging predictors for survival

BackgroundSpontaneous rupture of hepatocellular carcinoma (rHCC) poses a life-threatening complication with a mortality rate of 25–75%. Treatment aims at achieving hemostasis and includes options such as trans-arterial embolization, perihepatic packing, and hepatic resection. The optimal treatment remains a subject of debate. Our retrospective review evaluates these treatments and investigates imaging’s role in prognosis for rHCC patients.PurposeWe aimed to compare survival outcomes among rHCC patients who received transarterial embolization (TAE), surgery (perihepatic packing, hepatectomy), or best supportive care (BSC), while also identifying predictive imaging factors in these patients.Materials and methodsAll patients diagnosed with rHCC and admitted to Maharaj Nakorn Chiangmai Hospital between January 2012 and December 2021 were included. We reviewed clinical features, imaging results, treatment modalities, and outcomes. In order to balance pretreatment confounders, inverse probability treatment weighting (IPTW) was employed. Flexible parametric survival regression was utilized to compare survival outcomes and identify imaging factors predicting the survival of rHCC patients. Hazard ratios (HR) and the difference in restricted mean survival time (RMST) were reported.ResultAmong the 186 rHCC patients included, we observed 90-day and 1-year mortality rates of 64% and 84%, respectively. Both the TAE and surgery groups exhibited significantly lower 1-year mortality rates compared to BSC. The HR were 0.56 (95% CI 0.33–0.96) for TAE and 0.52 (95% CI 0.28–0.95) for surgery compared to BSC. Both the TAE and surgery also significantly extended the 1-yeaar life expectancy post-initial treatment when compared to BSC, with an RMST difference of + 55.40 days (95% CI 30.18–80.63) for TAE vs. BSC and + 68.43 days (95% CI 38.77–98.09) for surgery vs. BSC. The presence of active contrast extravasation and bleeding in both lobes were independent prognostic factors for 1-year survival.ConclusionsTAE and surgical treatments provide comparable survival benefits for rHCC patients, extending survival time by approximately 2 months compared to best supportive care. We strongly recommend active management for all rHCC patients whenever possible.

Utilizing machine learning to tailor radiotherapy and chemoradiotherapy for low-grade glioma patients.

There is ongoing uncertainty about the effectiveness of various adjuvant treatments for low-grade gliomas (LGGs). Machine learning (ML) models that predict individual treatment effects (ITE) and provide treatment recommendations could help tailor treatments to each patient's needs. We sought to discern the individual suitability of radiotherapy (RT) or chemoradiotherapy (CRT) in LGG patients using ML models. Ten ML models, trained to infer ITE in 4,042 LGG patients, were assessed. We compared patients who followed treatment recommendations provided by the models with those who did not. To mitigate the risk of treatment selection bias, we employed inverse probability treatment weighting (IPTW). The Balanced Survival Lasso-Network (BSL) model showed the most significant protective effect among all the models we tested (hazard ratio (HR): 0.52, 95% CI, 0.41-0.64; IPTW-adjusted HR: 0.58, 95% CI, 0.45-0.74; the difference in restricted mean survival time (DRMST): 9.11, 95% CI, 6.19-12.03; IPTW-adjusted DRMST: 9.17, 95% CI, 6.30-11.83). CRT presented a protective effect in the 'recommend for CRT' group (IPTW-adjusted HR: 0.60, 95% CI, 0.39-0.93) yet presented an adverse effect in the 'recommend for RT' group (IPTW-adjusted HR: 1.64, 95% CI, 1.19-2.25). Moreover, the models predict that younger patients and patients with overlapping lesions or tumors crossing the midline are better suited for CRT (HR: 0.62, 95% CI, 0.42-0.91; IPTW-adjusted HR: 0.59, 95% CI, 0.36-0.97). Our findings underscore the potential of the BSL model in guiding the choice of adjuvant treatment for LGGs patients, potentially improving survival time. This study emphasizes the importance of ML in customizing patient care, understanding the nuances of treatment selection, and advancing personalized medicine.

Abiraterone or Enzalutamide for Patients With Metastatic Castration-Resistant Prostate Cancer

Abiraterone acetate and enzalutamide are recommended as preferred treatments for metastatic castration-resistant prostate cancer (mCRPC), but differences in their relative efficacy are unclear due to a lack of head-to-head clinical trials. Clear guidance is needed for making informed mCRPC therapeutic choices. To compare clinical outcomes in patients with mCRPC treated with abiraterone acetate or enzalutamide. This retrospective, multicenter cohort study included patients with mCRPC in the US Department of Veterans Affairs health care system who initiated treatment with abiraterone acetate or enzalutamide between January 1, 2014, and October 30, 2022. Abiraterone acetate or enzalutamide. The study used inverse probability of treatment weighting to balance baseline characteristics between patients initiating abiraterone acetate or enzalutamide and evaluated restricted mean survival time (RMST) differences in overall survival (OS), prostate cancer-specific survival (PCS), time to next treatment switching or death (TTS), and time to prostate-specific antigen (PSA) response (TTR) at different time points after treatment initiation. The study included 5779 patients (median age, 74.42 years [IQR, 68.94-82.14 years]). Median follow-up was between 38 and 60 months. Patients initiating enzalutamide on average had longer OS than those initiating abiraterone acetate, with RMSTs of 24.29 months (95% CI, 23.58-24.99 months) and 23.38 months (95% CI, 22.85-23.92 months), respectively, and a difference in RMST of 0.90 months (95% CI, 0.02-1.79 months) at 4 years. Similarly, TTS and TTR were improved in patients initiating enzalutamide, with an RMST at 4 years of 1.95 months (95% CI, 0.92-2.99 months) longer for TTS and 3.57 months (95% CI, 1.76-5.38 months) shorter for TTR. For PCS, the RMST at 2 years was 0.48 months (95% CI, 0.01-0.95 months) longer. An examination of subgroups identified that enzalutamide initiation was associated with longer RMST in OS among patients without prior docetaxel treatment (1.14 months; 95% CI, 0.19-2.10 months) and in those with PSA doubling time of 3 months or longer (2.23 months; 95% CI, 0.81-3.66 months) but not among patients with prior docetaxel (-0.25 months; 95% CI, -2.59 to 2.09 months) or with PSA doubling time of less than 3 months (0.05 months; 95% CI, -1.05 to 1.15 months). In this cohort study of patients with mCRPC, initiation of enzalutamide was associated with small but statistically significant improvements in OS, PCS, TTS, and TTR compared with initiation of abiraterone acetate. The improvements were more prominent in short-term outcomes, including TTS and TTR, and in patient subgroups without prior docetaxel or with PSA doubling time longer than 3 months.

Impact of Thoracic Duct Resection on Long-Term Survival After Esophagectomy: Individual Patient Data Meta-analysis.

Radical esophagectomy, including thoracic duct resection (TDR), has been proposed to improve regional lymphadenectomy and possibly reduce the risk of locoregional recurrence. However, because of its impact on immunoregulation, some authors have expressed concerns about its possible detrimental effect on long-term survival. The purpose of this review was to assess the influence of TDR on long-term survival. PubMed, MEDLINE, Scopus, and Web of Science databases were searched through 15 March 2024. Overall survival (OS), cancer specific survival (CSS), and disease-free survival (DFS) were primary outcomes. Restricted mean survival time difference (RMSTD), risk ratio (RR), standardized mean difference (SMD), and 95% confidence intervals (CI) were used as pooled effect size measures. The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology was employed to evaluate the certainty of evidence. The analysis included six studies with 5756 patients undergoing transthoracic esophagectomy. TDR was reported in 49.1%. Patients' ages ranged from 27 to 79 years and 86% were males. At 4-year follow-up, the multivariate meta-analysis showed similar results for the comparison noTDR versus TDR in term of OS [- 0.8 months, 95% confidence interval (CI) - 3.1, 1.3], CSS (0.1 months, 95% CI - 0.9, 1.2), and DFS (1.5 months, 95% CI - 2.6, 5.5). TDR was associated with a significantly higher number of harvested mediastinal lymph nodes (SMD 0.57, 95% CI 0.01-1.13) and higher risk of postoperative chylothorax (RR = 1.32; 95% CI 1.04-2.23). Anastomotic leak and pulmonary complications were comparable. TDR seems not to improve long-term OS, CSS, and DFS regardless of tumor stage. Routine TDR should not be routinely recommended during esophagectomy.

Exploring the Bidirectional Relationship Between Periodontitis and Rheumatoid Arthritis in a Large Danish Cohort.

We investigated the bidirectional relationship between rheumatoid arthritis (RA) and periodontitis and their cross-sectional association using national administrative health care data. The sample included 3,308,903 individuals aged 20 to 79 years who resided in Denmark in 2000 and had remained free of RA and periodontitis in the previous 10 years. RA and periodontitis were defined using diagnosis and treatment codes. Marginal structural survival models were employed to estimate the effects of RA on periodontitis incidence and vice versa from 2000 to 2017. Using a cross-sectional sample of 2,574,536 individuals from 2017, the association of periodontitis with RA was investigated using regression analyses and probabilistic quantitative bias analyses, simulating RA and periodontitis misclassification and unmeasured confounding of smoking. Between 2000 and 2017, 20,348 individuals developed RA and 740,799 developed periodontitis. The estimated hazard ratio (HR) for the effect of periodontitis on incident RA was 1.05 (95% confidence interval [CI] 0.88-1.25), resulting in a restricted mean survival time difference of one day. The HR for the effect of RA on incident periodontitis was 0.84 (95% CI 0.80-0.88), corresponding to a restricted mean survival time difference of 151 days. Cross-sectionally, the unadjusted prevalence ratio for the association was 1.15 (95% CI 1.11-1.19), whereas the estimate adjusted for measured and simulated confounding was practically null (0.99, 95% simulation interval 0.93-1.04). These findings challenge previously reported bidirectional relationships between periodontitis and RA, pointing to potential residual confounding as an important link and prompting reconsideration of the biologic plausibility and clinical significance of these associations.

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.

Survival benefits of postoperative radiotherapy in patients with cT1 − 2N1M0 breast cancer after neoadjuvant chemotherapy: a SEER-based population study

BackgroundWhether patients with cT1 − 2N1M0 breast cancer can benefit from postoperative radiotherapy (RT) after receiving neoadjuvant chemotherapy (NAC) has been controversial. Therefore, the purpose of this study was to explore whether postoperative RT can benefit this group of patients in terms of survival.MethodsWe used Surveillance, Epidemiology, and End Results (SEER) data to conduct a retrospective review of women with cT1 − 2N1M0 breast cancer diagnosed between 20 and 80 years of age who received NAC between 2010 and 2015. Our study compared the impact of postoperative RT on overall survival (OS) and cancer-specific survival (CSS) in breast cancer patients using propensity score matching (PSM) and performed subgroup analysis.ResultsThis study finally included 1092 cT1 − 2N1M0 breast cancer patients. Regardless of the patient’s PSM status, postoperative RT was significantly associated with OS of cT1-2N1M0 breast cancer patients who received NAC. Specifically, the 10-year OS rate was 78.7% before PSM matching, compared with 71.1% in patients who did not receive postoperative RT, and the difference was more significant after PSM matching, which was 83.1% and 71.1% respectively. However, postoperative RT did not significantly benefit CSS in patients with cT1 − 2N1M0 breast cancer who received NAC. The 10-year CSS rate was 81.4% VS 76.2% (P = 0.085) before PSM matching and 85.8% VS 76.2%(P = 0.076) after matching. Due to the intersection of OS and CSS curves, this restricted mean survival time (RMST) method was chosen as a supplement. After 60 months, the OS difference in RMST between the postoperative RT group and the non-radiotherapy (noRT) group was 7.37 months (95%CI: 0.54–14.21; P = 0.034), and the CSS difference was 5.18 months (95%CI: -1.31-11.68; P = 0.118). Subgroup analysis found that in patients with right-sided breast cancer, postoperative RT improved the patient’s OS (HR = 0.45, 95%CI: 0.21–0.95, P = 0.037) and CSS (HR = 0.42, 95%CI: 0.18–0.98, P = 0.045).ConclusionsOur results showed that additional postoperative RT improved the OS of cT1 − 2N1M0 breast cancer patients who received NAC, but failed to improve their CSS. It is worth noting that in the subgroup analysis of patients with right-sided breast cancer, we observed significant improvements in OS and CSS. And further prospective studies are still needed to verify the effect of postoperative RT in different subgroups.

Harnessing cell-free orphan non-coding RNAs as a predictive measure of long-term survival in neoadjuvant breast cancer therapy.

585 Background: Pathologic complete response (pCR) is a valuable metric for predicting survival following neoadjuvant therapy (NAT) in breast cancer; however, blood-based biomarkers may refine the prediction of treatment outcomes and inform follow-up treatment decisions. Orphan non-coding RNAs (oncRNAs) are a novel category of small RNAs that are present in tumors and largely absent in healthy tissue. Here, we explore the feasibility of a tumor-naive oncRNA-based liquid biopsy assay for predicting distant recurrence-free survival (DRFS) in breast cancer patients using a standard blood draw. Methods: Our cohort included 538 high-risk breast cancer patients from the multicenter I-SPY2 trial having serum available after NAT and before surgery (timepoint T3). Of the 538 patients (mean age: 48.8 ± 10.3), 191 (36%) achieved pCR. We isolated small RNA from 0.8 mL of patient serum and sequenced it at an average depth of 50 million 100-bp single-end reads. We used our catalog of tumor-derived oncRNAs, discovered in The Cancer Genome Atlas, to develop an AI model for predicting tumor burden based on tumor size. Our AI model was trained on oncRNA profiles from an independent cohort of 719 serum samples collected at diagnosis from individuals with cancer. We assessed tumor burden by oncRNA in the I-SPY2 cohort at T3 and associated this measure with DRFS using robust cutpoints established for each of the two pCR groups: high- ( n=70) and low-burden ( n=468) cutpoints were verified through cross-validation and almost all folds converged on a single value, which we used in our analysis. Results: The continuous oncRNA-derived tumor burden at T3 had a hazards ratio (HR) of 2.4 (95% CI: 1.1–5.1) for predicting DRFS. This measure remained significant in multivariate Cox models that included pCR (HR = 2.7 [1.3–5.6]) or residual cancer burden (RCB II/III versus 0/I; HR = 3.4 [1.6–7.1]). Patients with pCR had a 3-year DRFS of 94%; patients with pCR having low ( n=180) versus high ( n=11) oncRNA burden resulted in 95% and 73% 3-year DRFS, respectively (HR = 7.4 [2.3–24]). Those without pCR had a 3-year DRFS of 78% and stratification by oncRNA burden resulted in 85% and 71% 3-year DRFS for the low ( n=288) and high ( n=59) burden groups, respectively (HR=2.4 [1.5–3.9]). Importantly, we saw no restricted mean survival time difference (RMST) at 3 years between those with and without pCR among the high oncRNA burden group (0.1-month difference, p=0.97). Conclusions: We demonstrate the utility of a tumor-naive, oncRNA-derived tumor burden AI model as a predictive measure of treatment outcome and as a prognostic biomarker that can be used in addition to pCR to further stratify patients as low or high risk of recurrence. Integration of our oncRNA assay with existing biomarkers and clinicopathologic variables, has the potential to add value for predicting outcomes and prioritizing patients that would benefit from additional care.

When to stop immunotherapy for advanced melanoma: Emulation of target trials.

9521 Background: Immune checkpoint inhibitors (ICI) have demonstrated their effectiveness with a 7.5-year overall survival (OS) close to 50% for advanced stages. The design of clinical trials allowed treatment until progression or toxicity, or for a maximum duration of two years. Prolonged follow-up of responders after cessation shows sustained response and a low risk of relapse in the months following cessation. As of yet, the optimal duration of anti-PD-1 therapy for metastatic melanoma remains unestablished. The objective of this work was to evaluate the optimal duration of ICI. Methods: We conducted emulated trials using the cloning, weighting and censoring approach. Each emulated trial aimed at comparing the causal effect of stopping versus continuing ICI at a specific timepoint, in patients still under treatment and with disease control at that time. Results: The study comprised 1017 participants to the MELBASE cohort. Results of the 6-month discontinuation emulated trial showed a significantly lower OS if treatment was discontinued, compared to continuing treatment for at least three months. The 48-month survival difference was 37.8% (95% confidence interval [CI] 19.8 to 60.5), and the corresponding restricted mean survival time difference 8.3 months (95% CI: 4.1 to 12.7). The 12-month and 18-month discontinuation emulated trials both showed no evidence of benefit of either discontinuing or continuing ICI at any of those timepoints. The 24-month discontinuation emulated trial results were more in favor of stopping compared to continuing treatment at that decision point, with an absolute 48-month survival 10.5% higher (95% CI 4.4 to 18.1). Conclusions: These results suggest that a one-year course of immunotherapy is both necessary and sufficient for patients with advanced melanoma. Prolonged treatment beyond 2 years does not appear to be beneficial in terms of survival and could even be detrimental.[Table: see text]

Time- vs Step-Based Physical Activity Metrics for Health

Current US physical activity (PA) guidelines prescribe moderate to vigorous PA (MVPA) time of at least 150 minutes per week for health. An analogous step-based recommendation has not been issued due to insufficient evidence. To examine the associations of MVPA time and step counts with all-cause mortality and cardiovascular disease (CVD). This cohort study analyzed data from an ongoing follow-up study of surviving participants of the Women's Health Study, a randomized clinical trial conducted from 1992 to 2004 in the US to evaluate use of low-dose aspirin and vitamin E for preventing cancer and CVD. Participants were 62 years or older who were free from CVD and cancer, completed annual questionnaires, and agreed to measure their PA with an accelerometer as part of a 2011-2015 ancillary study. Participants were followed up through December 31, 2022. Time spent in MVPA and step counts, measured with an accelerometer for 7 consecutive days. The associations of MVPA time and step counts with all-cause mortality and CVD (composite of myocardial infarction, stroke, and CVD mortality) adjusted for confounders. Cox proportional hazards regression models, restricted mean survival time differences, and area under the receiver operating characteristic curve (AUC) were used to evaluate the associations. A total of 14 399 women (mean [SD] age, 71.8 [5.6] years) were included. The median (IQR) MVPA time and step counts were 62 (20-149) minutes per week and 5183 (3691-7001) steps per day, respectively. During a median (IQR) follow-up of 9.0 (8.0-9.9) years, the hazard ratios (HR) per SD for all-cause mortality were 0.82 (95% CI, 0.75-0.90) for MVPA time and 0.74 (95% CI, 0.69-0.80) for step counts. Greater MVPA time and step counts (top 3 quartiles vs bottom quartile) were associated with a longer period free from death: 2.22 (95% CI, 1.58-2.85) months and 2.36 (95% CI, 1.73-2.99) months at 9 years follow-up, respectively. The AUCs for all-cause mortality from MVPA time and step counts were similar: 0.55 (95% CI, 0.52-0.57) for both metrics. Similar associations of these 2 metrics with CVD were observed. Results of this study suggest that among females 62 years or older, MVPA time and step counts were qualitatively similar in their associations with all-cause mortality and CVD. Step count-based goals should be considered for future guidelines along with time-based goals, allowing for the accommodation of personal preferences.

Does Thoracic Duct Ligation at the Time of Esophagectomy Impact Long-Term Survival? An Individual Patient Data Meta-Analysis.

Background: Thoracic duct ligation (TDL) during esophagectomy has been proposed to reduce the risk of postoperative chylothorax. Because of its role in immunoregulation, some authors argued that it had an unfavorable TDL effect on survival. The aim of this study was to analyze the effect of TDL on overall survival (OS). Methods: PubMed, MEDLINE, Scopus, and Web of Science were searched through December 2023. The primary outcome was 5-year OS. The restricted mean survival time difference (RMSTD), hazard ratios (HRs), and 95% confidence intervals (CI) were used as pooled effect size measures. The GRADE methodology was used to summarize the certainty of the evidence. Results: Five studies (3291 patients) were included. TDL was reported in 54% patients. The patients' age ranged from 49 to 69, 76% were males, and BMI ranged from 18 to 26. At the 5-year follow-up, the combined effect from the multivariate meta-analysis is -3.5 months (95% CI -6.1, -0.8) indicating that patients undergoing TDL lived 3.5 months less compared to those without TDL. TDL was associated with a significantly higher hazard for mortality at 12 months (HR 1.54, 95% CI 1.38-1.73), 24 months (HR 1.21, 95% CI 1.12-1.35), and 28 months (HR 1.14, 95% CI 1.02-1.28). TDL and noTDL seem comparable in terms of the postoperative risk for chylothorax (RR = 0.66; p = 0.35). Conclusions: In this study, concurrent TDL was associated with reduced 5-year OS after esophagectomy. This may suggest the need of a rigorous follow-up within the first two years of follow-up.

Assessing the effect of metastasis-directed therapy in oligometastatic disease using the restricted mean survival time

BackgroundMetastasis-directed therapy (MDT) with stereotactic body radiotherapy (SBRT) is emerging as an effective therapeutic option for oligometastatic disease (OMD). However, a lack of phase III data, consensus guidelines, and toxicity concerns limit its widespread use. Randomized controlled trials (RCTs) routinely report hazard ratios (HRs) and medians that lack clear clinical and robust interpretation. Restricted-mean survival time (RMST) is the duration of time a patient is expected to survive over the follow-up period, providing a robust and interpretable alternative. We analyzed the efficacy of SBRT using RMST.MethodsAll registered RCTs of ablative radiotherapy in OMD in ClinicalTrials.gov through 2022 were identified. Data were reconstructed from Kaplan–Meier curves, and the HRs and RMST differences were estimated for surrogate endpoints (SEs) and overall survival (OS).ResultsSix studies comprising 426 patients met the inclusion criteria. The RMST differences for SEs ranged from 4.6 months in a study by Iyengar et al. to 11.1 months in SABR-COMET. The RMST differences for OS in SABR-COMET, Gomez et al., and SINDAS studies were 12.6, 15 and 7.9 months, respectively.ConclusionRMST demonstrates the efficacy of local treatment in OMD. Representing the expected survival time, this method effectively communicates outcomes to patients and clinicians.

Long-Term Impact of Severe Postoperative Complications after Esophagectomy for Cancer: Individual Patient Data Meta-Analysis.

Severe postoperative complications (SPCs) may occur after curative esophagectomy for cancer and are associated with prolonged hospital stay, augmented costs, and increased in-hospital mortality. However, the effect of SPCs on survival after esophagectomy is uncertain. To assess the impact of severe postoperative complications (SPCs) on long-term survival following curative esophagectomy for cancer, we conducted a systematic search of PubMed, MEDLINE, Scopus, and Web of Science databases up to December 2023. The included studies examined the relationship between SPCs and survival outcomes, defining SPCs as Clavien-Dindo grade > 3. The primary outcome measure was long-term overall survival (OS). We used restricted mean survival time difference (RMSTD) and 95% confidence intervals (CIs) to calculate pooled effect sizes. Additionally, we applied the GRADE methodology to evaluate the certainty of the evidence. Ten studies (2181 patients) were included. SPCs were reported in 651 (29.8%) patients. The RMSTD overall survival analysis shows that at 60-month follow-up, patients experiencing SPCs lived for 8.6 months (95% Cis -12.5, -4.7; p < 0.001) less, on average, compared with no-SPC patients. No differences were found for 60-month follow-up disease-free survival (-4.6 months, 95% CIs -11.9, 1.9; p = 0.17) and cancer-specific survival (-6.8 months, 95% CIs -11.9, 1.7; p = 0.21). The GRADE certainty of this evidence ranged from low to very low. This study suggests a statistically significant detrimental effect of SPCs on OS in patients undergoing curative esophagectomy for cancer. Also, a clinical trend toward reduced CSS and DFS was perceived.

Individualized Treatment Effect Prediction with Machine Learning — Salient Considerations

BackgroundMachine learning–based approaches that seek to accomplish individualized treatment effect prediction have gained traction; however, some salient challenges lack wider recognition.MethodsWe describe key methodologic considerations for individualized treatment effect prediction models using data from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial for spironolactone in heart failure with preserved ejection fraction. The causal survival forest algorithm was used for model development. Calibration and discrimination were evaluated using a bootstrapping-based internal validation procedure. Observed benefits were described for predicted benefit quartiles and quartiles of a known effect modifier: ejection fraction. A negative control analysis with noncardiovascular death as the outcome was implemented to detect confounding.ResultsAmong 3445 participants, 671 events occurred over a median of 3.3 years of follow-up. In internal validation, a higher average observed benefit was noted among patients in the highest quartile of predicted benefit. The median (interquartile range) of the observed restricted mean survival time difference at 3.3 years at the highest quartile of model-predicted benefit was 62 days (32 to 83) and was 47 days (26 to 67) at the lowest quartile of ejection fraction. Body-mass index had higher contribution to prediction of benefit relative to other included measures (33.7% vs. glomerular filtration rate [27.3%], ejection fraction [15.1%], and younger age [12.8%]) No benefit was observed for noncardiovascular death at higher model-predicted benefit quartiles, although benefit for noncardiovascular death was observed at lower quartiles.ConclusionsCarefully applied and validated predictive models hold promise in identifying heterogeneous treatment effects and are useful for hypothesis generation regarding the role of phenotypic characteristics in modifying the benefit of experimental interventions in clinical trials. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00094302.)