Immortal Time Research Articles

Decreased Long-Term Survival of Patients With Newly Diagnosed Cancer Discharged Home After Unplanned ICU Admission: A Prospective Observational Study.

To compare the 18-month survival between patients with newly diagnosed cancer discharged home after early unplanned ICU admission and those without early unplanned ICU admission; we also evaluated the frequency and risk factors for early unplanned ICU admission. Observational study with prospectively collected data from September 2019 to June 2021 and 18 months follow-up. Single dedicated cancer center in São Paulo, Brazil. We screened consecutive adults with suspected cancer and included those with histologically proven cancer from among 20 highly prevalent cancers. None. The exposure was early unplanned ICU admission, defined as admission for medical reasons or urgent surgery during the first 6 months after cancer diagnosis. The main outcome was 18-month survival after cancer diagnosis, and the main analysis was Cox's proportional hazards model adjusted for confounders and immortal time bias. Propensity score matching was used in the sensitivity analysis. We screened 4738 consecutive adults with suspected cancer and included 3348 patients. Three hundred twelve (9.3%) had early unplanned ICU admission, which was associated with decreased 18-month survival both in the unadjusted (hazard ratio, 4.03; 95% CI, 2.89-5.62) and adjusted (hazard ratio, 1.84; 95% CI, 1.29-2.64) models. The sensitivity analysis confirmed the results because the groups were balanced after matching, and the 18-month survival of patients with early ICU admission was lower compared with patients without early ICU admission (87.0% vs. 93.9%; p = 0.01 log-rank test). Risk factors for early unplanned ICU admission were advanced age, comorbidities, worse performance status, socioeconomic deprivation, metastatic tumors, and hematologic malignancies. Patients with newly diagnosed cancer discharged home after early unplanned ICU admission have decreased 18-month survival compared with patients without early unplanned ICU admission.

Injurious Fall Risk Differences Among Older Adults With First-Line Depression Treatments

One-third of older adults in the US have depression, often treated with psychotherapy and antidepressants. Previous studies suggesting an increased risk of falls and related injuries (FRI) associated with antidepressant use may be affected by confounding by indication or immortal time bias. To evaluate the association between FRI risk and first-line treatments in older adults with depression. This cohort study used a target trial emulation framework with a cloning-censoring-weighting approach with Medicare claims data from 2016 to 2019. Participants included fee-for-service beneficiaries aged 65 years or older with newly diagnosed depression. Data were analyzed from October 1, 2023, to March 31, 2024. First-line depression treatments including psychotherapy, sertraline, escitalopram, citalopram, mirtazapine, duloxetine, trazodone, fluoxetine, bupropion, paroxetine, and venlafaxine. One-year FRI rate, restricted mean survival time (RMST), and adjusted hazard ratio (aHR) with 95% CI. Among 101 953 eligible beneficiaries (mean [SD] age, 76 [8] years), 63 344 (62.1%) were female, 7404 (7.3%) were Black individuals, and 81 856 (80.3%) were White individuals. Compared with the untreated group, psychotherapy use was not associated with FRI risk (aHR, 0.94 [95% CI, 0.82-1.17]), while other first-line antidepressants were associated with a decreased FRI risk (aHR ranged from 0.74 [95% CI, 0.59-0.89] for bupropion to 0.83 [95% CI, 0.67-0.98] for escitalopram). The FRI incidence ranged from 63 (95% CI, 53-75) per 1000 person-year for those treated with bupropion to 87 (95% CI, 83-90) per 1000 person-year for those who were untreated. The RMST ranged from 349 (95% CI, 346-350) days for those who were untreated to 353 (95% CI, 350-356) days for those treated with bupropion. In this cohort study of older Medicare beneficiaries with depression, first-line antidepressants were associated with a decreased FRI risk compared with untreated individuals. These findings provide valuable insights into their safety profiles, aiding clinicians in their consideration for treating depression in older adults.

Dementia Incidence in Survivors of Multiple Myeloma: A National Case-Control Study Conducted in Korea (The CAREMM-2106 Study)

BackgroundDementia, a growing global health issue, affects older adults and specific groups like long-term cancer survivors. The link between cancer survival and dementia is debated. Multiple myeloma (MM), a common blood cancer in older adults, is often linked with cognitive issues. This study investigated dementia incidence in long-term MM survivors using Korean national data. MethodsA retrospective case-control study used data from the Korea National Health Insurance Service (KNHIS), covering about 50 million Koreans. Patients diagnosed with MM between 2009 and 2020 formed the case cohort, while the control cohort included matched individuals without MM using propensity-score matching. Analyzing baseline characteristics, comorbidities, and socioeconomic status, the primary outcome was dementia incidence identified via ICD-10 codes. Statistical methods included Kaplan-Meier plots, cause-specific and Fine–Gray subdistribution hazard models, and a 3-year landmark analysis for immortal time bias. ResultsThe study included 33,864 patients, with 16,932 in each cohort. The overall cumulative dementia incidence was lower in the MM cohort compared to controls. However, in the first 3 years, MM patients had a higher dementia risk (HR: 1.711, 95% CI, 1.562-1.874) than controls. After 3 years, the risk significantly decreased (HR: 0.625, 95% CI, 0.560-0.696). Age-specific analysis showed a consistent pattern, particularly among MM patients aged 70-79, where dementia risk increased post-3 years. ConclusionThis study reveals a lower long-term dementia risk in MM survivors compared to non-MM individuals. Further prospective studies are needed to confirm these findings and explore the underlying mechanisms.

Antifibrotics and mortality in idiopathic pulmonary fibrosis: external validity and avoidance of immortal time bias

Background and objectivePooled analyses of previous randomized controlled trials reported that antifibrotics improved survival in patients with idiopathic pulmonary fibrosis (IPF), but the results were only based on short-term outcome data from selected patients who met strict criteria. Observational studies/meta-analyses also suggested that antifibrotics improve survival, but these studies failed to control for immortal time bias that considerably exaggerates drug effects. Therefore, whether antifibrotics truly improve long-term survival in patients with IPF in the real world remains undetermined and requires external validity.MethodsWe used data from the Japanese National Claims Database to estimate the intention-to-treat effect of antifibrotics on mortality. To address immortal time bias, we employed models treating antifibrotic initiation as a time-dependent covariate and target trial emulation (TTE), both incorporating new-user designs for antifibrotics and treating lung transplantation as a competing event.ResultsOf 30,154 patients with IPF, 14,525 received antifibrotics. Multivariate Fine–Gray models with antifibrotic initiation as a time-dependent covariate revealed that compared with no treatment, nintedanib (adjusted hazard ratio [aHR], 0.85; 95% confidence interval [CI], 0.81–0.89) and pirfenidone (aHR, 0.89; 95% CI, 0.86–0.93) were associated with reduced mortality. The TTE model also replicated the associations of nintedanib (aHR, 0.69; 95% CI, 0.65–0.74) and pirfenidone (aHR, 0.81; 95% CI, 0.78–0.85) with reduced mortality. Subgroup analyses confirmed this association regardless of age, sex, and comorbidities, excluding certain subpopulations.ConclusionsThe results of this large-scale real-world analysis support the generalizability of the association between antifibrotics and improved survival in various IPF populations.

Bariatric surgery and all-cause mortality: A methodological review of studies using a non-surgical comparator.

Non-randomized studies on bariatric surgery have reported large reductions in mortality within 6-12 months after surgery compared with non-surgical patients. It is unclear whether these findings are the result of bias. We searched PubMed to identify all non-randomized studies investigating the effect of bariatric surgery on all-cause mortality compared with non-surgical patients. We assessed these studies for potential confounding and time-related biases. We conducted bias analyses to quantify the effect of these biases. We identified 21 cohort studies that met our inclusion criteria. Among those, 11 were affected by immortal time bias resulting from the misclassification or exclusion of relevant follow-up time. Five studies were subject to potential confounding bias because of a lack of adjustment for body mass index (BMI). All studies used an inadequate comparator group that lacked indications for bariatric surgery. Bias analyses to correct for potential confounding from BMI shifted the effect estimates towards the null [reported hazard ratio (HR): 0.78 vs. bias-adjusted HR: 0.92]. Bias analyses to correct for the presence of immortal time also shifted the effect estimates towards the null (adjustment for 2-year wait time: reported HR: 0.57 vs. bias-adjusted HR: 0.81). Several important sources of bias were identified in non-randomized studies of the effectiveness of bariatric surgery versus non-surgical comparators on mortality. Future studies should ensure that confounding by BMI is accounted for, considering the choice of the comparator group, and that the design or analysis avoids immortal time bias from the misclassification or exclusion.

Effect of Antifibrotic Use on Mortality in Patients with Idiopathic Pulmonary Fibrosis.

Rationale: Observational studies report a significant protective effect of antifibrotics on mortality among patients with idiopathic pulmonary fibrosis (IPF). Many of these studies, however, were subject to immortal time bias because of the mishandling of delayed antifibrotic initiation. Objectives: To evaluate the antifibrotic effect on mortality among patients with IPF using appropriate statistical methods that avoid immortal time bias. Methods: Using a large administrative database, we identified 10,289 patients with IPF, of whom 2,300 used antifibrotics. Treating delayed antifibrotic initiation as a time-dependent variable, three statistical methods were used to control baseline characteristics and avoid immortal time bias. Stratified analysis was performed for patients who initiated antifibrotics early and those who initiated treatment late. For comparison, methods that mishandle immortal time bias were performed. A simulation study was conducted to demonstrate the performance of these models in a wide range of scenarios. Results: All three statistical methods yielded nonsignificant results for the antifibrotic effect on mortality, with the stratified analysis for patients with early antifibrotic initiation suggesting evidence for reduced mortality risk (for all patients, hazard ratio, 0.89; 95% confidence interval, 0.79-1.01; P = 0.08; for patients who were 65 years or older, hazard ratio, 0.85; 95% confidence interval, 0.73-0.98; P = 0.03). Methods that mishandle immortal time bias demonstrated significantly lower mortality risk for antifibrotic users. Bias of these methods was evident in the simulation study, where appropriate methods performed well with little to no bias. Conclusions: Findings in this study did not confirm an association between antifibrotics and mortality, with a stratified analysis showing support for a potential treatment effect with early treatment initiation.

Nonadjuvanted Bivalent Respiratory Syncytial Virus Vaccination and Perinatal Outcomes

A nonadjuvanted bivalent respiratory syncytial virus (RSV) prefusion F (RSVpreF [Pfizer]) protein subunit vaccine was newly approved and recommended for pregnant individuals at 32 0/7 to 36 6/7 weeks' gestation during the 2023 to 2024 RSV season; however, clinical vaccine data are lacking. To evaluate the association between prenatal RSV vaccination status and perinatal outcomes among patients who delivered during the vaccination season. This retrospective observational cohort study was conducted at 2 New York City hospitals within 1 health care system among patients who gave birth to singleton gestations at 32 weeks' gestation or later from September 22, 2023, to January 31, 2024. Prenatal RSV vaccination with the RSVpreF vaccine captured from the health system's electronic health records. The primary outcome is preterm birth (PTB), defined as less than 37 weeks' gestation. Secondary outcomes included hypertensive disorders of pregnancy (HDP), stillbirth, small-for-gestational age birth weight, neonatal intensive care unit (NICU) admission, neonatal respiratory distress with NICU admission, neonatal jaundice or hyperbilirubinemia, neonatal hypoglycemia, and neonatal sepsis. Logistic regression models were used to estimate odds ratios (ORs), and multivariable logistic regression models and time-dependent covariate Cox regression models were performed. Of 2973 pregnant individuals (median [IQR] age, 34.9 [32.4-37.7] years), 1026 (34.5%) received prenatal RSVpreF vaccination. Fifteen patients inappropriately received the vaccine at 37 weeks' gestation or later and were included in the nonvaccinated group. During the study period, 60 patients who had evidence of prenatal vaccination (5.9%) experienced PTB vs 131 of those who did not (6.7%). Prenatal vaccination was not associated with an increased risk for PTB after adjusting for potential confounders (adjusted OR, 0.87; 95% CI, 0.62-1.20) and addressing immortal time bias (hazard ratio [HR], 0.93; 95% CI, 0.64-1.34). There were no significant differences in pregnancy and neonatal outcomes based on vaccination status in the logistic regression models, but an increased risk of HDP in the time-dependent model was seen (HR, 1.43; 95% CI, 1.16-1.77). In this cohort study of pregnant individuals who delivered at 32 weeks' gestation or later, the RSVpreF vaccine was not associated with an increased risk of PTB and perinatal outcomes. These data support the safety of prenatal RSVpreF vaccination, but further investigation into the risk of HDP is warranted.

Metformin use and survival in people with ovarian cancer: A population-based cohort study from British Columbia, Canada

ObjectivesThere is an active debate regarding whether metformin use improves survival in people with ovarian cancer. We examined this issue using methods designed to avoid immortal time bias—as bias that occurs when participants in a study cannot experience the outcome for a certain portion of the study time. MethodsWe used time-dependent analyses to study the association between metformin use for all 4,951 patients diagnosed with ovarian cancer in 1997 through 2018 in the province of British Columbia, Canada. Cox proportional hazards models were run to estimate the association between metformin and survival in the full cohort of ovarian cancer patients and among a cohort restricted to patients with diabetes. ResultsMetformin use was associated with a 17 % better ovarian cancer survival in the full cohort (adjusted hazard ratio (aHR) = 0.83 (95 %CI 0.67, 1.02)), and a 16 % better ovarian cancer survival for serous cancers patient's cohort (aHR = 0.84 (95 %CI 0.66, 1.07)), although both were not significant. However, a statistically significant protective effect was observed when restricting to the diabetic cohort (aHR = 0.71 (95 %CI 0.54–0.91)), which was also seen among serous cancers (aHR = 0.73 (95 %CI 0.54–0.98)). ConclusionMetformin use was associated with improved ovarian cancer survival. The lack of statistical significance in the full cohort may reflect that diabetes is associated with reduced cancer survival, and thus diabetes itself may offset the benefit of metformin when examining the full cohort. Future research should examine metformin use among non-diabetic ovarian cancer patients.

Immune-Related Adverse Events Can Predict Progression-Free and Overall Survival In Patients With Metastatic Renal Cell Carcinoma Treated With Immune Checkpoint Inhibitors

BackgroundDifferent combination therapies using anti - PD-1 / PD-L1 or CTLA-4 immune checkpoint inhibition (ICI) are widely used in patients with metastatic renal cell carcinoma (mRCC). In the absents of established biomarkers, immune-related adverse events (irAEs) have been discussed as potential predictors of response. MethodsIn this retrospective cohort study, data of 134 patients with mRCC undergoing ICI treatment (Nivolumab, Ipilimumab and Nivolumab, Pembrolizumab and Axitinib or Avelumab and Axitinib) between 2015 and 2021 were analyzed. To examine the utility of irAEs as predictors of overall survival (OS) and progression-free survival (PFS), separate Kaplan–Meier analyses and Cox proportional regression analyses were applied. Landmark analysis was conducted after 12 weeks to reduce immortal time bias. ResultirAEs were observed in 85 patients (63.4%). Cutaneous (n = 52, 38.8%), endocrine (n = 33, 24.6%) and hepatic (n = 19, 14.2%) irAEs were most commonly observed. In Kaplan–Meier analysis, patients experiencing irAEs showed favorable median PFS (15 months, 95% CI, 9.91-20.09) compared to the non-irAE group (5 months, 95% CI, 3.56-6.44, P < .001). The median OS was 25 months (95% CI, 16.79-33.21) in the non-irAE group, while it was not reached in the irAE group (P = .002). In multivariable analysis, the presence of any irAE was associated with favorable PFS (HR 0.46 [95% CI, 0.26-0.82] P = .008) and OS (HR: 0.28 [95% CI, 0.12-0.63] P = .002), respectively. Landmark analysis after 12 weeks showed mixed results depending on the classification of the irAE group at the landmark time. ConclusionThe presence of irAEs under ICI therapy in patients with mRCC is associated with better PFS and OS. Thus, manageable irAEs should not be cause for premature discontinuation of ICI therapy, as they seem to indicate favorable outcomes.Considering the time-dependent nature of irAEs is crucial estimating their value as predictive markers.

Using Parametric g-Computation for Time-to-Event Data and Distributed Lag Models to Identify Critical Exposure Windows for Preterm Birth: An Illustrative Example Using in a Retrospective Birth Cohort Based in Eastern Massachusetts (2011-2016).

Parametric g-computation is an attractive analytic framework to study the health effects of air pollution. Yet, the ability to explore biologically relevant exposure windows within this framework is underdeveloped. We outline a novel framework for how to incorporate complex lag-responses using distributed lag models (DLMs) into parametric g-computation analyses for survival data. We call this approach "g-survival-DLM" and illustrate its use examining the association between during pregnancy and the risk of preterm birth (PTB). We applied the g-survival-DLM approach to estimate the hypothetical static intervention of reducing average in each gestational week by 20% on the risk of PTB among 9,403 deliveries from Beth Israel Deaconess Medical Center, Boston, Massachusetts, 2011-2016. Daily was taken from a grid model and assigned to address at birth. Models were adjusted for sociodemographics, time trends, nitrogen dioxide, and temperature. To facilitate implementation, we provide a detailed description of the procedure and accompanying R syntax. There were 762 (8.1%) PTBs in this cohort. The gestational week-specific median concentration was relatively stable across pregnancy at . We found that our hypothetical intervention strategy changed the cumulative risk of PTB at week 36 (i.e., the end of the preterm period) by (95% confidence interval: , 0.007) in comparison with the scenario had we not intervened, which translates to about 86 fewer PTBs in this cohort. We also observed that the critical exposure window appeared to be weeks 5-20. We demonstrate that our g-survival-DLM approach produces easier-to-interpret, policy-relevant estimates (due to the g-computation); prevents immortal time bias (due to treating PTB as a time-to-event outcome); and allows for the exploration of critical exposure windows (due to the DLMs). In our illustrative example, we found that reducing fine particulate matter [particulate matter (PM) with aerodynamic diameter ()] during gestational weeks 5-20 could potentially lower the risk of PTB. https://doi.org/10.1289/EHP13891.

A Critical Analysis of All-Cause Deaths during COVID-19 Vaccination in an Italian Province.

Immortal time bias (ITB) is common in cohort studies and distorts the association estimates between the treated and untreated. We used data from an Italian study on COVID-19 vaccine effectiveness, with a large cohort, long follow-up, and adjustment for confounding factors, affected by ITB, with the aim to verify the real impact of the vaccination campaign by comparing the risk of all-cause death between the vaccinated population and the unvaccinated population. We aligned all subjects on a single index date and considered the "all-cause deaths" outcome to compare the survival distributions of the unvaccinated group versus various vaccination statuses. The all-cause-death hazard ratios in univariate analysis for vaccinated people with 1, 2, and 3/4 doses versus unvaccinated people were 0.88, 1.23, and 1.21, respectively. The multivariate values were 2.40, 1.98, and 0.99. Possible explanations of this trend of the hazard ratios as vaccinations increase could be a harvesting effect; a calendar-time bias, accounting for seasonality and pandemic waves; a case-counting window bias; a healthy-vaccinee bias; or some combination of these factors. With 2 and even with 3/4 doses, the calculated Restricted Mean Survival Time and Restricted Mean Time Lost have shown a small but significant downside for the vaccinated populations.

Multiple immune-related adverse events secondary to checkpoint inhibitor therapy in patients with advanced cancer: association with treatment effectiveness.

Checkpoint inhibitors (CPI) are widely used in cancer treatment with a potential of causing immune-related adverse events (IRAEs). Several studies have reported a positive correlation between development of IRAEs and improved survival outcome. However, few studies have focused on the potential role of multiple IRAEs on treatment effectiveness. This study aimed at investigating the association between multiple IRAEs and treatment effectiveness in terms of progression-free survival (PFS) and overall survival (OS) in advanced cancer patients. We performed a retrospective cohort study at three Swedish centers. All patients (n=600) treated with PD-L1 or PD-1 inhibitor, in monotherapy or in combination for advanced cancer between January 2017 and December 2021 were included. Multiple IRAEs were defined as IRAEs involving more than one organ system either simultaneously or sequentially. Time-depending Cox-regression model to mitigate the risk for immortal time bias (ITB) was applied. The major tumor types were non-small cell lung cancer (205 patients; 34.2%) and malignant melanoma (196 patients; 32.7%). Of all patients,32.8% developed single IRAE and 16.2% multiple IRAEs. Patients with multiple IRAEs showed significantly improved PFS (Hazard Ratio, HR=0.78 95% Confidence Interval, CI: 0.57-0.98) and OS (HR=0.65 95% CI: 0.44-0.95) compared to patients with single IRAE or no IRAE (HR=0.46 95% CI:0.34-0.62 for PFS vs HR=0.41 95% CI: 0.28-0.60 for OS). In conclusion, our data supports a stronger association between development of multiple as opposed to single IRAEs and clinical effectiveness in advanced cancer patients treated with CPIs.

Acute kidney injury in Staphylococcus aureus bacteraemia: a recurrent events analysis

ObjectivesTo estimate risk factors for acute kidney injury (AKI) and the effect of AKI on mortality in Staphylococcus aureus bacteraemia, while taking into account recurrent AKI episodes, competing risks, time-varying variables, and time-varying effects. MethodsWe performed an unplanned analysis using data from a multicentre cohort study of patients with Staphylococcus aureus bacteraemia (SAB). The primary outcome was cumulative incidence of AKI, according to Kidney Disease Improving Global Outcomes definitions. ResultsWe included 453 patients in this study of whom 194 (43%) patients experienced one or more AKI episodes. Age (hazard ratio (HR) 1.013, 95% CI 1.001–1.024), Charlson comorbidity index (HR 1.07, 95% CI 1.01–1.14), prior chronic kidney disease (HR 1.76, 95% CI 1.28–2.42), septic shock (HR 3.28, 95% CI 2.31–4.66), persistent bacteraemia (HR 1.53, 95% CI 1.08–2.17), and vancomycin therapy (HR 1.80, 95% CI 1.05–3.09) were independently associated with AKI, but flucloxacillin, cefazolin, rifampicin, and aminoglycoside therapy were not. After adjustment for confounders and immortal time bias, AKI was associated with an increased risk of 90-day mortality (HR 4.26, 95% CI 2.91–6.23). DiscussionThe incidence of AKI in SAB is high and a substantial proportion of patients develop recurrent episodes of AKI after recovery. AKI is specifically linked to the use of vancomycin and not to anti-staphylococcal penicillins. The clinical outcome of patients with SAB complicated by AKI is worse than previously estimated.

Impact of ibrutinib dose adjustment on TTNT in first-line CLL/SLL: a real-world analysis using target trial emulation

AbstractIbrutinib, a once-daily Bruton tyrosine kinase inhibitor, is a standard-of-care first-line (1L) treatment for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Dosing flexibility (adjustment to daily dose of <420 mg/d) with ibrutinib can help prevent recurrence or worsening of adverse events while maintaining long-term efficacy. This study compared time to next treatment among patients with CLL/SLL in the United States initiating 1L single-agent ibrutinib at 420 mg/d (index date) and staying on this dose vs patients with dose adjustment (DA) within 3 to 12 months. Two databases were used: Komodo claims (a majority from community practices) and Acentrus electronic medical records (from academic and nonteaching hospital systems). To account for immortal time bias (patients with DA survived on 1L therapy until DA) and overlap between follow-up time and definition of treatment strategies, a target trial emulation approach was used, in which patients were cloned at index date and contributed follow-up to both treatment strategy arms until deviation from the strategy. Among 3343 patients in Komodo (mean age: 67.5 years; 37.6% female) and 1171 patients in Acentrus (mean age: 70.4 years; 34.6% female) who initiated 1L single-agent ibrutinib 420 mg/d, 18.0% and 19.6%, respectively, had a DA. DA was not associated with an increased risk of having a next treatment in both databases (adjusted hazard ratio [95% confidence interval]: Komodo: 0.95 [0.80-1.14], Acentrus: 1.14 [0.80-1.62]). These findings suggest that a flexible dosing approach with ibrutinib may be effective in allowing patients to achieve optimal outcomes while remaining on long-term continuous 1L treatment.

Length of treatment after partial or complete remission in immunotherapy for metastatic melanoma: An EUMelaReg real world study.

9531 Background: A significant proportion of patients (pts) with non-resectable melanoma treated with immune checkpoint inhibitors (ICI) achieve durable remissions, but there is limited data on the optimal duration of ICI therapy in these pts. Therefore, the influence of the duration and maintenance of ICI therapy in pts with a partial (PR) or complete remission (CR) on further outcome was investigated. Methods: Primary objectives was the survival outcome after achieving PR or CR in non-resectable stage III/IV melanoma in relation to baseline prognostic variables and duration of maintenance treatment with ICIs in 1st line. This retrospective study evaluated melanoma cases from the EUMelaReg treatment registry, who achieved a best overall response (BOR) of PR or CR with either single agent anti-PD1 or combined anti-PD1/anti-CTLA4 in 1st line. Cases were stratified according to treatment duration after achieving a PR or CR: &lt; 6 months (M), 6-12 M, &gt; 12 M. To address immortal time bias, cases with early progression were cloned into all respectively compatible strata. These synthetical strata were further analyzed and compared by propensity score weighting, and robust confidence intervals were retrieved by bootstrapping techniques. Results: A total of 1,291 pts were included in the analysis. After cloning, 2,144 cases could be stratified to the synthetical arms of &lt;6 M (26.5%), 6-12 M (31.4%) or &gt;12 M (42.1%) treatment continuation after achieving PR or CR. Adjusted Kaplan-Meier estimates showed that treatment until progressive disease (PD) or &gt; 12 M after remission resulted in prolonged progression-free (PFS) and overall survival (OS) compared to the &lt; 6 M arm (hazard ratio (HR): 0.82 [95% confidence interval (CI): 0.6-0.9] and HR: 0.67 [95% CI: 0.5-0.9], respectively).This effect was more pronounced in PR (HR 0.66 for OS) than in (HR 0.84 for OS). Treatment for 6-12 M compared to &lt; 6 M also showed a trend towards prolonged PFS and OS (HR: 0.85 [95% CI: 0.7-1.1] and HR: 0.82 [95% CI: 0.6-1.1], respectively). Conclusions: This study showed PFS and OS benefit for pts continuing on treatment for &gt; 12 M or until progression after achieving PR or CR compared to pts treated for &lt; 6 M. [Table: see text]

Prognostic significance of real-world (RW) recurrence patterns after resection or ablation of early-stage hepatocellular carcinoma (HCC): Insights from the US Medicare population.

e16241 Background: The prognosis after curative-intent resection or ablation of early-stage HCC remains poor, largely due to high rates of recurrence. We aimed to characterize real-world recurrence patterns and determine whether the timing of recurrence was associated with overall survival (OS). Methods: Patients (pts) with early-stage HCC who underwent resection and/or ablation were identified from the SEER-Medicare database (2010-2019). Pts who received liver transplant were excluded. A proxy for recurrence was defined as the receipt of new HCC treatments (surgery, locoregional therapy, systemic therapy) or a secondary malignant neoplasm claim (excluding liver). Pseudo-recurrence dates were assigned to pts without recurrence to match the distribution of time between initial resection/ablation and recurrence in the recurrence cohort, to avoid immortal time bias. Early vs late recurrence was defined as occurring within 1 year vs after 1 year of initial resection/ablation. Primary outcome was OS as measured both from the time of recurrence/pseudo-recurrence and initial resection/ablation. Results: 1,146 eligible pts with early-stage HCC were identified. 63% were male, mean age was 74 yrs, and initial therapy was resection (39%), ablation (50%), or both (11%). 736 (64%) experienced recurrence. Among them, 53% received ablation, 37% surgery, and 11% received both. Median OS from recurrence or pseudo-recurrence was 22 months (mo) vs 67 mo (p &lt; 0.001) for pts with vs without recurrence, respectively. When measured from resection/ablation date, median OS was 39 mo vs 83 mo (p &lt; 0.001). After adjusting for relevant demographic and clinico-pathologic factors, including type of index therapy, in a multivariable Cox regression model, recurrence remained significantly associated with an increased risk of death (hazard ratio [HR]: 2.24; 95% CI: 1.85-2.71; p &lt; 0.001). Among pts who recurred, 380 (52%) had early recurrence and 356 (48%) had late recurrence. Median OS from recurrence was 17 mo vs 30 mo (p &lt; 0.001) for early vs late recurrence, respectively, and 23 mo vs 63 mo when measured from resection/ablation The adjusted HR for the risk of death associated with early recurrence was 1.39 (95% CI: 1.14-1.68; p &lt; 0.001) compared to late recurrence. Other significant prognostic factors associated with reduced OS included larger tumor size ( &gt; = 5cm), greater extent of disease, and poor differentiation (grade III and above). Conclusions: In this study among US Medicare pts, early recurrence within one year after curative-intent treatment of early-stage HCC was significantly associated with decreased OS compared to pts who recur later or without recurrence. This highlights the need for developing and utilizing effective adjuvant therapy regimens to delay or avoid recurrence.

Associations of early adverse events with clinical outcomes in patients with NSCLC treated with EGFR tyrosine kinase inhibitors.

e20551 Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) constitute the primary treatment modality for EGFR-mutant non-small cell lung cancer (NSCLC). While efficacious, EGFR TKIs are associated with adverse events (AEs) like dermatologic toxicities, diarrhea, and stomatitis. This study examined the prognostic implications of these on-target AEs in NSCLC patients receiving EGFR TKI therapy. Methods: A retrospective cohort study was conducted, encompassing advanced NSCLC patients treated with first-line EGFR TKIs within two distinct healthcare delivery systems in Taiwan between June 2011 and December 2019. Patients were stratified by TKI type, and those who had received AE reliever medications within 180 days prior to EGFR TKI initiation were excluded. We examined correlations between AEs and key endpoints: time to next treatment (TTNT) and overall survival (OS). To minimize immortal time bias, a landmark analysis at 60 days post-treatment initiation was utilized. On-target AEs were identified based on the issuance of at least two prescriptions for AE management on different dates within this period. Multivariable Cox proportional hazards models were utilized to evaluate the association between AEs and clinical endpoints, and a random-effects meta-analysis was performed to combine findings from both institutions. Results: Our analysis included 1,605 patients on gefitinib, 848 on erlotinib, and 1,236 on afatinib. Despite potential variations in AE reporting due to prescribing behaviors, the incidence of AE within the first 60 days of treatment was highest for afatinib, particularly with diarrhea (76.7%) and stomatitis (14.9%), followed by erlotinib with notable skin reactions (49.4%). Gefitinib showed the lowest incidence rates across all examined AEs. Of note, afatinib-treated patients who experienced diarrhea within the initial 60 days demonstrated a statistically significant extension in OS (HR 0.75, 95% CI 0.60-0.92). No significant prognostic link was found for other AEs in afatinib users or any AEs among users of gefitinib and erlotinib. Sensitivity analyses, incorporating modified AE definitions, corroborated these outcomes. Conclusions: Identifying AEs via prescription records for symptom relief poses methodological challenges and introduces uncertainty. Nevertheless, the occurrence of diarrhea within the first 60 days of therapy emerged as a significant predictor of enhanced OS in EGFR-mutant NSCLC patients receiving afatinib. This finding suggests a potential prognostic implication. The correlation was not evident in patients treated with first-line gefitinib or erlotinib.

Effectiveness of post-COVID-19 primary care attendance in improving survival in very old patients with multimorbidity: a territory-wide target trial emulation.

Older adults with multimorbidity are at high risk of mortality following COVID-19 hospitalisation. However, the potential benefit of timely primary care follow-up on severe outcomes post-COVID-19 has not been well established. To examine the effectiveness of attending general outpatient within 30 days after discharge from COVID-19 on 1-year survival among older adults aged ≥85 years, with multimorbidity. We emulated a target trial using a comprehensive public healthcare database in Hong Kong. The cloning-censoring-weighting technique was used to minimise immortal time bias and confounding bias by adjusting for demographics, hospitalisation duration and ICU admission, baseline chronic conditions, and medication history. The outcome included all-cause and cause-specific mortality. Of 6183 eligible COVID-19 survivors, the all-cause mortality rate following COVID-19 hospitalisation was lower in general out-patient clinics (GOPC) group compared to non-GOPC group (17.1 versus 42.8 deaths per 100 person-year). After adjustment, primary care consultations within 30 days after discharge were associated with a significantly greater 1-year survival (difference in 1-year survival: 11.2%, 95% CI = 8.1% to 14.4%). We also observed better survival from respiratory diseases in the GOPC group. In a sensitivity analysis for different grace period lengths, we found that the earlier participants had a GOPC visit after COVID-19 discharge, the better the survival. Timely primary care consultations after discharge may improve survival following COVID-19 hospitalisation among older adults aged ≥85 years, with multimorbidity. Expanding primary care services and implementing follow-up mechanisms are crucial to support this vulnerable population's recovery and well-being.

Early opioid exposure (EOE) and impaired efficacy in patients with advanced NSCLC treated with PD-L1 inhibition: A pooled post hoc analysis of the POPLAR and OAK trials.

2607 Background: Mechanistic evidence suggests opioid signaling to modulate anti-tumor immunity. Whether opioids exposure may affect outcome of patients (pts) treated with immune checkpoint inhibitors is unproven, with clinical evidence being flawed by the negative associative bias between pain and higher burden of disease. Methods: We conducted a post-hoc analysis of the phase 3 OAK (NCT02008227) and phase 2 POPLAR (NCT01903993) trials, which randomized (1:1) pts with advanced NSCLC to receive either atezolizumab or docetaxel. We assessed the differential impact of early opioids exposure (EOE), defined as a minimum of 7 days exposure to any systemic opioids in the time window ranging between -30 to +30 from treatment initiation on efficacy from immunotherapy vs chemotherapy. Pts with ≤30 days survival follow-up were excluded to avoid immortal time bias. Results: After the exclusion of 60 pts, 718 and 686 pts treated with atezolizumab and docetaxel were included, with 341 (47.5%) and 308 (44.9%) pts with EOE respectively (p=0.32) and a median follow-up of 25.5 months (95% CI: 22.8-25.9). Baseline characteristics was balanced across cohorts. In the pooled population, EOE was significantly associated with poorer ECOG-PS (p&lt;0.01) and burden of disease (p&lt;0.01). Univariable analysis showed EOE to be significantly associated with decreased objective response rate (ORR, 11.7% vs 19.8%, p&lt;0.01) and progression free survival (PFS, 1.9 vs 4.2 months, p&lt;0.01) in the atezolizumab cohort, whereas no effect on ORR (17.7% vs 14.4%, p=0.25) and a less pronounced effect on PFS (3.5 vs 4.1 months, p=0.02) was reported for the docetaxel cohort. The pooled multivariable backward stepwise Cox regression used to select variables for validating the results individuated ECOG-PS, histology, tumor burden and race. In multivariable models EOE was associated with decreased ORR (OR 0.58, 95%CI: 0.37-0.92), increased risk of progression (HR 1.47, 95%CI: 1.26-1.72) and death (HR 1.70, 95%CI: 1.42-2.03) in the atezolizumab cohort while no negative impact on ORR/PFS was confirmed among the docetaxel cohort, with a less strong effect on OS (HR 1.44, 95%CI: 1.21-1.72). Multivariable interaction tests confirmed the differential impact of EOE on ORR (p&lt;0.01) and PFS (p&lt;0.01) between treatment modalities (immunotherapy vs chemotherapy). The results were additionally confirmed using IPTW models including all the baseline variables with an optimal distribution (SMD &lt;0.05). Conclusions: EOE is associated with worse response/PFS from immunotherapy but not from chemotherapy exposure, suggesting a possible immune-modulating effect of opioids signaling on anti-tumor immunity. Considering that systemic opioids are the cornerstone of pain management in oncology further research for mitigation strategies, such as the potential use of PAMORAs, is needed. Clinical trial information: NCT02008227 and NCT01903993 .

Can Chinese herbal medicine offer feasible solutions for newly diagnosed esophageal cancer patients with malnutrition? a multi-institutional real-world study

BackgroundEsophageal cancer (EC) is a major cause of cancer-related mortality in Taiwan and globally. Patients with EC are highly prone to malnutrition, which adversely affects their prognosis. While Chinese herbal medicine (CHM) is commonly used alongside conventional anti-cancer treatments, its long-term impact on EC patients with malnutrition remains unclear.MethodsThis study utilized a multi-center cohort from the Chang Gung Research Database, focusing on the long-term outcomes of CHM in EC patients with malnutrition between 1 January 2001, and 31 December 2018. Patients were monitored for up to 5 years or until death. Overall survival (OS) rates were calculated using the Kaplan-Meier method. Overlap weighting and landmark analysis were employed to address confounding and immortal time biases. Additionally, the study analyzed prescription data using a CHM network to identify key CHMs for EC with malnutrition, and potential molecular pathways were investigated using the Reactome database.ResultsEC patients with malnutrition who used CHM had a higher 5-year OS compared with nonusers (22.5% vs. 9% without overlap weighting; 24.3% vs. 13.3% with overlap weighting; log-rank test: p = 0.006 and 0.016, respectively). The median OS of CHM users was significantly longer than that of nonusers (19.8 vs. 12.9 months, respectively). Hazard ratio (HR) analysis showed a 31% reduction in all-cause mortality risk for CHM users compared with nonusers (HR: 0.69, 95% confidence interval: 0.50–0.94, p = 0.019). We also examined 665 prescriptions involving 306 CHM, with Hedyotis diffusa Willd. exhibiting the highest frequency of use. A CHM network was created to determine the primary CHMs and their combinations. The identified CHMs were associated with the regulation of immune and metabolic pathways, particularly in areas related to immune modulation, anti-cancer cachexia, promotion of digestion, and anti-tumor activity.ConclusionThe results of this study suggest a correlation between CHM use and improved clinical outcomes in EC patients with malnutrition. The analysis identified core CHMs and combinations of formulations that play a crucial role in immunomodulation and metabolic regulation. These findings lay the groundwork for more extensive research on the use of CHM for the management of malnutrition in patients with EC.