Stratified Cox Proportional Hazards Model Research Articles

KEYNOTE-867: Phase 3, Randomized, Placebo-Controlled Study of Stereotactic Body Radiotherapy (SBRT) with or without Pembrolizumab in Patients with Unresected Stage I or II Non–Small-Cell Lung Cancer (NSCLC)

<h3>Purpose/Objective(s)</h3> Anti–PD-(L)1-directed therapy following radiotherapy or following concurrent chemoradiation is associated with significantly longer PFS and OS in patients with advanced or metastatic NSCLC, including those with locally advanced inoperable tumors. KEYNOTE-867 (NCT03924869) evaluates the efficacy and safety of SBRT with or without pembrolizumab in patients with unresected stage I or II NSCLC. <h3>Materials/Methods</h3> In this phase 3, randomized, placebo-controlled study, approximately 530 adult patients with previously untreated, unresected, histologically/cytologically confirmed stage I or II (T1 to limited T3, N0, M0) NSCLC are randomized 1:1 to receive thoracic SBRT to primary tumors for ≤2 wk (Table) and either pembrolizumab 200 mg or placebo every 3 wk for 17 cycles (approximately 1 year) or until disease recurrence, development of unacceptable AEs, SBRT not started for any reason, or study withdrawal. Randomization is stratified by disease stage (I vs II), ECOG PS (0 or 1 vs 2), geographic region (East Asia vs non-East Asia), and reason for not receiving surgery (medically inoperable vs refused surgery). Imaging assessment by blinded independent central review (BICR) occurs at 12 wk (≥10 wk after SBRT completion), followed by every 16 wk for 3 y, and then every 6 mo. Primary endpoints are event-free survival (EFS) by BICR and OS. Secondary endpoints include time to death or distant metastases and safety; exploratory endpoints are time to subsequent treatment, disease-specific survival, and time to recurrence/progression on subsequent line of therapy. AEs are monitored throughout the trial until 30 d after last dose (90 for serious AEs) and graded according to NCI CTCAE version 4.0. EFS and OS are analyzed by the nonparametric Kaplan-Meier method, treatment differences by stratified log-rank test, and hazard ratios by stratified Cox proportional hazard model with Efron's method of tie handling. Enrollment started on June 17, 2019, and is ongoing at 169 sites in North America, South America, Europe, Asia and Australasia. <h3>Results</h3> TBD <h3>Conclusion</h3> TBD

Estimating power wheelchair battery lifespan based on real-world data

Purpose The purpose of this study was to: (1) estimate battery lifespan in power wheelchairs (PWCs) as measured by the length of time until battery replacement occurs and (2) identify factors associated with variability in battery lifespan after device distribution. Materials and methods PWCs distributed between 1 January 2016 and 31 December 2018 were retrieved from the Wheelchair Repair Registry (WRR) and included into this retrospective cohort study. Factors associated with battery lifespan were examined with the stratified Cox proportional hazard model. Results A data set of 1268 PWCs from four different manufacturers was analysed. Five hundred and ten PWCs (40.2%) had one battery replacement with median battery lifespan of 22.3 months. The overall cumulative incidences of battery replacement were 14.5%, 56.2% and 88.2% at the end of the first, second and third year after device distribution, respectively. Among PWC manufacturers, manufacturer C (hazard ratio (HR), 2.63; 95% confidence interval (CI), 1.35–5.12; p = 0.004) and manufacturer D (HR, 3.02; 95% CI, 1.51–6.01; p = 0.002) were associated with shorter battery lifespan. PWCs operated in warmer states (65–75 °F annual temperature averages) were associated with longer battery lifespan. Conclusions Results showed that the median battery lifespan was 22 months. PWC manufacturer and operating climate temperature were associated with variability in battery lifespan. This research has implications to better inform users, providers, manufacturers and payers to be more aware of battery lifespan across PWC types and manufactures to anticipate replacement timelines and avoid adverse situations associated with battery failures. Implications for rehabilitation There are differences in battery lifespan across different power wheelchair (PWC) manufactures. Power wheelchair batteries last longer in warmer operating climates. Future attention needs to be sought towards the types of batteries manufacturers are using for PWC group classifications. These types of studies could be useful to justify reasonable timelines and the costs associated with battery replacements.

Long-term exposure to air pollution and mortality from dementia, psychiatric disorders, and suicide in a large pooled European cohort: ELAPSE study

Ambient air pollution is an established risk factor for premature mortality from chronic cardiovascular, respiratory and metabolic diseases, while evidence on neurodegenerative diseases and psychiatric disorders remains limited. We examined the association between long-term exposure to air pollution and mortality from dementia, psychiatric disorders, and suicide in seven European cohorts. Within the multicenter project ‘Effects of Low-Level Air Pollution: A Study in Europe’ (ELAPSE), we pooled data from seven European cohorts from six countries. Based on the residential addresses, annual mean levels of fine particulate matter (PM2.5), nitrogen dioxide (NO2), black carbon (BC), ozone (O3), and 8 PM2.5 components were estimated using Europe-wide hybrid land-use regression models. We applied stratified Cox proportional hazard models to investigate the associations between air pollution and mortality from dementia, psychiatric disorders, and suicide. Of 271,720 participants, 900 died from dementia, 241 from psychiatric disorders, and 164 from suicide, during a mean follow-up of 19.7 years. In fully adjusted models, we observed positive associations of NO2 (hazard ratio [HR] = 1.38; 95 % confidence interval [CI]: 1.13, 1.70 per 10 µg/m3), PM2.5 (HR = 1.29; 95 % CI: 0.98, 1.71 per 5 µg/m3), and BC (HR = 1.37; 95 % CI: 1.11, 1.69 per 0.5 × 10−5/m) with psychiatric disorders mortality, as well as with suicide (NO2: HR = 1.13 [95 % CI: 0.92, 1.38]; PM2.5: HR = 1.19 [95 % CI: 0.76, 1.87]; BC: HR = 1.08 [95 % CI: 0.87, 1.35]), and no association with dementia mortality. We did not detect any positive associations of O3 and 8 PM2.5 components with any of the three mortality outcomes. Long-term exposure to NO2, PM2.5, and BC may lead to premature mortality from psychiatric disorders and suicide.

S29 Dilated Main Pancreatic Duct Without a Visible Pancreatic Mass: Long-Term Follow-Up and Predictors of Future Pancreatic Ductal Adenocarcinoma

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease frequently diagnosed at an advanced stage when therapeutic options are limited. Pancreatic imaging abnormalities that predate diagnosis of PDAC may serve as an early detection tool. Dilation of the main pancreatic duct (D-MPD) has been shown to occur up to a year before PDAC diagnosis. However, while D-MPD in the absence of a visible pancreatic mass raises concern for occult neoplasm, the natural history of D-MPD remains poorly understood. From a large cohort of patients with D-MPD and no pancreatic mass, we aimed to assess long-term outcomes and compare patients who were subsequently diagnosed with PDAC to those who did not develop PDAC. Methods: We identified all subjects ≥18 years old at our institution with D-MPD (MPD >3mm) on either abdomen/pelvis CT or MRI scans between 1/1/2012 and 12/31/2017. Patients with prior PDAC, pancreatic surgery, definite pancreas mass or other visible cause of D-MPD were excluded after expert review by study radiologist. Pertinent clinical, demographic, and imaging data were summarized. A stratified univariate Cox proportional hazards model was utilized to evaluate risk factors for PDAC development. Results: Among 2307 patients (baseline CT:1615, MRI: 692) who met our study criteria, 63.7% were female, median age was 71 (IQR 59.5 -80.1), and median follow-up was 1466 days (IQR 1426-1509). The 1-year and 3-year event rates for PDAC were 2.70 and 2.99 per 100-patient years respectively. Out of sixty-three (2.7%) patients who developed PDAC within 3 years of the baseline scan, the majority (58/63) were within 1 year (Figure). Factors associated with a significantly increased 3-year risk of PDAC included male gender, BMI >25, diabetes mellitus, non-O blood type, elevated serum CA 19-9, focal narrowing of MPD, equivocal pancreatic mass and suboptimal baseline scan quality (Table). Conclusion: D-MPD may predate the diagnosis PDAC and raises concern for neoplasm. However, in our study only a small subset of D-MPD patients without an overt pancreatic mass developed PDAC on follow-up. The risk is highest in the first year with rare events after one year of PDAC-free follow-up. Risk factors identified in this study may enrich assessment and guide surveillance of patients with D-MPD. Future studies exploring machine learning tools can further enhance the identification of those at risk of future PDAC and facilitate early detection.Figure 1.: Kaplan-Meier curve estimate of PDAC event rates over the 3-year followup duration Table 1. - Univariate Survival Analysis (w/ strata) assessing the risk of developing PDAC within 3 years from baseline CT/MRI in 2307 patients with D-MPD Characteristics Reference Hazard Ratio 95% HR CI p-value Age (years) ≥50 < 50 7.109 0.987 51.192 0.0515 Body Mass Index (kg/m2) ≥25 < 25 1.972 1.172 3.319 0.0105 Maximum MPD diameter (mm) ≥5-< 10 ≥3-< 5 3.773 1.987 7.167 < .0001 ≥10 ≥3-< 5 20.081 8.455 47.691 < .0001 CA19-9 ≥35 < 35 4.819 2.678 8.670 < .0001 Gender Male Female 1.937 1.181 3.176 0.0088 ABO Blood type Type Non- O Type O 2.238 1.162 4.310 0.0161 Alcohol Ever Use Never Use 1.029 0.612 1.731 0.9137 Aspirin Ever Use Never Use 0.936 0.534 1.640 0.8177 Diabetes mellitus Yes No 2.596 1.554 4.338 0.0003 Chronic Pancreatitis Yes No 0.386 0.094 1.576 0.1847 Acute Pancreatitis Yes No 1.116 0.551 2.260 0.7609 Family History of PDAC Yes No 1.952 0.930 4.097 0.0772 Pancreas Cyst on imaging Yes No 1.444 0.856 2.439 0.1688 Equivocal Mass on imaging Yes No 12.524 7.248 21.640 < .0001 Image Quality Suboptimal but diagnostic Optimal 2.241 1.309 3.839 0.0033 Dilation Pattern Segmental/Multifocal Diffuse 1.175 0.717 1.926 0.5214 Focal Narrowing of the MPD Present Absent 40.800 9.732 171.038 < .0001

An Analysis of Major Target Deviations in Craniospinal Irradiation Treatment Plans for Patients With Intermediate-Risk Medulloblastoma Within a Phase 3 Clinical Trial (Children's Oncology Group Study ACNS0331)

PurposeCraniospinal irradiation remains an essential and yet difficult part of the treatment of patients with medulloblastoma. Whereas technological advances offer promise of increased conformity, realiance on advanced technology is not without risk, and it remains critical to carefully delineate targets. We describe examples of target deviations (TDs) in craniospinal irradiation treatment plans for postoperative patients with medulloblastoma in a phase 3 clinical trial (ACNS 0331). Methods and MaterialsThe principal investigator independently performed a review of the treatment plans and portal films of enrolled patients and evaluated the plans for TDs. TDs of dose, dose uniformity, and volume were defined as major or minor deviations. Major TDs scored as protocol violations. The effect of major TDs on event-free survival (EFS) and overall survival (OS) was evaluated using the stratified Cox proportional hazards model. ResultsOf the 549 patients enrolled, 461 were available for this analysis. Thirty-two (7%) plans did not have data sufficient for TD evaluation. Major TDs were found in 32 of the 461 plans (7%). Of those, 21 were deviations of target volume alone, 7 were deviations of target dose alone, and 4 were deviations of both target volume and dose. The 25 patients with TDs of volume involved 29 sites. The most common major TDs of volume involved the brain (9 of 29) and the posterior fossa (9 of 29). On Cox proportional hazards modeling, the presence of a major TD did not statistically significantly affect EFS (hazard ratio, 0.98; 95% confidence interval, 0.45-2.11; P = .9541) or OS (hazard ratio, 1.10; 95% confidence interval, 0.51-2.38; P = .8113). ConclusionsAlthough intensity modulated radiation therapy and proton therapy are promising in improving conformity and sparing organs at risk, technology does not substitute for careful anatomic definition of target volumes. The study was not powered to evaluate the effect of TDs on EFS and OS; therefore, the statistical analysis presented in this study must be interpreted with caution.

Impact of long-term exposures of PM2.5 components and sources on cause-specific mortality in a US Medicare cohort: results from two-stage residual analysis

Background: Our understanding of the impact of long-term exposures to PM2.5 constituents and sources on mortality is limited due in large part to the often strong correlations between individual PM2.5 constituent concentrations. Methods: We examined associations between long-term exposures to PM2.5 constituents and sources and cause-specific mortality in US older adults using a two-stage residual method. We did so using demographic and mortality data for 15.4 million Medicare beneficiaries living within the conterminous United States (US) between 2000 and 2008. We assessed PM2.5 constituents exposures for each beneficiary and used factor analysis and residual-based methods to characterize PM2.5 sources and mixtures, respectively. In age-, sex-, race- and site- stratified Cox proportional hazard models adjusted for neighborhood socio-economic status (SES), we assessed associations of individual PM2.5 constituents, sources, and mixtures and cause-specific mortality and examined modification of these associations by participant demographics and location of residence. Results: Hazard ratios (HR) were highest for all causes of death, except COPD, for coal-related PM2.5 constituents and sources. We found Pb, nitrate, Si, and metal-, traffic-, and soil-related components to be significantly associated with increased HR for most causes of death. Using residual-based methods, we found attenuation in HRs to be greatest for all causes of death when variability from sulfate, Se, or coal-related PM2.5 was removed from the PM2.5 mixture. While attenuated, HRs for mortality from all-cause, CVD, and IHD remained statistically significant and positive when variability from NO3–, OC, Si, and traffic- and soil-related PM2.5 were removed from the analyses. Removal of variability due to oil and metal-related sources had no discernable effect on HRs. Discussion: PM2.5 components related to coal combustion, traffic, and to a lesser extent, soil were strongly associated with mortality from CVD, respiratory disease, and cancer.

LBA16 Dalpiciclib plus letrozole or anastrozole as first-line treatment for HR+/HER2- advanced breast cancer (DAWNA-2): A phase III trial

Dalpiciclib (dalp), a novel CDK4/6 inhibitor, with fulvestrant improved PFS in patients (pts) with HR+/HER2- advanced breast cancer (ABC) progressing after endocrine therapy (ET) in the phase 3, DAWNA-1 trial (Nature Medicine 2021). Here we assessed dalp with ET in the 1st-line setting. DAWNA-2 was a randomized, multicenter, double-blind, phase 3 trial done in 42 centers in China. Pts with untreated HR+/HER2- locally recurrent or metastatic BC, and any menopausal status were randomized 2:1 to receive dalp (150 mg, po, qd, d1-21, q4w) or placebo + letrozole (2.5 mg, po, qd) or anastrozole (1 mg, po, qd). The primary endpoint was PFS per investigator (INV). A prespecified interim analysis was done after 186 (70.5% of total expected) PFS events occurred (Jun 1, 2022), and the corresponding superiority boundary was 1-sided P <0.0076. 456 pts were randomized to dalp + letrozole/anastrozole (N=303) or placebo+ letrozole/anastrozole (N=153). With a median follow-up of 21.7 and 21.4 mo respectively, PFS per INV was significantly improved in the dalp group vs the placebo group (median, 30.6 mo [95% CI 30.6-NR] vs 18.2 mo [16.5-22.5]; HR 0.51 [95% CI 0.38-0.69], 1-sided P <0.0001). PFS benefit with dalp was evident regardless of menopausal status (Table 1). ORR and DoR per INV also favored the dalp group (Table 1). The most frequent grade ≥3 AEs in the dalp group was neutropenia (85.8% [grade 3/4, 64.6%/21.2%] vs 0 in the placebo group) and leukopenia (66.6% [grade 3/4, 65.9%/0.7%] vs 0). SAEs occurred in 11.9% in the dalp group and 6.5% in the placebo group; 4.0% and 2.0% discontinued any treatment due to AEs respectively.Table: LBA16Efficacy summaryDalp group (N=303)Placebo group (N=153)PFSOverall populationMedian (95% CI), mo30.6 (30.6-NR)18.2 (16.5-22.5)HR (95% CI)∗, P†0.51 (0.38-0.69), P <0.0001Pre/peri-menopausal womenMedian (95% CI), moNR (27.7-NR)16.6 (12.9-27.7)HR (95% CI)‡0.53 (0.33-0.85)Postmenopausal womenMedian (95% CI), mo30.6 (24.9-NR)19.4 (16.6-24.6)HR (95% CI)‡0.52 (0.36-0.75)ORR, % (95% CI)57.4 (51.6-63.1)47.7 (39.6-55.9)Median DoR (95% CI), moNR (26.9-NR)15.0 (12.9-20.3)∗ StratifiedCox proportional hazards model.† 1-sided stratified Log-rank test. ‡ Unstratified Cox proportional hazards model. NR=not reached. Open table in a new tab ∗ StratifiedCox proportional hazards model.† 1-sided stratified Log-rank test. ‡ Unstratified Cox proportional hazards model. NR=not reached. Adding dalp to letrozole/anastrozole significantly prolonged PFS in HR+/HER2- ABC, with manageable toxicities. Dalp is the 4th CDK4/6 inhibitor showing survival benefit with letrozole or anastrozole in untreated HR+/HER2- ABC, or with fulvestrant in pretreated HR+/HER2- ABC, in addition to palbociclib, ribociclib and abemaciclib.

714P Impact of viral aetiology in the phase III HIMALAYA study of tremelimumab (T) plus durvalumab (D) in unresectable hepatocellular carcinoma (uHCC)

In HIMALAYA (NCT03298451), a single, high priming dose of T plus D (STRIDE) significantly improved overall survival (OS) vs sorafenib (S), and D was noninferior to S in uHCC (Abou-Alfa et al. J Clin Oncol 2022;40(suppl 4). Abs 379). Viral aetiology is associated with hepatic impairment in HCC development, and may influence immunotherapy activity. Thus, we analysed the impact of viral aetiology on clinical outcomes. This exploratory analysis assessed STRIDE, D and S in patients (pts) with HBV (presence of HBsAg and/or anti-HBcAb with detectable HBV DNA), HCV or nonviral/other (NV) aetiology. OS hazard ratios (HRs) were calculated using a Cox proportional hazards model. As subsets were not sized for formal comparisons, no multiplicity adjustments were made. A post hoc multivariate analysis was used to identify chance imbalances in key prognostic factors that may bias estimated treatment effects. Baseline demographic and disease characteristics were similar across treatment arms in the HBV and NV subsets. However, in the HCV group, multivariate analysis identified imbalances in two prognostic variables: extrahepatic spread (EHS; more frequent for STRIDE than S) and ALBI (score ≥2 more frequent for STRIDE and D than S). OS and progression-free survival were improved with STRIDE vs S in the HBV and NV groups, but not in the HCV group (Table). Using a stratified Cox proportional hazards model to account for imbalances in EHS and ALBI in the HCV subset, OS HRs favoured STRIDE vs S. OS HRs continued to favour STRIDE when adjusting for EHS and ALBI in the other groups. Results for D vs S showed similar trends to those for STRIDE vs S (Table).Table: 714POSHR vs S; 95% CIOSCox-stratifieda HR vs S; 95% CIObjective response, %Disease control rate, %Median time to response, monthsMedian duration of response, monthsHBVSTRIDE n=1220.64; 0.48–0.860.64; 0.47–0.8621.359.01.925.7D n=1190.78; 0.58–1.040.78; 0.58–1.0414.349.61.99.5S n=1195.048.72.817.0HCVSTRIDE n=1101.06; 0.76–1.490.89; 0.63–1.2535.565.53.613.5D n=1071.05; 0.75–1.480.93; 0.66–1.3122.457.92.012.9S n=1049.670.27.315.7NVSTRIDE n=1610.74; 0.57–0.950.77; 0.59–1.00b18.057.12.113.2D n=1630.82; 0.64–1.050.80; 0.62–1.0319.056.43.713.8S n=1666.063.33.76.0aAdjusted for EHS and ALBI. bn=160; one pt with missing ALBI score excluded. Open table in a new tab aAdjusted for EHS and ALBI. bn=160; one pt with missing ALBI score excluded. In HIMALAYA, OS favoured STRIDE vs S (HR <1) for all aetiologies when subsets were adjusted for prognostic factor imbalances in the HCV cohort; similar trends were observed with D vs S across subsets. These results confirm the benefits of STRIDE and D in pts with uHCC, irrespective of underlying aetiology.

170. Utilizing big data to determine the safety profile of recombinant human BMP-2 in spinal fusion surgery: an analysis of 5 databases from 2003 to 2017

<h3>BACKGROUND CONTEXT</h3> The use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in spinal fusion remains controversial. While rhBMP-2 safety concerns revealed misrepresentations in industry-sponsored research, previous observational studies reached conflicting conclusions regarding rhBMP-2 safety and effectiveness. rhBMP-2 is FDA approved for lumbar fusion with specific fusion devices. <h3>PURPOSE</h3> The purpose of the study was to investigate the complications associated with the use of rhBMP-2 for spinal fusion at a population-based level to determine its risk. <h3>STUDY DESIGN/SETTING</h3> The study design was a retrospective observational comparative cohort design comparing a target group to a comparator group for the risk of an outcome. <h3>PATIENT SAMPLE</h3> The patient sample comprised of two groups. Our target group consisted of first-time recipients of any spinal fusion procedure, of at least 18 years of age at the time of procedure, who received rhBMP-2 at the time of the procedure. Our comparator group consisted of first-time recipients of any spinal fusion procedure, who did not receive rhBMP-2. We restricted the study dates from 1/1/2003, when rhBMP-2 was introduced to the market, to 12/31/2017. <h3>OUTCOME MEASURES</h3> The outcome measures investigated included any reoperations requiring refusion and postoperative complications, which comprised of infection, seroma/hematoma, radiculitis, heterotopic ossification and cancer. The analysis of cancer included 18 subtypes of benign and malignant neoplasms. The observation period for these outcomes started after the date of surgery and concluded at the end of the study period. <h3>METHODS</h3> We utilized research tools developed in the Observational Health Data Sciences and Informatics (OHDSI) community (Hripcsak et al, 2015) to develop a common research protocol and data vocabulary encompassing the four claims databases and one electronic records database. The four insurance claims databases were IBM MarketScan Commercial Claims and Encounters (US employer-based private payer; patient aged 65 years or older), Optum ClinFormatics (US private payer; primarily aged 65 years or younger), IBM MarketScan Medicare Supplemental Beneficiaries (US retirees; patients aged > 65 years), IBM MarketScan Multi-state Medicaid (US Medicaid enrollees; all ages). The electronic health record database is Optum Pan-Therapeutic (US health systems; all ages). We then implemented a suite of methods and analyses to address confounding and bias inherent to observation studies, including propensity scoring and estimation of hazard ratios using a stratified Cox proportional hazard model. We combined the estimates from the data sources into a summary HR using a random effects model meta-analysis. To control for unmeasured confounding, we employed negative and positive controls to quantify the systemic bias in the system and compute adjusted HR estimates and confidence intervals. <h3>RESULTS</h3> Across all five databases, 60,427 patients were identified in the target group and 349,771 patients were identified in the comparator group, totaling 161,213 and 923,822 years of patient observation, respectively. rhBMP-2 was associated with statistically significantly fewer postoperative infections, with a hazard ratio of 0.88 (95% CI: 0.78-0.99). No significant difference was seen with the other outcomes, including reoperations for refusion, seroma/hematoma, radiculitis, heterotopic ossification, and development of benign or malignant neoplasms. Substantial control of measured confounding was demonstrated by propensity score adjustment, and negative and positive controls revealed noticeable residual bias that was controlled for through confidence interval calibration. <h3>CONCLUSIONS</h3> In the largest longitudinal observational study to date, rhBMP-2 was determined to be safe and effective as compared to non-rhBMP-2 usage in spinal fusion, with lower rate of postoperative infections. Importantly, no increased rates of cancer were detected. Coding error and the retrospective design may be an important source of bias. Despite these limitations, the large population size and statistical design give considerable significance to the results and conclusions of this study. <h3>FDA DEVICE/DRUG STATUS</h3> Medtronic Infuse (Approved for this indication).

Are higher pre-diagnosis follicle stimulating hormone levels associated with long-term prostate cancer risk?

Follicle stimulating hormone (FSH) is a pituitary hormone that helps regulate testosterone homeostasis. Although it is generally accepted that FSH levels increase with LHRH-agonist therapy for prostate cancer (PC), the specific impact of FSH levels on risk of PC diagnosis is largely unknown. The objective of this study was to perform a population-level analysis to assess the association between FSH levels and PC diagnosis. All men (n = 386,018) who had a pre-PC diagnosis FSH level and complete data were identified within the Veterans Affairs Health System between 1999 and 2018. The association between FSH level and time from FSH test to PC diagnosis was tested using stratified Cox proportional hazards models. Multivariable models were adjusted for age, year, race, body mass index, and Charlson comorbidity index. Due to nonproportional hazards over time, time to PC was modeled separately: ≤4 years after an FSH test and >4 years following an FSH test. Median age at first FSH level was 64 years (interquartile range [IQR]: 54-72), median year of FSH was 2010 (IQR: 2005-2014), and 70% of the cohort was white. Median follow-up was 76 months (IQR: 38-126) during which 17,519 men (4.5%) were diagnosed with PC. On multivariable analysis, in the first 4 years after FSH test, there was no association between FSH and time to PC diagnosis. Starting from 4 years after FSH test, on multivariable analysis, a higher FSH level was associated with lower risk of PC with continuous modeling, but found no association with log continuous and categorical modeling. In this population-level study among male veterans receiving an FSH test for an unknown clinical indication, associations between FSH levels and PC risk were inconsistent and likely driven by selection bias and confounding variables. Future studies should consider different study designs.

Postoperative radiotherapy to the neck for pN1 status HNSCC patients after neck dissection

The significance of postoperative radiotherapy (PORT) to the neck for pN1 status head and neck squamous cell carcinomas (HNSCC) after neck dissection is unclear. A total of 208 patients with pN1 status HNSCC treated from January 1, 2001, to December 31, 2014, were enrolled in the current study. The 5-year regional recurrence-free survival (RRFS), overall survival (OS) and distant metastasis-free survival (DMFS) were compared between patients with or without PORT to the dissected neck. Moreover, the stratified Cox proportional hazards models were used to assess the association between PORT to the neck and survival before and after propensity score matching. Seventy-nine patients received PORT to the neck, while 129 did not. All patients were followed for over 5 years, with a median follow-up duration of 64.6 months. The PORT group did not show better survival results than the group without PORT to the neck in RRFS, OS or DMFS. Moreover, no evidence showed that PORT to the neck was independently associated with 5-year survival. PORT to the neck for pN1 status HNSCC after neck dissection did not lead to better survival. However, it is necessary to conduct prospective randomized clinical trials to confirm these results.

Assessment of drinking water safety in the Netherlands using nationwide exposure and mortality data.

Although drinking water in the Netherlands is generally accepted as safe, public concern about health risks of long-term intake still exist. The aim was to explore associations between drinking water quality for nitrate, water hardness, calcium and magnesium and causes-of-death as related to cardiovascular diseases amongst which coronary heart disease and colorectal cancer. We used national administrative databases on cause-specific mortality, personal characteristics, residential history, social economic indicators, air quality and drinking water quality for parameters specified by the EU Drinking Water Directive. We put together a cohort of 6,998,623 persons who were at least 30years old on January 1, 2008 and lived for at least five years on the same address. The average drinking water concentration over 2000-2010 at the production stations were used as exposure indicators. We applied age stratified Cox proportional hazards models. Magnesium was associated with a reduced risk for mortality due to coronary heart diseases: HR of 0.95 (95% CI: 0.90, 0.99) per 10mg/L increase. For mortality due to cardiovascular diseases, a 100mg/L increase in calcium was associated with a HR of 1.08 (95% CI: 1.03, 1.13) and an increase of 2.5mmol/L of water hardness with a HR of 1.06 (95% CI: 1.01, 1.10). The results show an elevated risk for coronary heart disease mortality at calcium concentrations below 30mg/L, but over the whole exposure range no exposure response relation was observed. For other combinations of drinking water quality parameters and cause-specific mortality studied, no statistical significant associations were identified. We identified in this explorative study a protective effect of magnesium for the risk of mortality to coronary heart disease. Also we found an increased risk of mortality due to cardiovascular disease associated with the concentration of calcium and the water hardness in drinking water.

P907: CARFILZOMIB, DEXAMETHASONE, AND DARATUMUMAB (KDD) VS CARFILZOMIB AND DEXAMETHASONE (KD) IN RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): FRAILTY SUBGROUP ANALYSIS OF THE CANDOR STUDY

Background: Frailty scores based on age, comorbidities, and functional status can help identify frail patients (pts) at risk of higher rates of treatment-related toxicity or poor outcomes. An analysis of carfilzomib-treated pts in ASPIRE, ENDEAVOR, and ARROW found that efficacy and safety of carfilzomib regimens is consistent regardless of frailty status (Facon Blood Adv 2020). Aims: To compare efficacy and safety across frailty subgroups in pts with RRMM treated with KdD vs Kd in the phase 3 CANDOR study. Methods: This post hoc analysis used a planned interim readout (June 15, 2020) of CANDOR (NCT03158688). Pts were categorized as fit, intermediate (int), or frail based on a frailty score of 0, 1, or ≥2. Scoring used an algorithm based on the International Myeloma Working Group (IMWG) frailty index: the final score is based on age (0 if ≤75 years, 1 if 76-80 years, 2 if >80 years), modified Charlson Comorbidity Index (CCI [Facon Blood Adv 2020]) (0 if CCI ≤1, 1 if CCI >1), and Eastern Cooperative Oncology Group performance status (ECOG PS) (0 if ECOG PS=0, 1 if ECOG PS=1, and 2 if ECOG PS=2). Progression-free survival (PFS) was summarized descriptively, with hazard ratio (HR) and 95% CI estimated by stratified Cox proportional hazards model. Overall response rate (ORR) was summarized descriptively, with odds ratio (OR) and 95% CI estimated by Mantel-Haenszel method. Response and progression were assessed by the Onyx Response Computer Algorithm using IMWG criteria. Results: Frailty status was generally proportional between arms, with 27% and 35% classified as fit, 43% and 36% int, 25% and 27% frail, and 5% and 2% unknown for KdD and Kd, respectively. Although baseline characteristics of the overall population were generally balanced, more pts had prior transplant in the KdD vs Kd arm for int (65% vs 36%) and frail (41% vs 27%) subgroups, and in the frail subgroup fewer pts were lenalidomide exposed (37% vs 61%)/refractory (25% vs 46%) in the KdD vs Kd arm. Median duration of treatment for KdD vs Kd was 99 weeks (wks) vs 68 wks for fit pts, 82 wks vs 31 wks for int pts, and 51 wks vs 21 wks for frail pts. Median PFS in KdD vs Kd arms was not reached (NR) vs 17.6 months (HR 0.64, 95% CI 0.38–1.07) for fit, NR vs 11.1 months (HR 0.44, 95% CI 0.28–0.69) for int, and 18.5 vs 9.3 months (HR 0.66, 95% CI 0.38–1.14) for frail pts. ORR for KdD vs Kd arms was 89% vs 89% (OR 1.09, 95% CI 0.35–3.38) for fit pts, 87% vs 70% (OR 2.95, 95% CI 1.31–6.62) for int pts, and 75% vs 54% (OR 2.39, 95% CI 1.09–5.22) for frail pts (Figure). Any grade treatment-emergent adverse events (TEAEs) occurred in >95% of pts across arms and subgroups. Grade ≥3 TEAEs occurred in 87% (KdD) and 70% (Kd) of fit pts, 84% and 71% of int pts, and 91% and 90% of frail pts. Fatal TEAEs occurred in 4% and 2% of fit pts, 11% and 9% of int pts, and 16% and 8% of frail pts in the KdD and Kd arms. Carfilzomib was discontinued due to TEAEs in 25% vs 17% of fit pts, 22% vs 29% of int pts, and 35% vs 23% of frail pts. Among TEAEs of interest, acute renal failure occurred in 0 fit pts, 3% vs 14% of int pts, and 8% vs 5% of frail pts, and infusion reactions occurred in 16% vs 2% of fit pts, 13% vs 4% of int pts, and 14% vs 13% of frail pts in the KdD vs Kd arms (Table). Image:Summary/Conclusion: Consistent with previous findings of the efficacy and safety benefits of KdD, a PFS benefit with KdD vs Kd was observed across frailty subgroups, without increased toxicity. The clinically meaningful ORR benefit in the frail subgroup may help physicians evaluate treatment options in this challenging group.

Open-source distributed learning validation for a larynx cancer survival model following radiotherapy

IntroductionPrediction models are useful to design personalised treatment. However, safe and effective implementation relies on external validation. Retrospective data are available in many institutions, but sharing between institutions can be challenging due to patient data sensitivity and governance or legal barriers. This study validates a larynx cancer survival model performed using distributed learning without any sensitive data leaving the institution. MethodsOpen-source distributed learning software based on a stratified Cox proportional hazard model was developed and used to validate the Egelmeer et al. MAASTRO survival model across two hospitals in two countries. The validation optimised a single scaling parameter multiplied by the original predicted prognostic index. All analyses and figures were based on the distributed system, ensuring no information leakage from the individual centres. All applied software is provided as freeware to facilitate distributed learning in other institutions. Results1745 patients received radiotherapy for larynx cancer in the two centres from Jan 2005 to Dec 2018. Limiting to a maximum of one missing value in the parameters of the survival model reduced the cohort to 1095 patients. The Harrell C-index was 0.74 (CI95%, 0.71–0.76) and 0.70 (0.66–0.75) for the two centres. However, the model needed a scaling update. In addition, it was found that survival predictions of patients undergoing hypofractionation were less precise. ConclusionOpen-source distributed learning software was able to validate, and suggest a minor update to the original survival model without central access to patient sensitive information. Even without the update, the original MAASTRO survival model of Egelmeer et al. performed reasonably well, providing similar results in this validation as in its original validation

Disease-Modifying Drugs for Multiple Sclerosis and Association With Survival

Background and ObjectivesWe examined the association between the disease-modifying drugs (DMDs) for multiple sclerosis (MS) and survival in a multiregion population-based study.MethodsWe accessed multiple administrative health databases from 4 Canadian provinces. Persons with MS were identified and followed from the most recent of the first MS or demyelinating event or January 1, 1996 (index date), until death, emigration, or December 31, 2017. Association between the first-generation and second-generation DMDs and all-cause mortality was examined using stratified Cox proportional hazard models, reported as adjusted hazard ratios (aHRs). Timing of DMD initiation was explored, with findings reported at 2, 5, or 10 years postindex date, representing very early, early, or late initiation.ResultsWe identified 35,894 persons with MS; 72% were female. The mean age at index date was 44.5 years (SD = 13.6). The total person-years of follow-up while DMD-exposed was 89,180, and total person-years while unexposed was 342,217. Compared with no exposure, exposure to any DMD or to any first-generation DMD was associated with a 26% lower hazard of mortality (both aHRs 0.74; 95% CI 0.56–0.98), while any second-generation DMD exposure was associated with a 33% lower hazard (aHR 0.67; 95% CI 0.46–0.98). Earlier DMD initiation (beta-interferon or glatiramer acetate vs no exposure) was associated with a significant mortality effect (p < 0.05), while later initiation was not (95% CIs included 1). However, the survival advantage with earlier initiation diminished over time, no longer reaching statistical significance at 15 years postindex date.DiscussionOur study demonstrates an association between the DMDs for MS and improved survival in the real-world setting.

Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial

Patients with large B-cell lymphoma (LBCL) primary refractory to or relapsed within 12 months of first-line therapy are at high risk for poor outcomes with current standard of care, platinum-based salvage immunochemotherapy and autologous haematopoietic stem cell transplantation (HSCT). Lisocabtagene maraleucel (liso-cel), an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell therapy, has previously demonstrated efficacy and manageable safety in third-line or later LBCL. In this Article, we report a prespecified interim analysis of liso-cel versus standard of care as second-line treatment for primary refractory or early relapsed (within 12 months after response to initial therapy) LBCL. TRANSFORM is a global, phase 3 study, conducted in 47 sites in the USA, Europe, and Japan, comparing liso-cel with standard of care as second-line therapy in patients with primary refractory or early (≤12 months) relapsed LBCL. Adults aged 18-75 years, Eastern Cooperative Oncology Group performance status score of 1 or less, adequate organ function, PET-positive disease per Lugano 2014 criteria, and candidates for autologous HSCT were randomly assigned (1:1), by use of interactive response technology, to liso-cel (100 × 106 CAR+ T cells intravenously) or standard of care. Standard of care consisted of three cycles of salvage immunochemotherapy delivered intravenously-R-DHAP (rituximab 375 mg/m2 on day 1, dexamethasone 40 mg on days 1-4, two infusions of cytarabine 2000 mg/m2 on day 2, and cisplatin 100 mg/m2 on day 1), R-ICE (rituximab 375 mg/m2 on day 1, ifosfamide 5000 mg/m2 on day 2, etoposide 100 mg/m2 on days 1-3, and carboplatin area under the curve 5 [maximum dose of 800 mg] on day 2), or R-GDP (rituximab 375 mg/m2 on day 1, dexamethasone 40 mg on days 1-4, gemcitabine 1000 mg/m2 on days 1 and 8, and cisplatin 75 mg/m2 on day 1)-followed by high-dose chemotherapy and autologous HSCT in responders. Primary endpoint was event-free survival, with response assessments by an independent review committee per Lugano 2014 criteria. Efficacy was assessed per intention-to-treat (ie, all randomly assigned patients) and safety in patients who received any treatment. This trial is registered with ClinicalTrials.gov, NCT03575351, and is ongoing. Between Oct 23, 2018, and Dec 8, 2020, 232 patients were screened and 184 were assigned to the liso-cel (n=92) or standard of care (n=92) groups. At the data cutoff for this interim analysis, March 8, 2021, the median follow-up was 6·2 months (IQR 4·4-11·5). Median event-free survival was significantly improved in the liso-cel group (10·1 months [95% CI 6·1-not reached]) compared with the standard-of-care group (2·3 months [2·2-4·3]; stratified hazard ratio 0·35; 95% CI 0·23-0·53; stratified Cox proportional hazards model one-sided p<0·0001). The most common grade 3 or worse adverse events were neutropenia (74 [80%] of 92 patients in the liso-cel group vs 46 [51%] of 91 patients in the standard-of-care group), anaemia (45 [49%] vs 45 [49%]), thrombocytopenia (45 [49%] vs 58 [64%]), and prolonged cytopenia (40 [43%] vs three [3%]). Grade 3 cytokine release syndrome and neurological events, which are associated with CAR T-cell therapy, occurred in one (1%) and four (4%) of 92 patients in the liso-cel group, respectively (no grade 4 or 5 events). Serious treatment-emergent adverse events were reported in 44 (48%) patients in the liso-cel group and 44 (48%) in the standard-of-care group. No new liso-cel safety concerns were identified in the second-line setting. There were no treatment-related deaths in the liso-cel group and one treatment-related death due to sepsis in the standard-of-care group. These results support liso-cel as a new second-line treatment recommendation in patients with early relapsed or refractory LBCL. Celgene, a Bristol-Myers Squibb Company.

Phase 3, randomized, placebo-controlled study of stereotactic body radiotherapy (SBRT) with or without pembrolizumab in patients with unresected stage I or II non–small cell lung cancer (NSCLC): KEYNOTE-867.

TPS8597 Background: Anti–PD-(L)1-directed therapy following radiotherapy or following concurrent chemoradiation is associated with significantly longer PFS and OS in patients with advanced or metastatic NSCLC, including those with locally advanced inoperable tumors. KEYNOTE-867 (NCT03924869) evaluates the efficacy and safety of SBRT with or without pembrolizumab in patients with unresected stage I or II NSCLC. Methods: In this phase 3, randomized, placebo-controlled study, approximately 530 adult patients with previously untreated, unresected, histologically/cytologically confirmed stage I or II (T1 to limited T3, N0, M0) NSCLC are randomized 1:1 to receive thoracic SBRT to primary tumors for ≤2 wk (Table) and either pembrolizumab 200 mg or placebo every 3 wk for 17 cycles (approximately 1 year) or until disease recurrence, development of unacceptable AEs, SBRT not started for any reason, or study withdrawal. Randomization is stratified by disease stage (I vs II), ECOG PS (0 or 1 vs 2), geographic region (East Asia vs non-East Asia), and reason for not receiving surgery (medically inoperable vs refused surgery). Imaging assessment by blinded independent central review (BICR) occurs at 12 wk (≥10 wk after SBRT completion), followed by every 16 wk for 3 y, and then every 6 mo. Primary endpoints are event-free survival (EFS) by BICR and OS. Secondary endpoints include time to death or distant metastases and safety; exploratory endpoints are time to subsequent treatment, disease-specific survival, and time to recurrence/progression on subsequent line of therapy. AEs are monitored throughout the trial until 30 d after last dose (90 for serious AEs) and graded according to NCI CTCAE version 4.0. EFS and OS are analyzed by the nonparametric Kaplan-Meier method, treatment differences by stratified log-rank test, and hazard ratios by stratified Cox proportional hazard model with Efron's method of tie handling. Enrollment started on June 17, 2019, and is ongoing at 168 sites around the world. Clinical trial information: NCT03924869. [Table: see text]

Long-term exposure to ozone and cardiovascular mortality in China: a nationwide cohort study

The evidence for a causal relationship between long-term ozone exposure and cardiovascular mortality is inconclusive, and most published data are from high-income countries. We aimed to investigate the association between long-term exposure to ozone and cardiovascular mortality in China, the most populous middle-income country. We did a nationwide cohort study comprising Chinese adults aged 18 years and older from the 2010-11 China Chronic Disease and Risk Factors Surveillance project; participants were followed up until Dec 31, 2018, or the date of death. Data on participants' deaths were obtained through linkage to the Disease Surveillance Point system, a national death registration database. Residential ozone exposure was estimated with a previously developed random forest model. We applied stratified Cox proportional hazards models to estimate the associations of ozone with mortality due to overall cardiovascular diseases, ischaemic heart disease, and stroke. The models were stratified by age and sex and adjusted for a set of individual-level and regional covariates. Warm-season average ozone concentration for the previous 1-3 years was added as a time-varying variable. We also did subgroup analyses by age, sex, level of education, smoking status, urban or rural residence, and geographical region. Data were analysed for 96 955 participants. The warm-season average ozone concentration during the follow-up period was 89·7 μg/m3 (SD 14·4). In the fully adjusted models, we observed significant and positive associations between ozone and mortality from overall cardiovascular diseases (hazard ratio [HR] 1·093 [95% CI 1·046-1·142] per 10 μg/m3 increase in warm-season ozone concentrations), ischaemic heart disease (1·184 [1·099-1·276] per 10 μg/m3 increase in warm-season ozone concentrations), and stroke (1·063 [1·002- 1·128] per 10 μg/m3 increase in warm-season ozone concentrations). After adjusting for fine particulate matter, the associations with overall cardiovascular disease and ischaemic heart disease mortality were almost unchanged, whereas the association with stroke mortality lost statistical significance. The association of long-term ozone exposure with cardiovascular mortality was more prominent in people aged 65 years and older than in those younger than 65 years. We did not find any effect modification of sex, level of education, smoking status, urban or rural residence, and geographical region. We observed an almost linear exposure-response relationship between ozone and cardiovascular mortality. This study is, to the best of our knowledge, the first nationwide cohort study to show that long-term ozone exposure contributes to elevated risks of cardiovascular mortality, particularly from ischaemic heart disease, in a middle-income setting. The exposure-response function generated from this study could potentially inform future air quality standard revisions and environmental health impact assessments. National Natural Science Foundation of China.

Health-related quality of life (HRQoL) impact of pembrolizumab (pembro) plus best supportive care (BSC) versus placebo (PBO) plus BSC as second-line (2L) therapy in patients (pts) in Asia with advanced hepatocellular carcinoma (HCC): Phase 3 KEYNOTE-394 study.

4088 Background: In the randomized, double-blind, phase 3 KEYNOTE-394 trial (NCT03062358), pembro + BSC vs PBO + BSC as 2L therapy significantly reduced the risk of death by 21% (HR 0.79, 95% CI 0.63-0.99, P= 0.0180), prolonged PFS (HR 0.74, 95% CI 0.60-0.92, P= 0.0032), and improved ORR (estimated difference 11.4%, 95% CI 6.7-16.0, P= 0.00004) with a manageable safety profile in pts in Asia with advanced HCC and progression on or intolerance to sorafenib or oxaliplatin-based chemotherapy. Here we present the results of prespecified exploratory HRQoL analyses. Methods: EORTC QLQ-C30 and EuroQol-5D3L (EQ5D-3L) questionnaires were administered at baseline (BL); wks 3, 6, 9, 12, 18; every 9 wks thereafter up to 1 yr or end of treatment; at treatment discontinuation, and at the 30-day safety follow-up visit. Pts who received ≥1 dose of study treatment and completed ≥1 HRQoL assessment were included in the analyses. Least squares mean (LSM) score changes from BL to wk 12 were compared using a constrained longitudinal data analysis model, including treatment by study visit interaction and stratification factors as covariates. Kaplan-Meier method was used to estimate time to deterioration (TTD) (time to 1st onset of ≥10-point decline from BL/confirmed by a 2nd adjacent ≥10-point decline from BL) for EORTC QLQ-C30 global health status (GHS)/QoL. Stratified Cox proportional hazards model was used to assess the magnitude of the treatment difference (HR) between treatment arms in TTD with nominal, one-sided P value calculated. Results: The HRQoL population included 450 pts (298 pembro; 152 PBO). HRQoL compliance rate at wk 12 was 95.7% for pembro for both questionnaires and 94.4% for EORTC QLQ-C30 and 95.3% for EQ5D-3L for PBO. There was a statistically significant difference in LSM for change from BL to wk 12, between the two arms for the QLQ-C30 GHS/QoL score and EQ-5D VAS score, with more decline observed in the PBO arm. Difference in LSM for QLQ-C30 GHS/QoL score between pembro (-3.97; 95% CI, -6.38, -1.56) and PBO (-8.40; 95% CI, -11.71, -5.10) arms was 4.43 (95% CI, 0.47, 8.40; P= 0.0142). Difference in LSM for EQ-5D VAS score between pembro (-2.74; 95% CI, -4.51, -0.96) and PBO (-6.94; 95% CI, -9.40, -4.48) arms was 4.20 (95% CI, 1.21, 7.19; P= 0.0030). GHS/QOL mean scores generally remained stable over time in pembro arm. TTD in EORTC QLQ-C30 GHS/QoL score was similar between arms (HR, 0.85; 95% CI, 0.58, 1.25; P= 0.1993). Conclusions: Over 12 wks, pts treated with PBO + BSC showed more decline in HRQoL than those receiving pembro + BSC. Combined with the efficacy and safety results from KEYNOTE-394, as well as other global 2L trials with pembro, including KEYNOTE-240 and KEYNOTE-224, our data support the benefit of pembro as 2L therapy for pts with advanced HCC. Clinical trial information: NCT03062358.

Associations Between Chronic Rhinosinusitis and Cancers: A Nationwide Population-Based Cohort Study.

Chronic rhinosinusitis (CRS) is one of the most common chronic inflammatory diseases. The effect of chronic inflammation caused by CRS on the occurrence of various cancers has not been thoroughly evaluated. This study aimed to investigate the increased incidences of 10 types of cancers among CRS patients with/without nasal polyps (NP) using a national population-based database from the Korean Health Insurance Review and Assessment Service. A case-control cohort study. We compared the prevalence of various comorbidities between CRS and control participants from a national cohort dataset of the Korean Health Insurance Review and Assessment Service. CRS participants (n=6,919) and non-CRS (n=27,676) participants were selected from among the 514,866 participants from 2002 to 2015. A stratified Cox proportional hazards model was utilized to assess the hazard ratio (HR) of CRS for 10 types of cancers. A stratified Cox proportional hazard model demonstrated that the adjusted HR for hematologic malignancy was significantly higher in the CRS patients than in the controls regardless of the presence of NP (2.90 for total CRS; 2.15 for CRS with NP; 4.48 for CRS without NP). The HR for thyroid cancer was significantly higher in the CRS patients without NP but not in those with NP (1.50 for total CRS; 1.78 for CRS without NP). This study showed that CRS participants had a significantly higher prevalence of hematologic malignancy and thyroid cancer. 4 Laryngoscope, 133:1044-1051, 2023.