Reliability, validity, and change thresholds of the NCCN/FACT Bladder Symptom Index (NFBlSI-18) in patients with advanced urothelial cancer.

BACKGROUND: The NCCN/FACT Bladder Symptom Index-18 (NFBlSI-18) is a bladder cancer-specific instrument. We aimed to psychometrically evaluate the reliability and validity of NFBlSI-18 and estimate change thresholds for total, disease-related symptoms-physical (DRS-P), DRS-emotional (DRS-E), and function/well-being (F/WB) scales in patients with locally advanced/metastatic urothelial cancer (la/mUC). METHODS: JAVELIN Bladder 100 trial data were analyzed. Anchors to evaluate validity included: 5-level EuroQoL-5D utility index (EQ-5D-5L UI), visual analog scale (VAS), Eastern Cooperative Oncology Group (ECOG) performance status, and number of symptoms. Responsiveness to change was tested by anchoring to time to tumor progression (TTP), best overall response (BOR), and differences in means between ECOG categories to estimate meaningful between-group differences. Meaningful within-group change thresholds were estimated using receiver operating characteristic curve analysis, anchoring to change in EQ-5D-5L UI. Significant within-individual patient change thresholds were estimated with reliable and likely change indexes. RESULTS: Correlations with EQ-5D-5L UI and VAS ranged from 0.53 to 0.73. Standardized effect sizes were >0.20. Compared with patients with TTP of ≥6 months, patients with TTP of >0-2 and 3-5 months had larger declines; results for BOR were similar. Thresholds (points) for meaningful between-group differences were: total, 6-11; DRS-P, 3-6; and DRS-E and F/WB, 1. Thresholds (points) for meaningful within-group worsening were: total, 4; and DRS-P, 3, and for significant individual change they were: total, 3-9; DRS-P, 2-6; DRS-E, 1-3; and F/WB, 2-4. CONCLUSIONS: NFBlSI-18 exhibited evidence of reliability, validity, and responsiveness to assess quality of life in studies of la/mUC, and change thresholds are established for future studies. PLAIN LANGUAGE SUMMARY: The NCCN/FACT Bladder Symptom Index-18 (NFBlSI-18) is a questionnaire used to assess quality of life for people with advanced bladder cancer. People with advanced bladder cancer who took part in the JAVELIN Bladder 100 study completed the NFBlSI-18 when they joined the study and after each treatment with avelumab maintenance or best supportive care. This study showed that NFBlSI-18 is suitable for capturing bladder cancer symptoms and is able to detect important changes in a person's quality of life over time. This study also provides thresholds for changes in NFBlSI-18 scores, which will be useful for future studies.

Meaningful within-patient change for clinical outcome assessments: model-based approach versus cumulative distribution functions.

OBJECTIVES: The FDA recommends the use of anchor-based methods and empirical cumulative distribution function (eCDF) curves to establish a meaningful within-patient change (MWPC) for a clinical outcome assessment (COA). In practice, the estimates obtained from model-based methods and eCDF curves may not closely align, although an anchor is used with both. To help interpret their results, we investigated and compared these approaches. METHODS: Both repeated measures model (RMM) and eCDF approaches were used to estimate an MWPC on a target COA. We used both real-life (ClinicalTrials.gov: NCT02697773) and simulated data sets that included 688 patients with up to six visits per patient, target COA (range 0 to 10), and an anchor measure on patient global assessment of osteoarthritis from 1 (very good) to 5 (very poor). Ninety-five percent confidence intervals for the MWPC were calculated by the bootstrap method. RESULTS: The distribution of the COA score changes affected the degree of concordance between RMM and eCDF estimates. The COA score changes from simulated normally distributed data led to greater concordance between the two approaches than did COA score changes from the actual clinical data. The confidence intervals of MWPC estimate based on eCDF methods were much wider than that by RMM methods, and the point estimate of eCDF methods varied noticeably across visits. CONCLUSIONS: Our data explored the differences of model-based methods over eCDF approaches, finding that the former integrates more information across a diverse range of COA and anchor scores and provides more precise estimates for the MWPC.

Special Issue PRO-Analysis of Clinically Meaningful Change on Patient-Reported Outcomes: Renewed Insights About Covariate Adjustment.

Determining clinically meaningful change (CMC) in a patient-reported (PRO) measure is central to its existence in gauging how patients feel and function, especially for evaluating a treatment effect. Anchor-based approaches are recommended to estimate a CMC threshold on a PRO measure. Determination of CMC involves linking changes or differences in the target PRO measure to that in an external (anchor) measure that is easier to interpret than and appreciably associated with the PRO measure. One type of anchor-based approach for CMC is the "mean change method" where the mean change in score of the target PRO measure within a particular anchor transition level (e.g. one-category improvement) is subtracted from the mean change in score of within an adjacent anchor category (e.g. no change category). In the literature, the mean change method has been applied with and without an adjustment for the baseline scores for the PRO of interest. This article provides the analytic rationale and conceptual justification for keeping the analysis unadjusted and not controlling for baseline PRO scores. Two illustrative examples are highlighted. The current research is essentially a variation of Lord's paradox (where whether to adjust for a baseline variable depends on the research question) placed in a new context. Once the adjustment is made, the resulting CMC estimate reflects an artificial case where the anchor transition levels are forced to have the same average baseline PRO score. The unadjusted estimate acknowledges that the anchor transition levels are naturally occurring (not randomized) groups and thus maintains external validity.

Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints in Cancer Clinical Trials-Innovative Medicines Initiative (SISAQOL-IMI): stakeholder views, objectives, and procedures.

Patient-reported outcomes (PROs), such as symptoms, functioning, and other health-related quality-of-life concepts are gaining a more prominent role in the benefit-risk assessment of cancer therapies. However, varying ways of analysing, presenting, and interpreting PRO data could lead to erroneous and inconsistent decisions on the part of stakeholders, adversely affecting patient care and outcomes. The Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints in Cancer Clinical Trials-Innovative Medicines Initiative (SISAQOL-IMI) Consortium builds on the existing SISAQOL work to establish recommendations on design, analysis, presentation, and interpretation for PRO data in cancer clinical trials, with an expanded set of topics, including more in-depth recommendations for randomised controlled trials and single-arm studies, and for defining clinically meaningful change. This Policy Review presents international stakeholder views on the need for SISAQOL-IMI, the agreed on and prioritised set of PRO objectives, and a roadmap to ensure that international consensus recommendations are achieved.

Comparing g-computation, propensity score-based weighting, and targeted maximum likelihood estimation for analyzing externally controlled trials with both measured and unmeasured confounders: a simulation study.

OBJECTIVES: To have confidence in one's interpretation of treatment effects assessed by comparing trial results to external controls, minimizing bias is a critical step. We sought to investigate different methods for causal inference in simulated data sets with measured and unmeasured confounders. METHODS: The simulated data included three types of outcomes (continuous, binary, and time-to-event), treatment assignment, two measured baseline confounders, and one unmeasured confounding factor. Three scenarios were set to create different intensities of confounding effect (e.g., small and blocked confounding paths, medium and blocked confounding paths, and one large unblocked confounding path for scenario 1 to 3, respectively) caused by the unmeasured confounder. The methods of g-computation (GC), inverse probability of treatment weighting (IPTW), overlap weighting (OW), standardized mortality/morbidity ratio (SMR), and targeted maximum likelihood estimation (TMLE) were used to estimate average treatment effects and reduce potential biases. RESULTS: The results with the greatest extent of biases were from the raw model that ignored all the potential confounders. In scenario 2, the unmeasured factor indirectly influenced the treatment assignment through a measured controlling factor and led to medium confounding. The methods of GC, IPTW, OW, SMR, and TMLE removed most of bias observed in average treatment effects for all three types of outcomes from the raw model. Similar results were found in scenario 1, but the results tended to be biased in scenario 3. GC had the best performance followed by OW. CONCLUSIONS: The aforesaid methods can be used for causal inference in externally controlled studies when there is no large, unblockable confounding path for an unmeasured confounder. GC and OW are the preferable approaches.

Patient-reported Outcomes from JAVELIN Bladder 100: Avelumab First-line Maintenance Plus Best Supportive Care Versus Best Supportive Care Alone for Advanced Urothelial Carcinoma.

BACKGROUND: In JAVELIN Bladder 100, avelumab first-line maintenance plus best supportive care (BSC) significantly prolonged overall survival (OS; primary endpoint) versus BSC alone in patients with advanced urothelial carcinoma (aUC) without disease progression with first-line platinum-containing chemotherapy. OBJECTIVE: To evaluate patient-reported outcomes (PROs) with avelumab plus BSC versus BSC alone. DESIGN, SETTING, AND PARTICIPANTS: A randomized phase 3 trial (NCT02603432) was conducted in 700 patients with locally advanced or metastatic urothelial carcinoma that had not progressed with first-line gemcitabine plus cisplatin or carboplatin. PROs were a secondary endpoint. INTERVENTION: Avelumab plus BSC (n = 350) or BSC alone (n = 350). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Bladder Symptom Index-18 (FBlSI-18) and EuroQol five-level EQ-5D (EQ-5D-5L) assessments were analyzed using descriptive statistics and mixed-effect models. Time to deterioration (TTD; prespecified definition: a ≥3-point decrease from baseline in the FBlSI-18 disease-related symptoms-physical subscale for two consecutive assessments) was evaluated via Kaplan-Meier analyses. RESULTS AND LIMITATIONS: Completion rates for scheduled on-treatment PRO assessments were >90% (overall and average per assessment). Results from descriptive analyses and mixed-effect or repeated-measures models of FBlSI-18 and EQ-5D-5L were similar between arms. TTD was also similar, both in the prespecified analysis (hazard ratio 1.26 [95% confidence interval: 0.90, 1.77]) and in the post hoc analyses including off-treatment assessments and different event definitions. Limitations included the open-label design and limited numbers of evaluable patients at later time points. CONCLUSIONS: Addition of avelumab first-line maintenance to BSC in patients with aUC that had not progressed with first-line platinum-containing chemotherapy prolonged OS, with a relatively minimal effect on quality of life. PATIENT SUMMARY: In this trial of people with advanced urothelial carcinoma who had benefited from first-line chemotherapy (ie, had stable disease or reduced tumor size), treatment with avelumab maintenance plus best supportive care (BSC) versus BSC alone improved survival significantly, without compromising quality of life, as reported by the patients themselves.

Impact of tanezumab on health status, non-work activities and work productivity in adults with moderate-to-severe osteoarthritis.

BACKGROUND: To evaluate the impact of tanezumab on health status, non-work activities, and work productivity in a pooled analysis of two large phase 3 osteoarthritis (OA) studies. METHODS: Subcutaneous tanezumab (2.5 mg and 5 mg) was tested in double-blind, placebo-controlled, 16-week (NCT02697773) and 24-week (NCT02709486) clinical trials in patients with moderate-to-severe OA of the hip or knee. At baseline and week 16, all patients completed EQ-5D-5L and the Work Productivity and Activity Impairment-OA (WPAI-OA) activity impairment item. Those currently employed also completed WPAI-OA work time missed, impairment while working, and overall work impairment items. Between-group differences in least squares (LS) mean changes from baseline at week 16 were tested using analysis of covariance. RESULTS: Of 1545 pooled patients, 576 were employed at baseline. Improvements in EQ-5D-5L index value at week 16 were significantly greater for the tanezumab 2.5-mg group (difference in LS means [95% confidence interval (CI), 0.03 [0.01, 0.05]; p = 0.0083) versus placebo. Percent improvements (95% CI) in activity impairment (- 5.92 [- 8.87, - 2.98]; p < 0.0001), impairment while working (- 7.34 [- 13.01, - 1.68]; p = 0.0112), and overall work impairment (- 7.44 [- 13.22, - 1.67]; p = 0.0116) at week 16 were significantly greater for the tanezumab 2.5-mg group versus placebo. Results for the tanezumab 5-mg group were generally comparable to the tanezumab 2.5-mg group, although, compared with placebo, percent improvement (95% CI) in work time missed was significantly greater for the tanezumab 5-mg group (- 3.40 [- 6.47, - 0.34]; p = 0.0294), but not the tanezumab 2.5-mg group (- 0.66 [- 3.63, 2.32]; p = 0.6637). CONCLUSIONS: These pooled analyses showed that health status, non-work activities, and work productivity were significantly improved following tanezumab administration, compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02697773, NCT02709486.

Finite Mixture Models, a Flexible Alternative to Standard Modeling Techniques for Extrapolated Mean Survival Times Needed for Cost-Effectiveness Analyses.

OBJECTIVES: To compare finite mixture models with common survival models with respect to how well they fit heterogenous data used to estimate mean survival times required for cost-effectiveness analysis. METHODS: Publicly available overall survival (OS) and progression-free survival (PFS) curves were digitized to produce nonproprietary data. Regression models based on the following distributions were fit to the data: Weibull, lognormal, log-logistic, generalized F, generalized gamma, Gompertz, mixture of 2 Weibulls, and mixture of 3 Weibulls. A second set of analyses was performed based on data in which patients who had not experienced an event by 30 months were censored. Model performance was compared based on the Akaike information criterion (AIC). RESULTS: For PFS, the 3-Weibull mixture (AIC = 479.94) and 2-Weibull mixture (AIC = 488.24) models outperformed other models by more than 40 points and produced the most accurate estimates of mean survival times. For OS, the AIC values for all models were similar (all within 4 points). The means for the mixture 3-Weibulls mixture model (17.60 months) and the 2-Weibull mixture model (17.59 months) were the closest to the Kaplan-Meier mean estimate of (17.58 months). The results and conclusions from the censored analysis of PFS were similar to the uncensored PFS analysis. On the basis of extrapolated mean OS, all models produced estimates within 10% of the Kaplan-Meier mean survival time. CONCLUSIONS: Finite mixture models offer a flexible modeling approach that has benefits over standard parametric models when analyzing heterogenous data for estimating survival times needed for cost-effectiveness analysis.

Treatment Sequencing Patterns in Patients with Metastatic Urothelial Cancer Treated in the Community Practice Setting in the United States: SPEAR-Bladder (Study informing treatment Pathway dEcision in bladder cAnceR).

PURPOSE: Clinical trial evidence has affirmed the role for immuno-oncology (IO) treatment for locally advanced or metastatic urothelial carcinoma (la/mUC). This Study informing treatment Pathway dEcision in bladder cAnceR (SPEAR-Bladder) aimed to provide insight into the optimal sequencing of IO treatments among la/mUC patients treated in the US Oncology Network. PATIENTS AND METHODS: This was a retrospective analysis of adult patients with la/mUC who initiated first-line chemotherapy followed by either IO therapy (C-IO subgroup) or chemotherapy (C-C subgroup) between 01/01/2015 and 04/30/2017 and included a potential follow-up period through 06/30/2017. Data were sourced from iKnowMed electronic health records. Patient and treatment characteristics were assessed descriptively, with Kaplan-Meier methods used to evaluate time-to-event outcomes, including overall survival (OS). RESULTS: A total of 117 patients were included in this analysis (median age 69 years, 74.4% male, 88.0% Caucasian): 79 and 38 patients were in the C-IO and C-C subgroups, respectively. The median OS was 19.2 months among patients who received the C-IO sequence and 11.9 months among those who received the C-C treatment sequence. CONCLUSION: These results suggest that patients who received the C-IO treatment sequence had notable improvement in OS compared with those who received the C-C sequence. In light of the rapidly evolving therapeutic landscape, further investigation will be required to determine how best to select the optimal therapeutic regimen and sequencing for patients with la/mUC.

Effect of radium-223 dichloride (Ra-223) on hospitalisation: An analysis from the phase 3 randomised Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial.

Symptomatic skeletal events (SSEs) commonly occur in patients with bone metastases, often leading to hospitalisations and decreased quality-of-life. In the ALSYMPCA trial, radium-223 significantly improved overall survival (hazard ratio 0.70, 95% confidence interval [CI] 0.58-0.83, P < 0.001) and prolonged time to first SSE (hazard ratio 0.66, 95% CI 0.52-0.83, P = 0.00037) and subsequent SSE (hazard ratio 0.65, 95% CI 0.51-0.83, P = 0.00039) versus placebo in patients with castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastases. Health care resource use (HCRU), including hospitalisation events and days, were prospectively collected in ALSYMPCA. We assessed health care resource use for the first 12 months post-randomisation. Significantly fewer radium-223 (218/589; 37.0%) versus placebo patients (133/292; 45.5%) had at least one hospitalisation event (P = 0.016). However, mean number of hospitalisation events per patient was similar (radium-223 0.69 versus placebo 0.79, P = 0.226), likely due to the significantly longer follow-up time for radium-223 (7.82 months versus 6.92 months for placebo; P < 0.001). There were significantly fewer hospitalisation days per patient for radium-223 (4.44 versus 6.68, respectively, P = 0.004). The reduction in hospitalisation days with radium-223 was observed both before first SSE (2.35 days versus 3.36 days, respectively) and after SSE (7.74 days versus 9.19 days, respectively). Our data suggest that this reduced hospital days along with the survival benefit and reduction in time to SSEs with radium-223 treatment may contribute to improvements in health-related quality-of-life in patients with castration-resistant prostate cancer with symptomatic bone metastases (ALSYMPCA ClinicalTrials.gov number, NCT00699751.).

Human risk of infection with Borrelia burgdorferi, the Lyme disease agent, in eastern United States.

The geographic pattern of human risk for infection with Borrelia burgdorferi sensu stricto, the tick-borne pathogen that causes Lyme disease, was mapped for the eastern United States. The map is based on standardized field sampling in 304 sites of the density of Ixodes scapularis host-seeking nymphs infected with B. burgdorferi, which is closely associated with human infection risk. Risk factors for the presence and density of infected nymphs were used to model a continuous 8 km×8 km resolution predictive surface of human risk, including confidence intervals for each pixel. Discontinuous Lyme disease risk foci were identified in the Northeast and upper Midwest, with a transitional zone including sites with uninfected I. scapularis populations. Given frequent under- and over-diagnoses of Lyme disease, this map could act as a tool to guide surveillance, control, and prevention efforts and act as a baseline for studies tracking the spread of infection.

Climate and tick seasonality are predictors of Borrelia burgdorferi genotype distribution.

The blacklegged tick, Ixodes scapularis, is of significant public health importance as a vector of Borrelia burgdorferi, the agent of Lyme borreliosis. The timing of seasonal activity of each immature I. scapularis life stage relative to the next is critical for the maintenance of B. burgdorferi because larvae must feed after an infected nymph to efficiently acquire the infection from reservoir hosts. Recent studies have shown that some strains of B. burgdorferi do not persist in the primary reservoir host for more than a few weeks, thereby shortening the window of opportunity between nymphal and larval feeding that sustains their enzootic maintenance. We tested the hypothesis that climate is predictive of geographic variation in the seasonal activity of I. scapularis, which in turn differentially influences the distribution of B. burgdorferi genotypes within the geographic range of I. scapularis. We analyzed the relationships between climate, seasonal activity of I. scapularis, and B. burgdorferi genotype frequency in 30 geographically diverse sites in the northeastern and midwestern United States. We found that the magnitude of the difference between summer and winter daily temperature maximums was positively correlated with the degree of seasonal synchrony of the two immature stages of I. scapularis. Genotyping revealed an enrichment of 16S-23S rRNA intergenic spacer restriction fragment length polymorphism sequence type 1 strains relative to others at sites with lower seasonal synchrony. We conclude that climate-associated variability in the timing of I. scapularis host seeking contributes to geographic heterogeneities in the frequencies of B. burgdorferi genotypes, with potential consequences for Lyme borreliosis morbidity.