Dataset Information

Clinical laboratory tests associated with survival in patients with metastatic renal cell carcinoma: A Laboratory Wide Association Study (LWAS).

ABSTRACT:

Background

Prognostic models for patients with metastatic renal cell carcinoma (mRCC) include select laboratory values. These models have important limitations, including reliance on a limited array of laboratory tests, and use of dichotomous ("high-low") cutoffs. We applied a Laboratory-Wide Association Study (LWAS) framework to systematically evaluate common clinical laboratory results associated with survival for patients diagnosed with mRCC.

Methods

We used laboratory data for 3,385 patients diagnosed with mRCC from 2002 to 2017. We developed a LWAS framework, to examine the association with 53 common clinical laboratory tests results (641,712 measurements) and overall survival. We employed false-discovery rate to test the association of multiple laboratory tests with survival, and validated these results using 3 separate cohorts to generate a standardized hazard ratio (sHR), reported for a 1 standard deviation unit change in each laboratory test.

Results

The LWAS approach confirmed the association of laboratory values currently used in prognostic models with survival, including calcium (HR 1.35, 95%CI 1.24-1.48), leukocyte count (HR 1.40, 95%CI 1.30-1.51), platelet count (HR 1.36, 95%CI 1.27-1.51), and hemoglobin (HR 0.79, 95%CI 0.72-0.86). Use of these tests as continuous variables improved model performance. LWAS also identified acute phase reactants associated with survival not typically included in prognostic models, including serum albumin (HR 0.66, 95%CI 0.61-0.72), ferritin (HR 1.25, 95%CI 1.08-1.45), alkaline phosphatase (HR 1.31, 95%CI 1.23-1.40), and C-reactive protein (HR 1.70, 95%CI 1.14-2.53).

Conclusions

Routinely measured laboratory tests can refine current prognostic models, facilitate comparisons across clinical trial cohorts, and match patients with specific systemic therapies.

SUBMITTER: Velaer K

PROVIDER: S-EPMC10313329 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Publications

Clinical laboratory tests associated with survival in patients with metastatic renal cell carcinoma: A Laboratory Wide Association Study (LWAS).

Velaer Kyla K Thomas I-Chun IC Yang Jaden J Kapphahn Kristopher K Metzner Thomas J TJ Golla Abhinav A Hoerner Christian R CR Fan Alice C AC Master Viraj V Chertow Glenn M GM Brooks James D JD Patel Chirag J CJ Desai Manisha M Leppert John T JT

Urologic oncology 20210924 1

<h4>Background</h4>Prognostic models for patients with metastatic renal cell carcinoma (mRCC) include select laboratory values. These models have important limitations, including reliance on a limited array of laboratory tests, and use of dichotomous ("high-low") cutoffs. We applied a Laboratory-Wide Association Study (LWAS) framework to systematically evaluate common clinical laboratory results associated with survival for patients diagnosed with mRCC.<h4>Methods</h4>We used laboratory data for ...[more]

PMID: 34580027

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Project description:BackgroundEstimates of overall patient health are essential to inform treatment decisions for patients diagnosed with cancer. The authors applied XWAS methods, herein referred to as "laboratory-wide association study (LWAS)", to evaluate associations between routinely collected laboratory tests and survival in veterans with prostate cancer.MethodsThe authors identified 133,878 patients who were diagnosed with prostate cancer between 2000 and 2013 in the Veterans Health Administration using any laboratory tests collected within 6 months of diagnosis (3,345,083 results). Using the LWAS framework, the false-discovery rate was used to test the association between multiple laboratory tests and survival, and these results were validated using training, testing, and validation cohorts.ResultsA total of 31 laboratory tests associated with survival met stringent LWAS criteria. LWAS confirmed markers of prostate cancer biology (prostate-specific antigen: hazard ratio [HR], 1.07 [95% confidence interval (95% CI), 1.06-1.08]; and alkaline phosphatase: HR, 1.22 [95% CI, 1.20-1.24]) as well laboratory tests of general health (eg, serum albumin: HR, 0.78 [95% CI, 0.76-0.80]; and creatinine: HR, 1.05 [95% CI, 1.03-1.07]) and inflammation (leukocyte count: HR, 1.23 [95% CI, 1.98-1.26]; and erythrocyte sedimentation rate: HR, 1.33 [95% CI, 1.09-1.61]). In addition, the authors derived and validated separate models for patients with localized and advanced disease, identifying 28 laboratory markers and 15 laboratory markers, respectively, in each cohort.ConclusionsThe authors identified routinely collected laboratory data associated with survival for patients with prostate cancer using LWAS methodologies, including markers of prostate cancer biology, overall health, and inflammation. Broadening consideration of determinants of survival beyond those related to cancer itself could help to inform the design of clinical trials and aid in shared decision making.Lay summaryThis article examined routine laboratory tests associated with survival among veterans with prostate cancer. Using laboratory-wide association studies, the authors identified 31 laboratory tests associated with survival that can be used to inform the design of clinical trials and aid patients in shared decision making.

Project description:Renal-cell carcinoma (RCC) affects over 330,000 new patients every year, of whom 1/3 present with metastatic RCC (mRCC) at diagnosis. Most mRCC patients treated with a first-line agent relapse within 1 year and need second-line therapy. The present study aims to compare overall survival (OS) between nivolumab and cabozantinib from two recent pivotal studies comparing, respectively, each one of the two emerging treatments against everolimus in patients who relapse following first-line treatment. Comparison is traditionally carried out using the Bucher method, which assumes proportional hazard. Since OS curves intersected in one of the pivotal studies, models not assuming proportional hazards were also considered to refine the comparison. Four Bayesian parametric survival network meta-analysis models were implemented on overall survival (OS) data digitized from the Kaplan-Meier curves reported in the studies. Three models allowing hazard ratios (HR) to vary over time were assessed against a fixed-HR model. The Bucher method favored cabozantinib, with a fixed HR for OS vs. nivolumab of 1.09 (95% confidence interval: [0.77, 1.54]). However, all models with time-varying HR showed better fits than the fixed-HR model. The log-logistic model fitted the data best, exhibiting a HR for OS initially favoring cabozantinib, the trend inverting to favor nivolumab after month 5 (95% credible interval <1 from 10 months). The initial probability of cabozantinib conferring superior OS was 54%, falling to 41.5% by month 24. Numerical differences in study-adjusted OS estimates between the two treatments remained small. This study evidences that HR for OS of nivolumab vs. cabozantinib varies over time, favoring cabozantinib in the first months of treatment but nivolumab afterwards, a possible indication that patients with poor prognosis benefit more from cabozantinib in terms of survival, nivolumab benefiting patients with better prognosis. More evidence, including real-world observational data, is needed to compare effectiveness between cabozantinib and nivolumab.

Project description:Background and objectivesInvestigations of the prognosis are vital for better patient management and decision-making in patients with advanced metastatic renal cell carcinoma (mRCC). The purpose of this study is to evaluate the capacity of emerging Artificial Intelligence (AI) technologies to predict three- and five-year overall survival (OS) for mRCC patients starting their first-line of systemic treatment.Patients and methodsThe retrospective study included 322 Italian patients with mRCC who underwent systemic treatment between 2004 and 2019. Statistical analysis included the univariate and multivariate Cox proportional-hazard model and the Kaplan-Meier analysis for the prognostic factors' investigation. The patients were split into a training cohort to establish the predictive models and a hold-out cohort to validate the results. The models were evaluated by the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. We assessed the clinical benefit of the models using decision curve analysis (DCA). Then, the proposed AI models were compared with well-known pre-existing prognostic systems.ResultsThe median age of patients in the study was 56.7 years at RCC diagnosis and 78% of participants were male. The median survival time from the start of systemic treatment was 29.2 months; 95% of the patients died during the follow-up that finished by the end of 2019. The proposed predictive model, which was constructed as an ensemble of three individual predictive models, outperformed all well-known prognostic models to which it was compared. It also demonstrated better usability in supporting clinical decisions for 3- and 5-year OS. The model achieved (0.786 and 0.771) AUC and (0.675 and 0.558) specificity at sensitivity 0.90 for 3 and 5 years, respectively. We also applied explainability methods to identify the important clinical features that were found to be partially matched with the prognostic factors identified in the Kaplan-Meier and Cox analyses.ConclusionsOur AI models provide best predictive accuracy and clinical net benefits over well-known prognostic models. As a result, they can potentially be used in clinical practice for providing better management for mRCC patients starting their first-line of systemic treatment. Larger studies would be needed to validate the developed model.

Project description:ImportanceTargeted therapies for advanced renal cell carcinoma (RCC) have shown increased tolerability and survival advantages over older treatments in clinical trials, but understanding of real-world survival improvements is still emerging.ObjectiveTo compare overall and RCC-specific survival associated with use of targeted vs nontargeted therapy for metastatic RCC.Design, setting, and participantsThis retrospective cohort study used Surveillance, Epidemiology, and End Results-Medicare data from 2000 to 2013 to examine patients with stage IV (distant) clear cell RCC at the time of diagnosis who received any targeted or nontargeted therapy. A 2-stage residual inclusion model was fitted to estimate the survival advantages of targeted treatments using an instrumental variable approach to account for both measured and unmeasured group differences. Data analyses were conducted from July 24, 2017, to April 4, 2019.ExposuresTargeted therapy (study group) or nontargeted therapy (control group).Main outcomes and measuresOverall survival and RCC-specific survival, defined as the interval between the date of first drug treatment and date of death or end of the observation period.ResultsThe final sample included 1015 patients (mean [SD] age, 71.2 [8.1] years; 392 [39%] women); 374 (37%) received nontargeted therapy and 641 (63%) received targeted therapy. The targeted therapy group had a greater percentage of disabled patients (ie, those <65 years old who were eligible for Medicare because of disability) and older patients (ie, those ≥75 years old) and higher comorbidity index and disability scores compared with the nontargeted therapy group. Unadjusted Kaplan-Meier survival curves showed higher overall survival for targeted vs nontargeted therapy (log-rank test, χ21 = 5.79; P = .02); median survival was not statistically significantly different (8.7 months [95% CI, 7.3-10.2 months] vs 7.2 months [95% CI, 5.8-8.8 months]; P = .14). According to the instrumental variable analysis, the median overall survival advantage was 3.0 months (95% CI, 0.7-5.3 months), and overall survival improvements associated with targeted therapy vs nontargeted therapy were statistically significant: 8% at 1 year (44% [95% CI, 39%-50%] vs 36% [95% CI, 30%-42%]; P = .01), 7% at 2 years (25% [95% CI, 20%-30%] vs 18% [95% CI, 13%-23%]; P = .009), and 5% at 3 years (15% [95% CI, 11%-19%] vs 10% [95% CI, 6%-13%]; P = .01). Receipt of targeted therapy was associated with a lower hazard of death compared with nontargeted therapy (overall survival hazard ratio, 0.78 [95% CI, 0.65-0.94]; RCC-specific survival hazard ratio, 0.77 [95% CI, 0.62-0.96]).Conclusions and relevanceTargeted therapies were associated with modest survival advantages despite a treatment group with more medical complexity, likely reflecting appropriateness for an expanded population of patients. As advances in cancer treatment continue, rigorous methods that account for unobserved confounders will be needed to evaluate their real-world impact on outcomes.

Dataset Information

Clinical laboratory tests associated with survival in patients with metastatic renal cell carcinoma: A Laboratory Wide Association Study (LWAS).

Background

Methods

Results

Conclusions

Publications

Clinical laboratory tests associated with survival in patients with metastatic renal cell carcinoma: A Laboratory Wide Association Study (LWAS).

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