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Improving clinical risk stratification at diagnosis in primary prostate cancer: a prognostic modelling study

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Publication Date: 2016-08-02

Journal Title: PLOS Medicine

Publisher: PLOS

Volume: 13

Issue: 8

Number: e1002063

Language: English

Type: Article

This Version: VoR

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Citation: Gnanapragasam, V. J., Lophatananon, A., Wright, K. A., Muir, K. R., Gavin, A., & Greenberg, D. C. (2016). Improving clinical risk stratification at diagnosis in primary prostate cancer: a prognostic modelling study. PLOS Medicine, 13 (8. e1002063)

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Abstract: Introduction: Over 80% of the nearly 1 million men diagnosed with prostate cancer annually worldwide will present with localised or locally advanced non-metastatic disease. Risk stratification is the cornerstone for clinical decision-making and treatment selection for these men. The most widely applied stratification systems use the presenting Prostate Specific Antigen (PSA), biopsy Gleason grade and clinical stage to classify patients as low, intermediate or high-risk. There is however significant heterogeneity in outcomes within these standard groupings. The International Society of Urological Pathology (ISUP) have recently adopted a prognostic based pathological classification. These however, have yet to be included within a risk group system. Here we developed and tested a new stratification system based on the number of individual risk factors and incorporating the new ISUP scores. Methods and findings: Diagnostic clinic-pathological data from 10,139 men with non-metastatic prostate cancer were available for this study from the Public Health England National Cancer Registration and Analysis Service Eastern Office. This cohort was divided into a training set (n=6026, 1557 total deaths with 462 from prostate cancer) and a testing set (n=4113, 1053 total deaths with 327 from prostate cancer). The median follow up was 6.9 years and the primary outcome measure was prostate cancer specific mortality (PCSM). An external validation cohort (n=1706) was also used. Risk groups were first assigned as low, intermediate and high-risk according to the current 3 strata criteria endorsed by the National Institute of Clinical Excellence (NICE) guidelines. These variables were then used to sub-stratify within each risk category by testing the individual and then combined number of risk factors. In addition, we incorporated the new ISUP prognostic scores as a discriminator. Using this approach, a new 5 strata risk criteria was produced and prognostic power compared against the current risk criteria with prostate cancer specific mortality as the outcome. The results were analysed using Cox hazards model, the Log rank test, Kaplan Meier curves, competing risk regression and concordance indices. In the training set the new risk system identified distinct subgroups with different risks of PCSM in pair-wise comparison (p<0.0001). Specifically, the new classification identified a very low-risk group (Group 1), a subgroup of intermediate-risk cancers with a low PCSM risk (Group 2, HR 1.62[0.97-2.75]) and a further subgroup with an increased PCSM risk (Group 3, HR 3.35[2.04-5.59]) (p<0.0001). High-risk cancers were also sub-classified by the new risk strata into a better and worse outcome group: Group 4 (HR 5.03 [3.25-7.80]) and Group 5 (HR 17.28 [11.2-26.67]) (p<0.0001). These results were recapitulated in the testing set and remained robust after inclusion of competing risks. In comparison to the current criteria the new risk stratification system demonstrated improved prognostic performance with a concordance index of 0.75 (95% CI 0.72-0.77) versus 0.69 (95% CI 0.66-0.71) (p<0.0001). In an external cohort the new system achieved a concordance index of 0.79 (95% CI 0.75-0.84) for predicting PCSM versus 0.66 (95% CI 0.63-0.69) (p<0.0001) for the current NICE criteria. The main limitations of the study were that it was registry based and that follow-up was relatively short. Conclusion: A novel and simple 5 strata risk classification system out-performs the standard 3 strata risk criteria in predicting the risk of PCSM at diagnosis in men with primary non-metastatic prostate cancer even when accounting for competing risks. This model also allows delineation of new clinically relevant sub-groups of men who might potentially receive more appropriate therapy for their disease. Future research will seek to validate our results in external datasets and explore the value of including additional variables in improving prognostic performance.

Embargo Lift Date: 2100-01-01


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Autor: Gnanapragasam, Vincent J.Lophatananon, ArtitayaWright, Karen A.Muir, Kenneth R.Gavin, AnnaGreenberg, David C.



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