Assessment of a prognostic model, PSA metrics and toxicities in metastatic castrate resistant prostate cancer using data from Project Data Sphere (PDS)

PLoS One. 2017 Feb 2;12(2):e0170544. doi: 10.1371/journal.pone.0170544. eCollection 2017.

Abstract

Background: Prognostic models in metastatic castrate resistant prostate cancer (mCRPC) may have clinical utility. Using data from PDS, we aimed to 1) validate a contemporary prognostic model (Templeton et al., 2014) 2) evaluate prognostic impact of concomitant medications and PSA decrease 3) evaluate factors associated with docetaxel toxicity.

Methods: We accessed data on 2,449 mCRPC patients in PDS. The existing model was validated with a continuous risk score, time-dependent receiver operating characteristic (ROC) curves, and corresponding time-dependent Area under the Curve (tAUC). The prognostic effects of concomitant medications and PSA response were assessed by Cox proportional hazards models. One year tAUC was calculated for multivariable prognostic model optimized to our data. Conditional logistic regression models were used to assess associations with grade 3/4 adverse events (G3/4 AE) at baseline and after cycle 1 of treatment.

Results: Despite limitations of the PDS data set, the existing model was validated; one year AUC, was 0.68 (95% CI 95% CI, .66 to .71) to 0.78 (95%CI, .74 to .81) depending on the subset of datasets used. A new model was constructed with an AUC of .74 (.72 to .77). Concomitant medications low molecular weight heparin and warfarin were associated with poorer survival, Metformin and Cox2 inhibitors were associated with better outcome. PSA response was associated with survival, the effect of which was greatest early in follow-up. Age was associated with baseline risk of G3/4 AE. The odds of experiencing G3/4 AE later on in treatment were significantly greater for subjects who experienced a G3/4 AE in their first cycle (OR 3.53, 95% CI 2.53-4.91, p < .0001).

Conclusion: Despite heterogeneous data collection protocols, PDS provides access to large datasets for novel outcomes analysis. In this paper, we demonstrate its utility for validating existing models and novel model generation including the utility of concomitant medications in outcome analyses, as well as the effect of PSA response on survival and toxicity prediction.

Publication types

  • Validation Study

MeSH terms

  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Area Under Curve
  • Cyclooxygenase 2 Inhibitors / adverse effects
  • Cyclooxygenase 2 Inhibitors / therapeutic use
  • Disease Progression
  • Docetaxel
  • Heparin, Low-Molecular-Weight / adverse effects
  • Heparin, Low-Molecular-Weight / therapeutic use
  • Humans
  • Male
  • Metformin / adverse effects
  • Metformin / therapeutic use
  • Models, Theoretical
  • Proportional Hazards Models
  • Prostate-Specific Antigen / blood*
  • Prostatic Neoplasms, Castration-Resistant* / blood
  • Prostatic Neoplasms, Castration-Resistant* / drug therapy
  • Prostatic Neoplasms, Castration-Resistant* / mortality
  • ROC Curve
  • Taxoids / adverse effects*
  • Taxoids / therapeutic use*
  • Treatment Outcome
  • Warfarin / adverse effects
  • Warfarin / therapeutic use

Substances

  • Antineoplastic Agents
  • Cyclooxygenase 2 Inhibitors
  • Heparin, Low-Molecular-Weight
  • Taxoids
  • Docetaxel
  • Warfarin
  • Metformin
  • Prostate-Specific Antigen

Grants and funding

Work presented in this manuscript was supported by the Princess Margaret Cancer Foundation Hold’em for Life Prostate Cancer Research Fund and Stanley Tessis Research Fund. LK is an employee of Astrazeneca plc. The specific roles of these authors are articulated in the ‘author contributions’ section. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.