Journal of the National Cancer Institute Advance Access originally published online on September 11, 2007
JNCI Journal of the National Cancer Institute 2007 99(18):1366-1374; doi:10.1093/jnci/djm130
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© The Author 2007. Published by Oxford University Press.
ARTICLES |
Detection Bias Due to the Effect of Finasteride on Prostate Volume: A Modeling Approach for Analysis of the Prostate Cancer Prevention Trial
Affiliations of authors: Gamida Cell Ltd, Cell Therapy Technologies, Jerusalem, Israel (YCC); Merck & Co Inc, Rahway, NJ (KSL, NLH, ADC, KMA, AGD); Department of Pathology, University of Illinois at Chicago, Chicago, IL (PHG)
Correspondence to: Peter H. Gann, MD, ScD, Department of Pathology, University of Illinois at Chicago, 840 South Wood St, Chicago, IL 60612 (e-mail: pgann{at}uic.edu).
Background: The Prostate Cancer Prevention Trial (PCPT) demonstrated a 24.8% reduction in the 7-year prevalence of prostate cancer among patients treated with finasteride (5 mg daily) compared with that among patients treated with placebo; however, a 25.5% increase in the prevalence of high–Gleason grade tumors was observed, the clinical significance of which is unknown. One hypothesized explanation for this increase is that finasteride reduced prostate volume, leading to detection of more high-grade tumors due to increased sampling density. This possibility was investigated in an observational reanalysis of the PCPT data, with adjustment for sampling density.
Methods: A logistic model for the association of high-grade (Gleason score 7–10) prostate cancer with baseline covariates and/or baseline covariates plus prostate volume and number of cores obtained at biopsy was developed using the placebo group (n = 4775) of the PCPT. This model was then applied to the finasteride group (n = 5123) to compare the predicted and observed numbers of high-grade tumors in that group. In a second approach, odds ratios (ORs) for prostate cancer in the finasteride versus placebo groups calculated from binary and polytomous logistic regression models that contained or excluded covariates for gland volume and number of needle cores were compared.
Results: Median prostate volume was 25% lower in the finasteride group (median = 25.1 cm3) than in the placebo group (median = 33.5 cm3). The logistic model developed in the placebo group showed that the likelihood of detection of high-grade prostate cancer decreased as volume increased (for each 10 cm3 increase in prostate volume, OR = 0.81, 95% confidence interval [CI] = 0.74 to 0.90). Based on this model, 239 high-grade prostate cancers were predicted in the finasteride group, whereas 243 were observed, a non–statistically significant difference. Among all participants, the odds ratios for high-grade cancer in the finasteride versus placebo groups decreased from 1.27 (95% CI = 1.05 to 1.54) with adjustment for baseline covariates to 1.03 (95% CI = 0.84 to 1.26) following additional adjustment for gland volume and number of biopsy cores in binary outcome models and from 1.14 (95% CI = 0.94 to 1.38) to 0.88 (95% CI = 0.72 to 1.09) following these adjustments in the polytomous models.
Conclusions: Although analyses using postrandomization data require cautious interpretation, these results suggest that sampling density bias alone could explain the excess of high-grade cancers among the finasteride-assigned participants in the PCPT.
| CONTEXT AND CAVEATS Prior knowledge
In the Prostate Cancer Prevention Trial (PCPT), the 5 Study design In an observational reanalysis of data from the PCPT, several kinds of regression models were used to investigate the contribution of prostate volume and number of cores obtained at biopsy to the increased prevalence of high-grade cancer in the finasteride arm. Contribution Adjustment for gland volume and number of cores biopsied (i.e., sampling density) eliminated the differences in high-grade cancer between the two arms. Implications The apparent increase in high-grade cancer in the finasteride arm of the PCPT may be an artifact due to sampling density bias. Limitations Adjustment for postrandomization variables that are affected by treatment, such as gland volume, can lead to confounding and complicate causal interpretation. Further adjustment for other possible biases could change the results.
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-reductase inhibitor finasteride reduced the overall incidence of prostate cancer but was associated with an increase in high-grade cancer specifically. However, whether finasteride actually promotes high-grade cancer or rather creates a bias that leads indirectly to the detection of more high-grade cancer has not been clear. One possibility is that finasteride reduces the volume of the prostate, increasing the likelihood that a biopsy sample will contain high-grade cancer.Manuscript received November 1, 2006; revised July 2, 2007; accepted July 27, 2007.
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J Natl Cancer Inst 2007 99: 1355-1356.
J Natl Cancer Inst 2007 99: 1353.
J Natl Cancer Inst 2007 99: 1353.
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