Suggestions of bias in decisions about who got biopsies in the SELECT trial

A re-analysis of data from men participating in the placebo arms of the Prostate Cancer Prevention Trial (PCPT) and the Selenium and Vitamin E Cancer Prevention Trial (SELECT) has suggested a problem with bias in decisions about who gets biopsies during certain types of clinical trial.

Specifically, in the PCPT, all patients in the placebo arm of the trial got a biopsy at the end of the trial, whereas, in the SELECT, men in the placebo arm of the trial only got biopsy if there appeared to be some good clinical reason to give them a biopsy — a decision that was basically being made by each individual investigator in conjunction with the individual patient.

The full text of this paper by Tangen et al. is available on line, along with a media release from the Fred Hutchinson Cancer Research Center in Seattle.

To use a good example from the original paper itself, imagine that we did a research study in which every single man were to get a prostate biopsy (regardless of whether he had any suggestion of risk for prostate cancer or not). We know that in a study like that, we would find cancer in something like 15 percent of the study participants. Now imagine that we used the same cohort of men and looked at the rate of positive biopsies only in men with blue eyes — and we were to find that 23 percent of men with blue eyes had positive biopsies. Then we would know that men with blue eyes were at greater risk for a positive prostate biopsy than men with eyes of all other colors combined. Having blue eyes would then be known to be a risk factor for prostate cancer. (Of course we don’t actually know this is true, … because no one has ever done such a study.)

So if we are already introducing bias into decisions about who gets biopsied in certain types of prostate cancer prevention trial, then, “Houston. We have a problem.” Why? Because that bias may not be taking appropriate account of the known or unknown possibility that certain groups of men are already at lower or higher risk for prostate cancer.

What Tangen and her colleagues have shown, using a complex epidemiological and statistical re-analysis of the data from the PCPT and SELECT trials, is that after making adjustments for patient age, PSA levels, and whether patients got a rectal exam,

  • Among men between 60 and 69 years of age who were enrolled in these two very large trials,
    • Some sets of men were more likely to get a biopsy than others, including
      • Men with benign prostatic hyperplasia
      • Men with a family history of prostate cancer
    • Some sets of men were less likely to get a biopsy than others, including
      • Men with a body mass index (BMI) of ≥ 25
      • Men with diabetes
      • Men with a history of smoking
  • Medication use, education, and marital status also influenced who was given a biopsy; for example,
    • Men on a statin were less likely to get a biopsy
      • Odds ratio (OR) = 0.99 in PCPT
      • OR = 0.65 in SELECT
  • Some risk factor estimates for prostate cancer varied substantially across cohorts.
  • Black men (as compared to men of other ethnicities) were more likely to get a biopsy
    • OR = 1.83 in PCPT
    • OR = 1.20 in SELECT

The degree to which this may have affected results in SELECT is obviously unknown. What we can be sure of, however, is that if there is ever going to be another large prostate cancer prevention trial, we are going to have to design such a trial in a way that eliminates the possibility for such bias.

To quote Dr. Ian Thompson, one of the authors of this recent paper, and the lead investigator for SELECT:

In medicine, we don’t want to do the wrong thing, and in research we don’t want to look in the wrong places. Our work shows we may be doing both in prostate cancer. So the message is this: Risk factors for cancer are very complex. Before we all leap to conclusions, we need to collect very detailed research data on who is screened and why and be very rigorous in our analysis of that data and what it might mean for clinical care.

Basically, if we all want to be able to “get to the truth”, we may need to do a lot more work to be able to find out exactly what that truth may be.

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