Everyone knows about the law of unintended consequences, right? A good idea backfires. A classic example happened during British rule of colonial India. The city of Delhi was overrun by cobras – very dangerous poisonous snakes – and the governor was determined to get the situation under control. What better way to eliminate cobras than to offer a lucrative bounty for their skins? Well, the attractively high reward encouraged enterprising local citizens to raise cobras, something relatively cheap to do, and cash in at a substantial profit per snake. When the governor caught on, he promptly ended the bounty policy. When the cobra industry collapsed, the snakes were set free. The result? An even greater infestation! This is now known as the Cobra Effect.

Changing the PSA screening practice leads to unintended consequences

The decade following the mid-1990s implementation of broad PSA screening for prostate cancer (PCa) brought much joy throughout the land. While the rate of PCa detection went up, by the early 2000s the death rate dropped rather steeply. However, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) found that PSA screening had no impact on PCa mortality compared with controls (men not screened). This seemed counterintuitive, but numbers don’t lie. The belief prevailed.

Therefore, based on the data, in 2008 the U.S. Preventive Services Task Force (USPSTF) recommended against screening for men ages 75+. They were also influenced by the rather knee-jerk practice of overtreating PCa that left countless men leaking urine and unable to have erections. Then, after four more years of continued overtreatment of insignificant PCa, the USPSTF ratcheted things up. This time, in 2012, they broadened their recommendation to all men. Their intentions, of course, were good.

But some researchers foresaw trouble. In 2014, a team from the Fred Hutchinson Cancer Research Center (Seattle, WA) developed a predictive statistical model regarding screening. It suggested that discouraging screening would lead to needless deaths. On the other hand, “Continuing PSA screening for men aged <70 years could prevent greater than one-half of these avoidable cancer deaths while dramatically reducing overdiagnoses compared with continued PSA screening for all ages.”[i]

Oops, the PLCO study made a mistake

In 2017, a new study reanalyzed the PLCO findings that had swayed the USPSTF.  A multi-center group (including some of the Hutchinson team) found that the statistics in the control (non-screened) arm of the PLCO study had been contaminated; in fact, half of those men had, in fact, been screened at least once by their own doctors. When this error was corrected for, the PLCO study indicated the opposite: PSA screening lowered PCa mortality by 27-32%. This turned the misinformed belief on its head.

Meanwhile, back to the unintended consequences

While all of this was going on, a very bad thing had been unfolding as a result of discontinued broad screening. The rate of diagnosing high-risk cancer was escalating because it was not being detected earlier through PSA testing. At the 2010 American Society of Clinical Oncology meeting in Chicago, a paper was presented by a team from the Cleveland Clinic. By tracking PCa diagnoses from 2004-2015, they found a steady upward trend in the rates of newly diagnosed men with lymph node involvement (advanced PCa) and metastatic disease—as predicted by the Hutchinson model five years earlier.

The cobras were back. How did this happen when the USPSTF intentions were to save men from the toxicity of overtreatment? To summarize, there are two main factors:

1. Wrong belief based on statistical error – the PLCO study’s findings that PSA screening does not reduce death rates from prostate cancer was erroneous but wasn’t caught until years later.
2. Overtreatment based on incomplete understanding of insignificant PCa – until the recent past, all PCa was treated as if it’s multifocal and must inevitably become more aggressive. Today we know that at least 1/3 of cases are unifocal, and that Gleason 3+3 PCa appears “indolent” (unlikely to progress in aggression).

New treatment tools justify life-saving early detection

Now that we have confirmed that PSA testing reduces mortality rates, how do we ensure that  a) the right patients are screened, b) unnecessary biopsies can be avoided, and c) each man’s PCa is accurately diagnosed in order to treat his disease appropriately? I have addressed these questions in previous blogs, and I will add updates in future blogs. But here are clues to the answers:

• If PSA raises PCa suspicion, do a multiparametric MRI (mpMRI)
• If mpMRI shows a region of interest, perform an in-bore mpMRI targeted biopsy for the most accurate diagnosis with fewest needles
• For qualified patients, focal ablation or Active Surveillance is an alternative to radical treatment.

 

To avoid the Cobra Effect in the world of prostate cancer, use a step-by-step focused approach. A mongoose is a natural tool against cobras because it’s a born enemy of snakes. It targets the problem, avoiding the unintended consequences of mass annihilation. Perhaps the USPSTF can take a lesson from Mother Nature’s book, now that we have a more natural toolkit.

NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.

References

[i] Gulati R, Tsodikov A, Etzioni R, Hunter-Merrill RA et al. Expected population impacts of discontinued prostate-specific antigen screening. Cancer. 2014 Nov 15;120(22):3519-26.