RP vs. WW: 15-year outcomes of the Scandinavian trial

Bill-Axelson et al. have reported a second update to the results of the Scandinavian trial of radical prostatectomy (RP) compared to watchful waiting in patients with “early” (but not necessarily localized) prostate cancer diagnosed between October 1989 and February 1999.

As reported elsewhere, this important trial enrolled a total of 695 men who were randomly assigned to treatment with radical prostatectomy or to management by watchful waiting. Data from this study were first reported in 2005 and previously updated in 2008.

The most recent results of this study, based on follow-up though December 2009, are as follows:

  • The average (median) follow-up was 12.8 years.
  • 166/347 men (47.8 percent) in the radical prostatectomy group and 201/348 men (57.9 percent) in the watchful waiting group had died (P = 0.007).
  • 55/347 men (15.9 percent) assigned to surgery and 81/348 men (23.3 percent) assigned to watchful waiting died of prostate cancer.
  • The cumulative incidence of death from prostate cancer at 15 years was 14.6 percent for the radical prostatectomy group and 20.7 percent for the watchful waiting group.
  • The relative risk with surgery was 0.62.
  • The survival benefit was similar before and after 9 years of follow-up, was observed among men with low-risk prostate cancer, and was confined to men younger than 65 years of age.
  • The number needed to treat to avert one death was 15 overall and 7 for men younger than 65 years of age.
  • Among men treated by radical prostatectomy, the relative risk of prostate cancer-specific mortality was 6.9 times as high among those with extracapsular prostate cancer compared to men with organ-confined disease.

This study continues to show a clear benefit of radical prostatectomy compared to watchful waiting (in contrast to active surveillance) in a cohort of men diagnosed based on clinical criteria alone. The benefit is only evident in men diagnosed at < 65 years of age. However, it is critically important to understand that the patients enrolled in this trial were not diagnosed as a consequence of prostate cancer screening using the PSA test, so all patients had some form of clinical symptom at the time of diagnosis.

What we can certainly not conclude from this trial is that surgery is a superior form of management to active surveillance in the type of low-risk patient who is being commonly diagnosed based on PSA testing today, and most particularly in men > 65 years with a life expectancy of less than 15 years.

6 Responses

  1. The interpretation of this study is likely to lead to many arguments. If we believe the results for younger men, then we would need to accept the findings for older men — that this study found no benefit for men over 65 in unscreened men at 15 years. Is that a message that is likely to be passed on to newly diagnosed men, especially those with low-risk disease?

  2. Mike,

    Why are you always so, so, so careful to qualify an endorsement of active surveillance away from younger men? Men under 65 have just as much reason or more for wanting to avoid the devastating, quality-of-life destroying effects (note the “side” is not used) as men over 65!

    The evidence that diagnosed prostate cancer in men under 65 is more aggressive than men over 65 has been pretty thoroughly debunked. I pretty sure every man under 65 considering AS pretty much gets it that it might be an interim treatment …. But they also understand that by treating a slow-growing cancer with AS, they get years of a functional life.

    It is cruel to deny men under 65 access to AS protocols because of population-based statistics about life expectancy. This “protocol” that excludes the otherwise healthiest, most functional men isn’t about risk to many, many, many of those men’s lives, it’s about risk to urology practices’ liability premiums.

  3. Dear Tracy:

    I have no idea how you are managing to twist my remarks to think I am implying that active surveillance is an inappropriate strategy for men under 65 years of age.

    What I very specifically stated is that this study can not be interpreted to imply that immediate surgery is superior to active surveillance. It happens to be even more likely that this is true in men > 65 (see also Dr. Chodak’s comment above) but nowhere did I either imply or suggest that active surveillance is inappropriate in younger men … we just don’t have the data.

  4. Thanks for providing notice of this update of the Holmberg/Bill-Axelson study.

    I have a copy of the complete paper of the original Holmberg paper published in the NEJM back in 2002, with Bill-Axelson as the second author. Back then, with a median follow-up of just 6.2 years, with less than half of the current 12.8 years being reported, there was no statistically significant difference in overall survival, but there was a significant difference favoring surgery in prostate cancer-specific survival. Actually, death due to other causes than prostate cancer was higher in the surgery group, 31 (8.9%) in in the WW group and 37 (10.6%) in the RP group. Now we see that death from all causes, including prostate cancer, is higher in the WW group.

    Among other take-away points, these updated results may help us to keep in mind that maturity of follow-up is critically important. The PLCO and ERSPC screening trial reporters also need to keep this in mind.

    However, despite the Holmberg trialists best efforts at the launching of this trial in October 1989, unpredictable developments have somewhat confounded these results, and we should remember this when interpreting results. Specifically, while men “with a poorly differentiated tumor were not eligible,” Gleason scoring had not yet become a norm. Rather tumor differentiation was done in accordance with a 1980 guideline published by the WHO, “Histological typing of prostate tumors” (reference 12 of the Holmberg paper).

    Unfortunately, while the two arms turned out to be pretty well stratified for Gleason scoring for most patients, assigned during histopathological review — not up front, except for 2% more Gleason 8-10 subjects in the WW arm, 9.5% of subjects in the WW arm and 13.3% in the RP arm had unknown Gleason scores. We must depend on chance to assure an even stratification between arms — by no means a sure thing.

    Moreover, 103 patients in the WW arm, 29.6% of the total, had known Gleason scores ranging from 7 to 10, something that would not be deemed acceptable today except for patients with other serious illness or otherwise short life expectancies. In other words, one could argue that RP was being compared, however inadvertently, to a patsy.

    Fortunately, PSA testing had just come into vogue, and PSAs were available for all but 0.9% of patients in the WW arm and 2.0% in the RP arm.

    It also appears that patients in the RP arm had a better path to access to hormonal therapy than patients in the WW arm, based on the “Interventions” paragraph of the paper. This too could have influenced survival.

    I’m glad the researchers did this study, but I remain concerned about the degree of confounding.


  5. It is worth noting the additional fact that — at a median 12.8 years of follow-up — a total of 328/695 patients (47.2 percent) enrolled in this trial are still alive of all causes and that “only” 136/695 patients (19.6 percent) have actually died of prostate cancer, despite the fact that many of these patients actually had extracapsular or even more advanced forms of disease at the time of diagnosis. It might be interesting, in the context of this trial, to know the mean ages of the patients who had died and of those who were still alive.

  6. Since all men in the study were treated with hormone therapy (HT) at the sign of progression this lower death rate supports the notion that HT improves survival by delaying cancer growth.

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