“Observation” in the management of low-risk prostate cancer

In an article in Recent Results in Cancer Research, Wilt argues (yet again)  that “observation” (i.e., something less than active surveillance and perhaps more like “watchful waiting”) is an entirely appropriate way to manage selected men with low-risk prostate cancer.

Wilt’s premise is based largely on data generated from the PIVOT trial, of which he was the principle investigator. His key points include the following:

  • Men diagnosed with low-risk prostate cancer or with any type of prostate cancer and a PSA level < 10 ng/ml comprise up to 70 percent of all patients diagnosed with prostate cancer in the USA today.
  • These men have an excellent long-term prognosis when managed with observation (as opposed to radical surgery).
  • The PIVOT trial provides Level 1 evidence that — for such patients — when compared to radical prostatectomy, observation results in similar outcomes, specifically including
    • Comparable, long-term overall survival
    • Comparable prostate cancer-specific survival
    • Comparable prevention of bone metastases
  • Observation also avoids any need for surgery-related harms.
  • Physicians can reduce diagnostic- and treatment-related harms without adversely impacting overall or disease-specific mortality and morbidity by
    • Recommending against PSA testing
    • Raising thresholds of PSA values used to define abnormality in men who still desire testing
    • Lengthening intervals between PSA tests
    • Discontinuing testing in men with a life expectancy less than 15 years

Now there is  little to no doubt that some form of observational management is entirely appropriate for appropriately selected patients. The key questions are going to be

  • How should we characterize these patients?
  • What, precisely, does Wilt mean by “observation”?

It is important to note that the average age of the patients enrolled in the PIVOT trial was 67 years. And 656/731 patients enrolled in the study were aged between 60 and 75 years of age. Assuming a normal life expectancy for these men, their reasonable average life expectancy was therefore about 15 years at the time the trial began.

In the Appendix to the original results of the PIVOT trial, comparing the outcomes of men randomized to observation to those randomized to initial radical prostatectomy,

  • For the 479 patients initially diagnosed with a PSA of ≤ 10 ng/ml,
    • Figure S2a shows no meaningful difference in overall mortality at 15 years.
    • Figure S3a shows no meaningful difference in prostate cancer-specific mortality at 15 years.
  • For the 296 patients initially diagnosed with low-risk disease,
    • Figure S2c shows no meaningful difference in overall mortality at 15 years.
    • Figure S3c shows no meaningful difference in prostate cancer-specific mortality at 13 years, but it does show a difference in favor of surgery for prostate cancer-specific mortality at 15 years.

There is no disputing Wilt’s premise with respect to mortality data for these patients with a PSA level ≤ 10 ng/ml. However, it is interesting to note the apparent prostate cancer-specific mortality benefit of radical prostatectomy in the low-risk patients after 13 years.

What was implied by “observation” as a management strategy in the PIVOT study?

In a separate publication, addressing the design of the PIVOT study, Wilt wrote that:

Men randomized to WW [i.e., watchful waiting] were offered palliative (noncurative) therapies (eg, transurethral resection of the prostate for local progression causing urinary obstruction, [androgen deprivation], and/or targeted radiation therapy for evidence of distant spread). Interventions for asymptomatic progression (eg, changes in PSA value) were discouraged. Protocol breaches in the WW group consisted of therapies performed for “curative intent,” ie, RP, external-beam radiotherapy, or brachytherapy. Scheduled study visits were every 6 months for a minimum of 8 years, maximum of 15 years, or patient death.

So by “observation” Wilt and his colleagues did, in fact, mean classic watchful waiting for up to 15 years, with treatment interventions recommended only for palliative care.

Many people find the results of the PIVOT study to be distressing. They feel that the trial was designed to prove that we could just save money by “not treating” men diagnosed with prostate cancer. The “New” Prostate Cancer InfoLonk takes a rather different position, which is that “observation” or “watchful waiting”, just like active surveillance, is an entirely appropriate management strategy for appropriately selected patients. If there is an improvement to the “observation” protocol that would seem appropriate today, it is that the same level of rigor should be used to ensure we have identified patients with a significant risk for progression over time as Klotz and his colleagues now use in their active surveillance protocol. Those patients can then be given a series of options about how they wish to be managed, but they can certainly be told that, at 12 years of follow-up, men with an initial PSA of ≤ 10 ng/ml, regardless of their Gleason score, had a comparable overall and prostate cancer-specific survival on observation as the men who had an immediate radical prostatectomy.

The key issue that we are all trying to deal with today is not so much how to treat localized prostate cancer, but in whom localized prostate cancer really needs immediate treatment.

Neither active surveillance nor observation are going to be wise management strategies for men with a biopsy-based Gleason score of 8-10 if they have a reasonable life expectancy of > 10 years (even if their PSA is ≤ 10 ng/ml).

Similarly, “observation” may not be an appropriate strategy for men with low-risk disease who have a life expectancy of 20+ years. On the other hand, active surveillance certainly is a potentially appropriate strategy for those men. What is sad is that so many of these men today — from 40 to 80 years of age — are still being encouraged (by surgeons, by radiation oncologists, by their family members, and by others — including others in the prostate cancer advocacy community) to have immediate treatments that may offer them no long-term benefit and subject them to multiple forms of complications and adverse effects, the consequences of which they may need to live with for decades.

8 Responses

  1. Your last paragraph also speaks to what Dr. Klotz mentioned, about when he spoke at some support groups. I believe he seemed to feel that sometimes his message (like your last paragraph) is not taken too well in some circles.

    I have tried to discuss just that in certain places, and the blow-back can be intense. Not for the feint of heart!

  2. So a 58 year old healthy man with a PSA of 8 should not pursue biopsy? It would be a mistake to repeat the PSA in 6 weeks and get a value of 16? What if biopsy showed Gleason 9 cancer in all cores, 60 percent of the gland? I think this study is interesting but cannot be extrapolated to all men in all cases.

  3. Dear Dr. Hanline:

    I don’t think that either Dr. Wilt or I am implying that at all.

    As I was careful to point out, the mean age of the men in this study was 67 years; almost all of them were 60-75 years of age; all the men enrolled in the study had already been diagnosed with prostate cancer (so the study had nothing to do with diagnosis and was exclusively focused on treatment); I specifically stated that I didn’t think “observation” would be an appropriate strategy for anyone diagnosed with Gleason 8-10 disease and a life expectancy of 10+ years; etc.

    Dr Wilt, in his most recent article, was talking exclusively about men in the PIVOT trial who were already diagnosed with either D’Amico low-risk disease or diagnosed with prostate cancer and a PSA level of 10 ng/ml or less.

  4. To me it is a simple balance of risk. Accept a small increase in risk for 10 years complete with my prostate, balanced against the advance of research 10 years in the future, which may, if I am a lucky one, may found to be a targetable cancer, and increase my chances of cure.

    Some risk up, some risk down; I choose to risk with prostate and functions intact. There are no redos. Each of us has to make the call, the info here makes that call much less of a blind call.

  5. Mike H,

    We are of one mind.

  6. I’ll stick with my “observations” as to which patients are reasonable candidates for “active surveillance” as explained here.

  7. I think I was surprised by statements attributed to the study such as men with an initial PSA of 10 or less had comparable survival at 12 years regardless of Gleason scores and that interventions for an asymptomatic rise in PSA were discouraged. I agree completely with your own comments about considering treatment of high-risk cancer in men who have a life expectancy > 10 years and in those who have low-risk cancer and a life expectancy > 20 years. One issue here is that most of us assume we will live another 10 years, we and resent anyone telling us differently!

  8. Dear Dr. H.:

    For clarity, what I had said about men with low-risk disease and a life expectancy of 20+ years was that active surveillance might be a wiser strategy than simple “observation” or watchful waiting.

    The discouragement of early intervention for non-symptomatic rises in PSA levels has been a hallmark of watchful waiting/”observation” strategies since time immemorial. Indeed, until the PSA test became widely available in the early 1990s there was no effective test that had been available to provide any meaningful guidance about progression in men on watchful waiting unless the patient had symptoms or there was a positive bone scan. One of the key premises of the PIVOT trial was the idea that a rising PSA alone did not necessarily indicate the need for early ADT or a consequent reduction in risk for metastasis or prostate cancer-specific mortality, and Wilt et al. would certainly argue that their data confirmed that hypothesis. All too often, early use of ADT has more to do with “managing PSA levels” and managing anxiety than it does with actually managing cancer. It needs to be borne in mind that ADT of any type, when used on its own, is a palliative form of treatment.

    With regard to life expectancy, few people (doctors, patients, even insurance adjusters) are good at predicting the life expectancy of individuals, and it is a characteristic of American society that we all think we are entitled to live forever with a high level of quality of life! These decisions can be very difficult for men who are in normal, reasonable health for their ages. However, a degree of realism is also wise when one is faced with a 65-year-old male who has had two heart attacks already, is diabetic, is morbidly obese, and has now been diagnosed with a Gleason 3 + 4 prostate cancer. Does this man really have a realistic life expectancy of another 20 years — unless he is prepared to do something really radical about his obesity?

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