Final report of the 30-year-long Swedish study of watchful waiting in management of localized prostate cancer


Since 1977 a group of Swedish researchers has followed a prospectively evaluated, population-based cohort of 223 consecutive patients, all diagnosed clinically with localized prostate cancer, who received no treatment other than observation (“watchful waiting”) until symptomatic progression and androgen deprivation therapy (ADT) became necessary.

Popiolek et al. have now issued their most recent (and their final) report on this long-term study of the natural history of localized prostate cancer managed by watchful waiting. You can access the full text of this article on line on the European Urology web site. Their last report was issued about 7 years ago.

In reading this article, however, it is very important to appreciate that these men were all diagnosed clinically, long before the PSA test was widely available. Therefore, even when they were diagnosed, they had much more advanced disease than the average man being diagnosed today. It is also important to understand that they were not on any sort of active surveillance protocol. They were treated only for clinical symptoms of their disease (e.g., a transurethral resection of their prostate if they needed relief from urinary tract blockage and ADT to palliate actual symptoms of progressive and metastatic disease).

Based on the 32 years of follow-up of these patients, the main outcome measures were: progression-free, cause-specific, and overall survival, and rates of progression and mortality per 1000 person-years.

Here are the final set of core findings from this study:

  • During the 32 years of follow-up,
    • 220/223 men (99 percent) have died.
    • There have been local progression events in 90/223 patients (41.4 percent).
    • 41/223 patients (18.4 percent) exhibited clear evidence of distant metastasis.
    • 38/223 patients (17.0 percent) actually died of prostate cancer.
  • Prostate cancer-specific survival (i.e., cause-specific survival) decreased between 15 and 20 years after diagnosis, but stabilized with further follow-up.
  • All nine men initially diagnosed with Gleason grade 8-10 disease died within the first 10 years of follow-up.
    • Five of these nine patients (55 percent) died of prostate cancer.
  • Overall survival for men initially diagnosed with well-differentiated, non-palpable tumors
    • Declined slowly through the first 20 years from diagnosis
    • Declined more rapidly between the 20th and 25th years from diagnosis (from 75.2 percent in the 20th year to  25.0 percent in the 25th year).
  • The frequency of clinical progression and the frequency of death from prostate cancer was similar between patients with palpable and non-palpable tumors at the time of initial diagnosis.
  • 142/223 patients in this study (64 percent) remained hormonally untreated throughout the entire follow-up period
    • None of these 142 patients developed non-metastatic symptomatic disease or distant metastases.
    • None of these 142 patients died of prostate cancer.

The authors state very straightforwardly that, “It is unclear whether these data are relevant for tumors detected by elevated prostate-specific antigen levels.” They go on to conclude as follows: “Although localized [prostate cancer] most often has an indolent course, local progression and distant metastasis can develop over the long term, even among patients considered low risk at diagnosis.”

The “New” Prostate Cancer InfoLink, first and foremost, would like to point out our indebtedness to the research team and all the patients who willingly committed themselves to this important 30-year-long study. It has clearly demonstrated a number of key things that were far from clear back in 1977 when this study began:

  • Men diagnosed with clinically localized, Gleason 8 to 10 disease are going to die from prostate cancer or other causes rapidly if they don’t receive early treatment.
  • Most men diagnosed with clinically localized disease (133/223 or 59.6 percent) can be followed (for up to 32 years) with no sign of clinical progression of their disease until death occurs from other causes.
  • About 17 percent of men diagnosed with clinically localized disease will go on to die with metastatic prostate cancer if they receive no other treatment prior to ADT as a treatment for clinical symptoms of progressive disease.
  • Digital rectal examination does not differentiate between men at risk for prostate cancers-specific mortality and men who are not at such risk.

Figure 1 in the full text of the paper suggests that the mean overall (all-cause) survival of the patients in this study was of the order of 8 years, whereas the mean prostate cancer-specific survival was more like 22 years!

Some of these results may seem “obvious” to us today, 36 years after this study was initiated. However, what this study has done is to provide us, in a long series of reports issued over the time-span of the study, with a far better appreciation of the progression of untreated prostate cancer in the real world.

It is now very clear that most men who get diagnosed with low-risk prostate cancer (even if it is clinically evident at diagnosis) will live out their lives without progression to evident metastatic disease. This raises important questions about the appropriate timing of initiation of ADT in men who have no clear indication of metastatic disease. While it is probably true that we do need to initiate ADT early in some men with early signs of progression (i.e., a rising PSA with a short PSA doubling time), it also seems probable that we should defer initiation of ADT for as long as possible in others (e.g., those with a long PSA doubling time).

The “New” Prostate Cancer InfoLink is in complete concurrence with the authors that it is difficult to determine the real significance of this study to men being diagnosed today based on PSA testing and much earlier biopsies. There is general concurrence that PSA testing introduces a “lead time” of some 7 to 14 years over clinical diagnosis of prostate cancer. If that were shown to really be the case, then one can probably conclude with reasonable decisiveness that, if this trial was conducted again today with men being diagnosed based on biopsies after PSA testing, then the study would have taken more like 40 years to complete than 30, and would have shown the same results over that time-span. Such a conclusion is bound to make one wonder how many of the 240,000 men getting diagnosed in America each year today are really acting wisely when they get treatment at all (unless they have high-risk disease at diagnosis). The majority of them clearly would be wiser to start with some form of active monitoring program.

12 Responses

  1. The study said

    •142/223 patients in this study (64 percent) remained hormonally untreated throughout the entire follow-up period ◦None of these 142 patients developed non-metastatic symptomatic disease or distant metastases.
    ◦None of these 142 patients died of prostate cancer

    How do you interpret this?

    Does this mean if you don’t get ADT, you won’t die of prostate cancer?

    You may think I am kidding, but why would not even one man die in this group?

    Doug

  2. The answer to your question: “how many of the 240,000 men getting diagnosed in America each year today are really acting wisely when they get treatment …” is quite simple, as we’ve discussed before. When a man gets cancer, there is significant emotional and family concern to get rid of the cancer now. Not many people find it comfortable rolling the dice, and then just wait it out. It takes rational cajones.

    Then you have the urology community that will tell their patients their choices … some of which is suspect, with urologists receiving personal financial benefit from some of the choices … and we have the perfect storm.

  3. Dear Doug:

    As some people have been pointing out for years, many prostate cancers really are extremely slowly growing. As a consequence, an awful lot of men get treatment that they never need.

  4. Dear Elucidated1:

    Actually we have never “discussed” this at all. You have a strong personal opinion. I disagree with it because I happen to think that every person diagnosed with any form of signifciant clinical condition needs to think hard about what they want to do.

    I have little doubt that many men who have just monitored their prostatre cancer — as opposed to either rushing themselves (or letting themselves be rushed) into treatment — would agree with me. It’s not as though the existence of the data provided by this study and others like it is any great secret!

  5. I am confused when the Sitemaster states:

    “The “New” Prostate Cancer InfoLink is in complete concurrence with the authors that it is difficult to determine the real significance of this study to men being diagnosed today based on PSA testing and much earlier biopsies.”

    Surely, as the Sitemaster points out above, there are key and significant conclusions that can be drawn — namely that men with high-risk disease require early intervention and are not suitable candidates for what today we would call active surveillance; and secondly; that a percentage of men diagnosed initially with localized disease will progress (17%) and they will require immediate intervention as soon as progression is identified … hopefully through active surveillance.

    I am not trying to split hairs here, but both the above conclusions validate the clinical significance of the trial … or am I missing your meaning, Mike?

  6. Rick:

    This trial confirms the hypothesis that early detection and active monitoring really should allow us to be able to differentiate between those men who need immediate early treatment (e.g., men with Gleason 8 to 10 cancer), those men who will likely need first-line treatment at some point in time (because of signals that their risk level is increasing), and those men who are likely to never need treatment. What it does not tell us is precisely how to apply that knowledge to men who are being diagnosed 5 to 15 years earlier in the progression of their disease than were the men in this trial.

    My hope is that the ongoing British ProtecT trial will help to resolve that question.

  7. Mike,

    I was diagnosed at 42 years old with 6 cores out of 52 of Gleason 3 + 3 = 6. Each core was small focus per Epstein at Johns Hopkins, so I am confident in the initial diagnopsis. My PSA was 2.76 and and had only gone up 0.36 ng/ml from the previous PSA test I had had when I was 38.

    Based on this study, I could have gone 32 years without developing metastatic disease or progression. Am I reading this wrong? Should I have done nothing? I am happy with my continence level, but obviously sex is not what it was. I wish I had my prostate back sometimes. … Ha ha

  8. Actually, Site, you and I do agree with “active surveillance” as the first choice. And yes I do have strong opinions since I have interviewed a few dozen patients who “just want their prostate back.” Although we haven’t “discussed” this, I have brought it up before.

    I waited 18 months on AS until my 9/12 cores kept increasing as well as PSA and was told by a urologist not to wait.

    What is most compelling, though, is, out of 240,000 newly diagnosed patients … why is it more of them don’t choose AS?

    You said “It’s not as though the existence of the data provided by this study and others like it is any great secret!”

    To that point, I can tell you that to most newly diagnosed prostate cancer patients, it is a secret. It is overwhelming to meander through the choices, complicated by different doctors recommending different solutions. This choice is emotional. This choice affects everyone in the family.

    Why is it so difficult for the newly diagnosed to figure out the current data is “no secret?”

  9. I have now discussed my prostate cancer with 7 different physicians of various specialties, one discussed active surveillance. The only place it is not a secret is here. Thank you.

  10. Mike,

    Most prostate cancer patients just listen to one or two doctors. They don’t research … to the very point of this web site. And that is the biggest lament of the sitemaster.

    Just because you did due diligence does not mean that others are even capable of doing it. It is formidable for most people. I also interviewed 7 urologists … and one had the guts to tell me, in the first 10 minutes, how long I was going to live. I’m just sure he was right … but I guess I’d better start counting the days. Heck … only 5,475 days to go.

  11. Sitemaster:

    Not to diminish the effort of the authors by following these 223 men for over 30 years, it is significant to mention that the mean age of the cohort at diagnosis was 72 years; the life expectancy of a 65-year-old man in Sweden at the time was less than 13 years and that 66% of the men that died of prostate cancer were 70 years old or less.

    The conclusion of the study was: “Although localized PCa most often has an indolent course, local progression and distant metastasis can develop over the long term even among patients considered low risk at diagnosis”

    How are the results of this study pertinent to younger men diagnosed these days when the highest percentage of men that died of prostate cancer were younger than 70?

    The fact that many men avoid dying of prostate cancer by dying of something else should not keep them from educating themselves about the disease and to avoid both under- and over-treatment if they face the occasion.

    Ralph V

  12. I was a “young man” of 54 when I was diagnosed in 1996. I chose what was then termed “watchful waiting” but would now be termed “active surveillance”.

    I have, in the 16 years plus since I was diagnosed, been fairly active on the prostate cancer field, and from time to time I have asked the question “What has age got to do with it?” when “young men” relate the fact that they were urged to choose early intervention — because there were no data to support any other choice.

    Ralph V and I have agreed to disagree over the years, so let me state quite clearly that I agree with his statement: The fact that many men avoid dying of prostate cancer by dying of something else should not keep them from educating themselves about the disease and to avoid both under- and over-treatment if they face the occasion.

    And in answer to his question: How are the results of this study pertinent to younger men diagnosed these days when the highest percentage of men that died of prostate cancer were younger than 70? I would suggest that the study which formed the basis of Mike’s commentary “Active surveillance as a management strategy for younger men with low-risk disease” might give them some insight in the conclusion:

    “Nearly half of young men with PSA screen-detected prostate cancer are AS candidates but the overwhelming majority seek treatment. Considering that many tumors show favorable pathology [after surgery], there is a possibility that these patients may benefit from AS management.”

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