The initial results of the PIVOT study


So Dr. Timothy Wilt presented the initial results of the Prostate Cancer Intervention Versus Observation Trial (PIVOT) at the annual meeting of the AUA yesterday morning. They showed what many of us may have been expecting.

The trial was initiated in 1994, and was a large, randomized, multi-center trial designed to assess the effectiveness of radical prostatectomy compared to observation on overall (all-cause) and prostate cancer-specific mortality in men with localized prostate cancer in the early PSA era. As we have stated earlier, the investigators had a real problem persuading patients to be randomized to this trial, and of the more that 5,000 patients who were assessed and found to be eligible for this trial, only 731 actually agreed to be randomized to the trial. Let’s cut straight to the conclusions and then we can get into the details.

According to Dr. Wilt, in stating his conclusions based on the data:

  • “Surgery did not reduce mortality more than observation in men with low PSA or low-risk prostate cancer.”
  • The trial results “suggest a benefit from surgery in men with higher PSA or higher risk disease.”
  • Compared to observation, surgery offered “reductions in all-cause and prostate cancer mortality that were not significant and less than 3 percent in absolute terms over 12 years.”

So what did the trial data actually show? Well here are the details:

  • 364 patients were randomized to surgery and 367 to observation.
  • The characteristics of the patients (age, PSA level, and other factors) were very closely comparable between the two groups.
  • 48 percent of patients died during the trial follow-up.
  • 7.1 percent of those who died were evaluated as having actually or probably died of prostate cancer.
  • Formal monitoring of all patients occurred at 4, 8, and 12 years after initiation of treatment or observation.
  • The median follow-up was 10 years.
  • For all-cause mortality, the absolute relative risk (ARR) after observation as opposed to surgery was 2.9 percent, and the hazard ratio (HR) was 0.88 (neither of which were statistically significant).
  • For prostate cancer-specific mortality, the ARR after observation as opposed to surgery was 2.7 percent, and the HR was 0.63 (the latter of which showed a trend toward statistical significance but was still not actually statistically significant).
  • For patients initially diagnosed with high-risk disease and a PSA > 10 ng/ml, there was a prostate cancer-specific mortality benefit associated with surgery as compared to observation (ARR = 7.2 percent; HR = 0.36; p = 0.03).

Since Dr. Wilt only had 10 minutes to present these data, it may take time to get further insight into the implications of these data, but it does seem that for men with a life expectancy of 12 years or less the value of surgical intervention for treatment of low- or intermediate-risk disease is very questionable in the PSA era, and it is limited even for men with high-risk disease.

22 Responses

  1. I wonder what the results are for men with a minimum of 10 years follow up … as opposed to a median of 10 years.

  2. Tony:

    Looking at the data that Dr. Wilt presented, I can tell you that I could see no reason to expect them to be any different (at a minimum of 10 years) for men with low- and intermediate-risk disease.

    Might there be a difference at 15 or 20 years? I think that’s a better question. But I also think that this trial (which was originally designed to enroll 1,500 or so patients) is too small to show clearly any small differences that might be evident for men with low- and intermediate-risk disease, and I would also point out that this trial did not (as far as I am aware) enroll many men under the age of 50.

  3. Yes I agree. These studies on AS typically need to have more participants. Do you know if they will continue follow up to year 15 and beyond?

  4. There was an interesting paper by Vickers et al. that modeled survival in the Swedish randomized trial. It was presented the day after the PIVOT data and, using different techniques, showed similar trends: survival benefits for younger men with higher grade cancer. That paper is not yet published so any real detail will have to await that, as will any comparisons with the PIVOT paper. The two papers could make for an interesting pair of “bookends” when they are both published.

  5. Tony:

    No. I do not know for sure what the future status of the PIVOT study is. However, I hope they will continue to follow these patients for at least another 5 years.

  6. The important part of this study to remember is the follow-up period of 12 years. This study definitely demonstrates that for men with a life expectancy 12 years or less and low-risk prostate cancer, prostatectomy is most likely not necessary. However, this information is nothing new as the generally accepted rule has been that treatment for prostate cancer should be reserved for men with life expectancies greater than 10-15 years. The problem with this study is that the general public and media will apply the conclusions to men of all age groups. This is very dangerous because healthy men diagnosed with prostate cancer in their 40s, 50s, and 60s generally have a much longer life expectancy than 12 years. More mature data extending to 15 or 20 years need to be evaluated to really draw conclusions about the usefulness of prostatectomy in these men, particularly given the results of another recent study demonstrating that young men with prostate cancer do benefit significantly from prostatectomy. That being said, the results of this study are important as they, once again, demonstrate that prostate cancer treatment needs to be tailored to each individual patient rather than applied in a “once size fits all” manner.

    Prostate Doc
    myprostatedoc.blogspot.com

  7. Prostate Doc:

    I think you underestimate the capacity of the “general public” (after all, medical research scientists and clinicians are hardly the only professions that base their work in measuring and managing risk and probability) to use the results of this research to inform decision-making on managing the risks for both diagnosis of prostate cancer and outcomes of treatment for prostate cancer.

    Healthy men in their 40s, 50s, and 60s do have a much longer life expectancy than men in older age cohorts and they’re much more likely to be fully sexually functional and active (and so likely to be fully continent that it’s hardly worth mentioning) than men in older age cohorts. When these men < 60 are diagnosed, they have no positive choices to make — they only have horrible choices to make. Radical treatments may marginally diminish their probability of a painful and early death, but guarantees some degree of permanent diminution in their quality of life — and in somewhere between 35 to 50% of these men the diminution is total and permanent (and 30 to 40 years is a long damned time to live without physical intimacy).

    I cannot wait for the day when some clinician has it in him to step to the fore and advocate for authentically attempting to protect the quality of life in men < 60 diagnosed with PCa — because right now their only choices are to live miserably for a short time or a long time.

  8. It is interesting to hear people say that the study is too small to detect a meaningful benefit without stating what would be a meaningful benefit. The PIVOT study is showing that overall in the population there might be a benefit of about 3% which means that even 12 years after having a prostatectomy only about 1 in 33 men would see a benefit while the remaining 32 men would face the harms of the surgery with no benefit yet. Now someday a few more of those men might benefit if they live long enough, but there isn’t a great rationale for why the effect should become dramatically different after 15 to 20 years, since presumably the biggest advantage to having surgery early instead of watchful waiting would be to remove the cancers that are going to kill earlier. I think that this study provides some very helpful information about the size of benefit men should expect to receive (i.e., it is small). The study also shows that if you break this 3% out further by risk of cancer, then for men with lower risk cancer the possible benefits for early surgery are basically zero while the harms of surgery still exist. Also for men with higher risk cancer the benefit is likely greater such that at 12 years 1 in 14 mean would have benefited from treatment. This might be a benefit to harm ratio that makes surgery look like a good decision to some men and a bad decision to other men depending on their preferences. However, men should at the least be told that by far the vast majority of men will only be harmed by surgery and receive no benefit. Conducting a study with 1 million men instead of 731 will not dramatically change these numbers. The large study would only make a person more confident whether or not 1 in 33 or 1 in 14 is statistically different than what would be expected by chance.

    As to the question of whether younger and higher-risk men might benefit at a rate even better than 1 in 14, that question seems to still be not fully answered. This is where a much larger study could have presented more information about subgroups of men for which the benefit to harm ratio is more favorable. So there are questions remaining for younger men with higher risk cancer, but for most other men the results are fairly clear.

  9. Tracy wrote: “I cannot wait for the day when some clinician has it in him to step to the fore and advocate for authentically attempting to protect the quality of life in men < 60 diagnosed with PCa — because right now their only choices are to live miserably for a short time or a long time."

    I completely disagree with that last line and I would fire any doctor who presented things in this manner. Many men do well after therapy and they shouldn't hear it this way before they begin because quite a few men live great lives after surgery or other therapies. And even though many men do suffer from side effects, they will tell you that they still have a good quality of life. Quality of life is not only measured by one's sex life — or even for some by incontinence.

    I for one would like to have skipped the last four and a half years of advanced disease therapies ~ but I am far from miserable …

  10. As an RP survivor of 5 years now I can only give my results. I had radiation treatment 3 months after the prostate cancer was removed and was left with both incontinence and ED.

    Life is good but I live a life of no sex and wetting myself which I can handle by the use of pads daily. To have sex I would have to inject Cavaject and I certainly would not go down that path or use other oral methods because they are not suitable for men with heart problems, so frustration rather than depression.

  11. OLDFARTDAN,

    Consider getting a penile implant. I have never seen a patient with a penile implant who was not delighted with it. I think that the procedure is done far too infrequently. I am looking forward to getting one myself, someday, but hope that the nuclear-powered model with built in heat and massage is available by then.

    All the best,

    Josh

  12. I have recently been diagnosed with prostate cancer. I am 57.

    It appears to me after my reading of the quite similar Swedish trial, now augmented by the preliminary PIVOT data, that radical prostatectomy has very little benefit to anyone beyond the urologist. While I scheduled a surgery at Johns Hopkins, I am having serious buyer’s remorse. If I can find instead a nice randomized controlled trial for some therapy with minimal side effects that would calm down my poor frightened wife, I think that’s where I would like to wind up. Let’s face it, we’re all going to die. I think I’d rather spend the rest of my life having sex and control of my bladder, rather than hoping to be the one out of 14 men who might benefit from radical prostatectomy.

  13. Dear Paul:

    It kinda depends on the exact nature of your diagnosis. If you join our social netwoek we might be able to give you some assistance in considering your opportunities.

  14. These numbers can’t be right.

    There were 731 men enrolled.

    If 48% of the population died, that’s 351 men.

    If “7.1% of those who died were evlauated as having died or probably died of prostate cancer” that’s 7.1% of 351 = 25 prostate cancer deaths in total.

    So after 10 years, only 25 men out 731 died of prostate cancer? And half of the 731 weren’t treated?

    Something isn’t right.

  15. Dear Paul:

    The formal results of this trial have still not been published (which is really rather embarrassing in my personal opinion since it is now > 8 months since these data were initially presented). However, these are the data reported by the principal author of the study; he has given the same data at other presentations, and there is no reason to believe they are inaccurate.

    You do need to appreciate that the 10-year mortality rate among men diagnosed with low- and intermediate-risk prostate cancer in the PSA era is really extremely low indeed, which is precisely the point behind the conclusions from this study. Why are we aggressively treating men with a reasonable life expectancy of 10 years and less who are actually highly unlikely to die of prostate cancer when they are much more likely to die of other age-related problems first?

  16. How do you know if you have “high risk” prostate cancer? Is that still just being determined by one’s Gleason score? I have heard that there are two “kinds” of prostate cancer — one that is aggressive if it penetrates the prostate and one that isn’t. I have also heard that it can’t be determined which kind one has until it gets out of the prostate. I’m not sure if this is true or not? I was told that by a prostate surgeon.

    I got flagged by our family doctor when my PSA doubled over a couple of years. He said I should get checked out. I was given a Gleason score of 8 at diagnosis. I was told by the urologist who did the biopsy that there were several small tumors covering about 40% of my prostate. The urologist said I had time to study my options, but at age 58 he recommended that I seek some kind of treatment to arrest the cancer (radiation, freezing, or surgery) before it penetrated the prostate wall. Meanwhile, a close friend a little younger than m, ignored his symptoms for a long time. He finally went to get checked out and his prostate cancer had penetrated the wall of his prostate. They removed the prostate, but found the cancer had spread to his bones. He was given hormone therapy, then chemotherapy. He died this January, lasting about a year and a half from his original diagnosis. What is one to do? It seems like a “damned if you do, damned if you don’t” situation. He was told that if they could have caught it earlier, it would have saved the cancer from spreading to his bones. However, according to this study, he would be one who did the right thing by not seeking treatment. Ignoring the situation would be the correct decision, right? Now he is dead.

  17. Dear “HayesCeramics”:

    First and foremost … anyone who is diagnosed with Gleason 8 prostate cancer has, by definition, high-risk prostate cancer. (There are several slightly differing definitions of what constitutes “high-risk” prostate cancer, but they all concur that if you have Gleason 8 disease at the time of biopsy, then you are at high risk.)

    Second, all the men in the PIVOT study were veterans, and most of them were > 65 years of age. Despite this, treatment was clearly beneficial compared to observation (“doing nothing”) among all the men in this study with high-risk disease.

    Third, there is “high risk” and then there is “very high risk”. If you (for example) have a single biopsy core showing Gleason 8 disease, but other factors that indicate lower risk levels (e.g., a clinical stage of T1c and a PSA level of < 10 ng/ml), then you are almost certainly at much lower risk than your friend who "did nothing" and was then found to have metastatic disease.

    I would encourage you to join our social network, where we can discuss in detail your precise risk factors, but to do this we are going to need some additional information about you and your diagnosis. Based on the information you have provided so far, and without being able to make any guarantees, there is good reason to believe that your prostate cancer can currently be treated with curative intent. However, the longer you go without taking action, the higher the possibility that the cancer will start to metastasize out of your prostate.

  18. Following my RRP surgery in April 2012, I still have doubts about my treatment decision, but ultimately the PIVOT results played almost no part in the choice I made. The trial is too “diluted” with lower risk cases, and there are other studies and trials that concentrate on higher risk cancers like mine (Gleason 8, palpable). While the case for surgery is far from a slam-dunk, I believe that there is a moderate reduction of risk gained by treating cancers like mine.

  19. Following up on my comment above, the raw data as depicted is not exactly right. 7.1% of all enrolled patients died of prostate cancer, not 7.1% of deaths. That means that 51 out of 731 men died, not 25. I listened to Dr Wilt’s presentation on a webcast to verify this.

  20. Dear Paul:

    According to Dr. Wilt, 48% of 731 men enrolled in the PIVOT trial died during the trial follow-up period, i.e., 351 men. Of these 351 men who died, 7.1% “actually or probably died of prostate cancer” is exactly what is stated in the original report above, as stated by Dr. Wilt in May 2011 at the AUA annual meeting (which I attended). That is, in fact, 25/351 men. We never suggested any other number. It also means that 25 of the entire 731 men enrolled in the trial (i.e., 3.4%) “actually or probably died of prostate cancer” during the trial follow-up period, but that doesn’t tell us how many died after surgery and how many died after being just monitored.

    We are unable to make any further interpretation of the data provided by Dr. Wilt until there is a formal, peer-reviewed, and published report of the results of this trial. Dr. Wilt has used the same slides multiple times now to communicate the same information.

  21. No. You have misunderstood what Dr Wilt said.

  22. Dear Paul:

    The data-specific bullet points in the report above came precisely from the slides used by Dr. Witt in his original presentation to the AUA. This is why I am so disturbed that … a year later … there is still no formal publication of the results of the PIVOT trial.

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