The initial (10-year) results of the ProtecT trial: much as we might have expected?

So the majority of the readers of The “New” Prostate Cancer InfoLink will be well aware that we have never had data from a large, randomized clinical trial comparing the outcomes of the commonest first-line forms of management of men diagnosed with localized prostate canceruntil now!

Today, in the New England Journal of Medicine, Hamdy et al. report the 10-year outcomes from the ProtecT trial, which randomized > 1,500 men, diagnosed with clinically localized prostate cancer, to first-line management in one of three different ways: active monitoring, radical prostatectomy, and external beam radiation therapy. For those who want to read the outcomes for themselves, just click here; the entire text is freely available on line. The “New” Prostate Cancer InfoLink would like to begin by congratulating all of the patients and all of the clinicians and researchers who participated in this trial for their commitment to finally getting us some sound level 1 data about the relative effectiveness and safety of these different management options.

We should also note that many readers may be interested in reading the Editorial commentary on this trial by Dr. Anthony D’Amico that appears in the same issue of the NEJM. We do not agree with Dr. D’Amico’s conclusions, which completely ignore the progress that has been made over the past 20 years in the ways we select men for active monitoring. We would also note that Dr. D’Amico’s conclusions do not appear to correspond to those of the ProtecT research team at all.

As the authors are careful to point out, this trial was initially planned some 20 years ago. We were in the earliest stages of understanding how to appropriately carry out active surveillance; there was no multiparametric MRI capability; robot-assisted laparoscopic prostatectomy didn’t exist; brachytherapy was experimental in the UK (and so very few in this trial were treated with that form of radiation therapy); and there have been major improvements in the quality and nature of external beam radiation over that 20-year period. All of these factors need to be borne in mind while evaluating the data presented below.

Between 1999 and 2009, in the UK, the ProtecT research group gave PSA tests to 82,429 men aged between 50 to 69 years. Of those 82,429 men, 2,664 (3.2 percent) received a diagnosis of clinically localized prostate cancer, and nearly two-thirds of those men agreed to be randomized to one of the three different forms of initial management. However, patients were able to “change their minds” and have a different form of management after they had initially been randomized, which raises all sorts os issues (see below).

We don’t believe that such a trial could ever have been carried out in the US. The primary outcome of the trial was prostate cancer-specific mortality at an average (median) 10 years of follow-up. Secondary outcomes included the rates of disease progression, metastases, and all-cause mortality.

And here is a summary of those results:

  • 1,643 patients agreed to undergo randomization.
    • 545 men were randomized to active monitoring.
    • 553 men were randomized to first-line surgery.
    • 545 men were randomized to first-line EBRT (with three-dimensional conformal radiotherapy at a total dose of 74 Gy in 37 fractions) + neoadjuvant androgen deprivation therapy
  • Most of these patients were low-risk prostate cancer patients
    • 77 percent had a Gleason score of 3 + 3 = 6
    • 76 percent were clinical stage T1c (i.e., identified only one the basis of an elevated PSA level)
  • 14 patients were lost to follow-up but the causes of deaths of any of these patients who died were identified.
  • At a median 10 years of follow-up, on an “intent to treat” basis,
    • Prostate cancer-specific survival was at least 98.8 percent in all groups.
    • The numbers of prostate cancer-specific deaths were
      • 17/1,643 in total (0.1 percent)
      • 8 (7 definite and 1 probable) in the active monitoring group (1.5 deaths per 1,000 person-years)
      • >5 (3 definite and 2 probable) in the surgery group (0.9 deaths per 1,000 person-years)
      • 4 (all definite) in the EBRT group (0.7 deaths per 1,000 person-years)
    • The difference in the rates of prostate cancer-specific deaths among the groups was not statistically significant (P = 0.48) for the overall comparison.
    • The numbers of patients who exhibited progression of their disease (inclusive of metastasis) was
      • 204 in total
      • 112 in the active monitoring group (22.9 events per 1,000 person-years)
      • 46 in the surgery group (8.9 events per 1000 person-years)
      • 46 in the EBRT group (9.0 events per 1,000 person-years)
    • The difference in the rates of prostate cancer progression among the groups was statistically significant (P < 0.001 ) for the overall comparison.
    • The numbers of patients who progressed to having metastatic prostate cancer were
      • 62 in total (certainly < 4 percent)
      • 33 in the active monitoring group (6.3 events per 1,000 person-years)
      • 13 in the surgery group (2.4 per 1,000 person-years)
      • 16 in the EBRT group (3.0 per 1,000 person-years)
    • The difference in the rates of metastatic disease was statistically significant (P = 0.004) for the overall comparison.
    • The numbers of patients who died of any cause were
      • 169/1,643 in total (10.3 percent)
      • 59 in the active monitoring group (10.9 events per 1,000 person-years)
      • 55 in the surgery group (10.1 events per 1,000 person-years)
      • 55 in the EBRT group (10.3 events per 1,000 person-years)
    • The difference in the rates of all-cause mortality was not statistically significant (P = 0.87).
  • Primary treatment failure occurred in 18 men in the surgery group and in 55 men in the EBRT group.
  • 44 percent of patients assigned to active monitoring  have never received any form of radical treatment and thus avoided all side effects of such treatment.

The authors basic conclusion was the following:

At a median of 10 years, prostate cancer-specific mortality was low irrespective of the treatment assigned, with no significant difference among treatments. Surgery and radiotherapy were associated with lower incidences of disease progression and metastases than was active monitoring.

However, you will note that the results given above are all based on how the patients were intended to be treated (as opposed to what actually happened). In fact, as of November 2015

  • Only 482 of the 545 men randomized to active monitoring actually started the assigned active monitoring according to the trial protocol.
  • Only 391 of the 553 men randomized to surgery (74.9 percent) actually had surgery according to the trial protocol (and 95 men initially randomized to surgery actually decided to have active monitoring according to the trial protocol).
  • Only 405 of the 545 men randomized to EBRT (74.3 percent) actually had EBRT according to the trial protocol (and 75 men initially randomized to EBRT actually decided to have active monitoring according to the trial protocol).
  • Thus, in fact:
    • The total number of men who actually started on active surveillance according to the trial protocol was 482 + 95 (originally assigned to surgery) + 75 (originally assigned to EBRT) = 652.
    • The total number of men who actually had initial surgery according to the trial protocol was 391 + 37 (originally assigned to active monitoring) + 41 (originally assigned to radiation therapy) = 469.
    • The total number of men who actually had EBRT according to the trial protocol was 405 + 17 (originally assigned to active monitoring) + 33 (originally assigned to surgery) = 455.
    • 67 patients were actually treated off protocol.
    • This raises all sorts of questions about whether “intent to treat” analysis was apporpriate for a trial of this nature or whether the study should only have been analyzed based on the results of the patients who were treated per protocol.
  • 291/545 men randomized to active monitoring (53.4 percent) actually did have radical treatment at some point in time.
    • 142 received surgery
    • 97 received per-protocol EBRT
    • 22 received brachytherapy
    • 27 received off-protocol EBRT
    • 3 received high-intensity focused ultrasound (HIFU)

With regard to treatment complications:

  • There were no surgically-related deaths.
  • 9 patients had thromboembolic or cardiovascular events.
  • 14 patients required a transfusion of > 3 units of blood.
  • 1 patient had a rectal injury.
  • 9 patients required intervention because of anastomoses.
  • 3 patients died of causes unrelated to prostate cancer within 90 days of completion of EBRT.

The authors also note that:

  • 27 men would have needed immediate initial surgery as opposed to initial active monitoring to avoid 1 case of metastatic disease
  • 9 men would have needed immediate initial treatment (with surgery or EBRT) as opposed to active monitoring to avoid 1 case of clinical progression

In the “Discussion” section of their paper, the authors go on to make several other important points, as follows:

  • The prostate cancer mortality rate in this trial was significantly lower than the authors had originally projected.
  • While there were clearly significant differences between the short-term efficacy of immediate surgery or EBRT over active monitoring, these difference had not translated into significant differences in disease-specific or all-cause mortality at 10 years of follow-up.
  • Longer-term follow-up of these patients will therefore be essential.

The authors are also extremely careful to point out that much of their data needs to be interpreted with caution — most particularly any data regarding comparison of outcomes between individual groups of patients and outcomes of men who went on to have treatment after initial assignment to the active monitoring arm.

At this stage, The “New” Prostate Cancer InfoLink is willing to state only that, 17 years after the first patient was enrolled in the ProtecT trial, it appears that:

  • There is apparently no significant difference in oncologic outcomes at all any more between men treated with first-line EBRT and men treated with first-line surgery.
  • It was inevitable that men on active monitoring in this trial were going to be more likely to “progress” than those receiving immediate treatment, but this seems to have made no significant difference to their prostate cancer-specific or their overall survival at 10 years.
  • A separate article by Donovan et al., also in this week’s NEJM, reports on the patient-reported, health-related quality of life of the participants in this trial at 6 years of follow-up; we will try to get to that later today.
  • There is no doubt that we have got better at implementation of all three of the forms of management addressed in this trial … and probably a very great deal better at being able to select the patients who are most appropriate for active monitoring.

Given these initial outcomes of the ProtecT trial, the key question now for many prostate cancer patients — and most particularly those with low-risk disease — should probably be, “Why do I need treatment at all?” as opposed to “How should I get treated?”

9 Responses

  1. Wonderful summation, thanks. I could not readily find in the study any discussion of the treatments’ outcomes and their correlation with Gleason scores. 77% of the patients had Gleason 6 sums, as I recall. What about outcomes for patients who were Gleason 8, 9, or 10? Thank you.

  2. Excellent commentary, and your caution about evaluating the data including only those getting their assigned treatment would be very helpful. But, based on the intention to treat analysis, AS does have a higher risk of disease progression so far and that is what needs to be conveyed to patients. On a separate note is the information this study gives us about routine PSA screening. For every 10,000 men between 55-69, not having routine PSA testing will result in 3 dying from prostate cancer and about 7.5 developing metastatic disease over 10 years. That is what we should be telling men (not necessarily African-Americans) about the risk of not getting tested.

  3. Bill:

    I’d be very surprised if the study contained many patient with a Gleason score of 8 to 10; I think that most of the patients who were not Gleason 6 were Gleason 7. I was also not able to identify outcome data by Gleason score.

  4. Dear Gerry:

    While I fully accept that in this study, as carried out and as evaluated, there was a higher risk for metastasis among the men on active monitoring, I would again emphasize that: (a) this had no statistically significant impact on disease-specific or overall survival; (b) it is less than entirely clear exactly how the men on active monitoring were being monitored; and (c) we are way better today than we were in 1999 at being able to differentiate between good and poor candidates for active surveillance up front.

    Clearly every patient who is advised that active surveillance is a potentially appropriate initial form of management needs to be advised that it comes with risk for all sorts of things, and metastasis is one of them, but I doubt if that risk today (on a good, current active surveillance protocol) is twice that of the risk for men who have immediate treatment.

    With respect to the issue of PSA testing, as we have said several times now, we believe that individual, risk-based testing is entirely appropriate, based on something similar to the protocol recommended by Memorial Sloan-Kettering Cancer Center. We do not believe that annual screening of everyone is justifiable on the basis of the available data.

  5. I think it’s worth adding that ProtecT allowed in men whose PSA was in the range of 10-20 ng/ml and men with Gleason scores of 7 or higher. In fact, 10% of those on active monitoring had PSA levels > 10 ng/ml, and 22% had Gleason scores ≥ 7. They checked for distant metastasis in those with high PSA using a bone scan. Few of these would be allowed into most contemporary active surveillance programs.

    Their active surveillance protocol would also be considered substandard. Men were not given confirmatory follow-up biopsies within the first year. As you showed recently in your <a href= commentary on the Göteborg active surveillance trial, this is a disastrous misstep. In the ProtecT trial, “active monitoring” patients were screened for a high PSA (> 20 ng/ml), emergent symptoms, or a 12-month PSA increase ≥ 50%. So those with a form of prostate cancer with a low PSA output (such as some of those with predominant Gleason pattern 5) would never be discovered until symptomatic metastases occurred. I don’t know what percent ever got a second biopsy.

    Like you, I wish they would analyze only those patients who were randomized and received the treatment they were randomized to. What they would lose in statistical power, they would gain in meaningfulness. But I doubt they will do that because they didn’t set it up that way.

  6. I wonder how many men are misdiagnosed and thus receive improper treatment. 20-40% of all men who get either surgery or radiation have disease progression, I recently learned. Makes you wonder.

  7. Dear Sitemaster,

    Thank you for doing this detailed presentation. Right now I am in discussion with a Dutch medical writer about two popular articles that report on this paper. One is in the New York Times, the other is in a major Dutch paper. Neither mention risk categories, neither saw the danger of metastasis. I made Bill and Allen’s points in the earlier Dutch exchange. I wish I did not have to. I told the Dutch writer I would check here, and there it is, right now. I sent her the link. Much better work from Sitemaster and commentators than I see in either popular article. By neglecting, or not understanding, details, they are dangerous.

  8. Dear Bill:

    I think it is important to distinguish between what tends to happen in “real life” (where I am in no doubt that there are a lot of men who get misdiagnosed and inappropriately treated) and what happens in a clinical trial like this today (where the chances of misdiagnosis prior to treatment would now be extremely low) because almost every patient would be given several tests that would help to ensure an accurate biopsy.

    Having said that, I (and almost certainly the research team too) would acknowledge that if they were planning the ProtecT trial now, as opposed to 20 years ago, there are multiple things that they would be doing differently to ensure that only truly appropriate patients were being enrolled and randomized into the active monitoring arm of the trial.

  9. High Similarity of 5- and 10-Year Overall Mortality Rates in ProtecT and US Records

    Thanks again for your work, Sitemaster!

    In essence the ProtecT trial numbers for mortality of diagnosed patients in the trial are virtually 0% (100% survival) at 5 years and about 1% (99% survival) at 10 years. According to the latest statistics on the American Cancer Society web site (updated in March 2016), “relative” overall survival for US patients is nearly 100% at 5 years and 98% at 10 years (95% at 15 years). There are at least three differences between the populations in addition to nationality. The US numbers were not strained through an age group filter as was used in the ProtecT trial. The US numbers include all patients, not just those with localized disease. Also, the US numbers are for “relative survival”, which is a comparison of deaths of patients to deaths of age-matched peers, rather than peers because of prostate cancer as in ProtecT. Still, it appears that the US and the UK population that was screened in this study (as contrasted with the total UK male population in the age range) have remarkably similar survival rates.

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