Clinical trial design, clinical advice to patients, and clinical decision-making: not the same thing at all

In a recent opinion piece in the Journal of Clinical Oncology, Dr. Anthony D’Amico (a prostate cancer specialist for whom we have great respect) has again aired his concerns about risk for progression to metastatic disease among men on active surveillance. This opinion piece has also been discussed at length in a commentary on the Medscape web site.

Dr. D’Amico’s concerns relate primarily to the fact that, in the recent ProtecT trial, at a follow-up of 10 years, about twice as many of the men initially randomized to active surveillance progressed to have metastatic disease (33/545 patients or 6.3 events per 1,000 person-years) compared to the numbers of men who went on to have metastatic disease when randomized to either radical surgery (13/553 patients or 2.4 events per 1,000 person-years) or radiation therapy (16/545 patients or 3.0 events per 1,000 person-years). We should also note that the numbers of deaths from prostate cancer in the ProtecT trial was low, with only 17 events (1 percent) among the 1,643 patients randomized to treatment or active surveillance, and there was no significant difference between the numbers of prostate cancer deaths among the three trial arms.

The biggest concerns that we have with Dr. D’Amico’s opinion are these:

  • The operational structure of the ProtecT trial (for a variety of good reasons) was highly unusual. Being initially randomized to active surveillance or surgery or external beam radiation therapy did not mean that patients were actually treated that way. The patients could opt, after randomization, to be treated in other ways to the one to which they had initially been randomized, and in fact many did (see Figure 1 on page 1417 of the original report in the New England Journal of Medicine).
  • In fact,
    • Only 482 of the original 545 patients originally randomized to active surveillance were initially managed on active surveillance within 9 months of randomization.
    • Only 391 of the original 553 patients originally randomized to surgery had surgery within 9 months of randomization.
    • Only 405 of the original 545 patients originally randomized to radiation therapy started radiation therapy within 9 months of randomization.
  • However, the initial analysis of the patients’ outcomes was based on an “intent to treat” analysis (i.e., what arm of the trial they were randomized to) as opposed to on the basis of how they were actually treated. We are still waiting to see the results of an outcomes analysis based on the actuality of how they were really managed.
  • In total, we know that, at the end of the day
    • 652/1,643 patients (39.6 percent) were initially managed on active surveillance per the trial protocol.
    • 469/1,643 patients (28.5 percent) received first-line surgery per the trial protocol.
    • 455/1,643 patients (27.7 percent) received first-line esternal beam radiation therapy per the trial protocol.
    • 67/1,643 patients (4.1 percent) either had a different type of treatment (n = 24) or had no immediate treatment within 9 months (n = 43).
  • Until we know whether there were major differences in the outcomes based on how patients were actually treated, Dr. D’Amico’s current concerns could be entirely spurious. Note that 43 patients declined initial treatment altogether, and of those 43 patients
    • 7 were originally randomized to active surveillance.
    • 23 were originally randomized to surgery.
    • 13 were originally randomized to external beam radiation therapy

Now the place where we are in complete agreement with Dr. D’Amico is when he states that the best potential endpoint for future trials in which active surveillance is a key form of management should be onset of metastasis and not prostate cancer-specific or overall survival. This makes perfect, logical sense, and would drastically accelerate the completion of trials for appropriate patients enrolled into such trials.

The two other things that we would point out are things that Dr. D’Amico also notes in his opinion piece:

  • Current selection of patients for and monitoring of patients on active surveillance has already changed drastically since the initiation of the ProtecT study back in 1999. The ProtecT study quite certainly enrolled men who we would not consider to be good candidates for active surveillance today. Therefore such inappropriately enrolled patients who were randomized to the active surveillance arm of the trial and who went on to have active surveillance, were, by definition, more likely to be at risk for metastasis than the men who were enrolled into the surgery or the radiation therapy arms of the trial and who actually had treatment per the trial protocol.
  • The monitoring techniques used to track risk for progression of the men  in the active monitoring arm of the ProtecT trial were nothing like as sophisticated as the ones being used in good active surveillance protocols today, and so this would also have increased the risk that men on active surveillance in this arm of the trial would have progressive disease that was caught too late for effective, curative therapy.

Dr. D’Amico’s academic concerns about the ProtecT trial outcomes are one thing. How active surveillance is being actually conducted today, and how to use the available data from the ProtecT trial to help in advising patients about the risks and benefits of active surveillance are quite another. But

We are in absolutely no doubt that every patient who is told that active surveillance may be a good initial option for the management of his, individual case of prostate cancer should also be being told that there is, quite certainly, a small risk that his cancer may progress to become metastatic disease, with the concurrent risk for the need for long-term androgen deprivation therapy (ADT). Of course that is also true for all the patients who decide to have any form of invasive, first-line treatment like surgery, radiation therapy, or anything  else.

2 Responses

  1. Ever-Improving Methods and Prospects for Prostate Cancer Patients on Active Surveillance

    Dr. D’Amico notes a number of important improvements in active surveillance since the period of this trial, improvements that might very well have reduced the small number of AS patients developing metastases even further. (I read his full paper.)

    There are some other important advances that he did not mention. Here are several, just for illustration. Some doctors have their AS patients on one or more supportive drugs that appear to increase odds of safely staying on AS longer or indefinitely. For instance, at the Conference on Prostate Cancer last September in Los Angeles, Drs. Charles (“Snuffy”) Myers, Mark Moyad, Mark Scholz, and Nick Vogelzang all mentioned at least one drug they felt AS patients should be taking.

    For Dr. Vogelzang, the drug was Proscar (finasteride), based on a good record against Gleason score 6 (and lower) cancer (Disc 4, 2:04:28).

    Dr. Moyad mentioned the usefulness of baby aspirin (Disc 2, 2:54:11, but also noted that it needed to be used with care as some patients experienced adverse effects (“highly toxic”; Disc 2, 3:02:40). Dr. Myers explained that aspirin was very effective in combating problems from the very common gene fusion of TMPRSS2 and ERG (about half of the US prostate cancer population), but he routinely now checks his new AS patients for such gene fusion before advising aspirin use. If they have such gene fusion, he monitors iron regularly to guard against deficiency associated at times with aspirin use, and I assume he puts the patient on an iron supplement if needed. He stated that your cancer is “much more likely” to progress if you are on AS and have TMPRSS2/ERG gene fusion, adding that “PTEN loss and this gene fusion is a particularly lethal combination. Aspirin and metformin are the two best drugs for both of those.” (Disc 2, 2:04:06; Disc 2 about 2:14)

    Dr. Myers also routinely uses metformin and a statin for his AS patients (Disk 4, 3:02:23), explaining that he starts at the lowest dose for metformin and either stops at the full dose of 2,000 mg or reverts back to the dose that is fully tolerated without side effects, and Drs. Scholz and Moyad agreed with those drugs in reviewing highpoints of his talk, with Dr. Moyad underlining the need for monitoring B12 and magnesium when taking metformin (Disc 2, about 2:54).

    An interesting but fairly small difference among the presenting doctors was that Dr. Vogelzang used Proscar (finasteride) as the 5-alpha reductase inhibitor to support AS where Dr. Myers used Avodart (dutasteride). Dr. Myers has previously noted that some men have genes that do not allow a benefit from Avodart, which is for most men more effective than Proscar, but that those men can be switched to Proscar. I don’t specifically recall that any of the doctors mentioned BRCA2 gene testing for AS, but I suspect they did. I’m wondering if anyone here had BRCA2 assessment before deciding on AS.

    All of this has research behind it, as well as the clinical experience of the doctors commenting. It seems we are in a period of awesome progress in the use of active surveillance. Now we have all these genetic tools that were not on the map just a few years ago. Multiparametric MRI appears to be moving into a dominant position in place of biopsies, at least beyond the second follow-up biopsy. Before that, use of finasteride was an advance advocated by a few — I remember Dr. Klotz reporting about it — that now seems more common or even mainstream. All of this progress will surely make stealthy and lethal metastatic disease even less likely for AS patients.

    Regarding the other of Dr. D’Amico’s main points, I suspect that many of us would like to see metastasis used as a major or primary endpoint in our trials rather than overall survival.

  2. Many thanks for sharing this.

    I was surprised to learn that the arms of the trial did not align with the actual treatments. And yes, not all AS regimes are equal … particularly with mpMRI technology that is useful in monitoring for progression during AS.

    I agree that metastasis should be a primary measure or endpoint. However, I believe overall mortality is very important. For example, when a patient has radiation, how does this affect overall mortality? It is a legitimate question that should be addressed. Prostate cancer mortality is interesting but of questionable accuracy, in my opinion.

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