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.