We have already reported data, presented by Dr. Maha Hussain yesterday, that appear to show that — at least in men with clearly metastatic prostate cancer — continuous and complete androgen deprivation (CAD) extends survival significantly better than intermittent androgen deprivation (IAD).
The data presented by Dr. Hussain at ASCO were discussed, immediately following her presentation, by Dr. William Oh. There is no formal abstract of Dr. Oh’s presentation that you can be referred to. Following Dr. Oh’s presentation there was a special session organized by ASCO specifically for the “open” discussion of the results of this trial.
Before we get into a detailed discussion of these data, we do want to point out two very simple facts:
- This trial has now, for the first time ever, established that the median survival of men with metastatic prostate cancer who have a good initial response to hormonal therapy is of the order of 5.8 to 6.5 years. This fact has got lost in the controversy over the other trial results, but it is a key piece of new information that is very important indeed. On the other hand,
- We are regrettably none the wiser about the appropriate timing of initiation of hormonal therapy than we have been for most of the past 20 years. Should it be started immediately after the patient’s PSA starts to rise in indication of recurrent disease? Should we wait until there are either clear signs and symptoms of metastasis? Should we set “standard” PSA levels at which to start hormonal therapy (e.g., at 20 or 50 ng/ml) unless signs and symptoms of disease demonstrate the need to start hormonal therapy at lower PSA levels in individual patients? We really don’t have a clue.
Now, moving forward, there appear to be several critical issues about this trial and its results that were extremely worrisome to many in the audience at ASCO.
First, the results seem to be counter-intuitive, particularly the subgroup analysis which showed that men with more extensive metastatic disease did better on IAD than men with minimal metastatic disease. These observations led many in the audience to question whether there was something about the way that the trial was conducted that could have led to a result that is actually inaccurate.
Dr. Hussain, who is widely recognized to be a highly reputable and skilled clinical investigator, fully acknowledged that that this trial was initiated 17 years ago, when we certainly knew less about the progression and treatment of metastatic prostate cancer than we do today. However, she was also very clear that the trial was designed and executed to the highest possible standards given the knowledge available at the time of trial initiation, that every attempt was made to assure appropriate data collection to a very high level of quality, and that “the data are the data.” They had surprised her just as much as they had surprised most of the rest of the audience.
Second, Dr. Hussain, Dr. Oh, and others all agreed that we need to be careful not to over-interpret the difference in results between the men with extensive and minimal metastatic disease. This trial was not originally designed to identify such a difference as a primary endpoint. The difference between these two groups of patients is based on a subgroup analysis. Also, there are many who feel that the way the difference between extensive and minimal metastatic disease was defined back in the early to mid 1990s would not be the way we did that today. However, the difference did appear to be very clear, and Dr. Hussain simply “stuck to her guns” and repeated that “the data are the data” even if they make many of us feel distinctly uncomfortable.
The third, and perhaps the most critical of all the issues was the practical, day-to-day, clinical implications of the results of this trial. What are ASCO and other guideline-developing organizations such as the National Comprehensive Cancer Network (NCCN) going to make of these data and are they going to tell practicing physicians that CAD is now established as the standard of care for the treatment of men with hormone-sensitive, metastatic prostate cancer?
In thinking through this third issue, The “New” Prostate Cancer InfoLink considers that there are a number of very important factors that need to be taken carefully into account:
- CAD is well known to come with risk for serious side effects that affect quality of life. Newly diagnosed patients need to be made very clear about this in discussing hormonal therapy with their physicians.
- This trial — whatever its flaws may or may not be — is the only large, randomized clinical trial that has ever been conducted in men with metastatic, hormone-sensitive prostate cancer and sufficiently powered to prove any difference in survival benefit between IAD and CAD. And Dr. Hussain is correct in her statement that we need to understand that “the data are the data.” They show that IAD is inferior to CAD in extending the survival of this well-defined set of men.
- The only other trial ever carried out and sufficiently powered to demonstrate a difference in survival between men treated with CAD or IAD was the NCIC CTG PR.7 trial. The results of this trial, first presented over a year ago at the Genitourinary Cancers symposium, showed that IAD was non-inferior to CAD — but the men enrolled into this trial were not metastatic at the time of entry into the trial and, furthermore, that trial randomized patients at the time of trial entry. It did not randomize them after they had clearly shown a good and stable response to their first cycle of androgen deprivation.
- Quality of life and extent of life are key issues that are subject to something known as “physician bias.” In other words, there is a tendency in the academic medical community to see survival as a more important outcome than quality of life. However, from a practical, day-to-day patient management perspective, the wishes of the patient need to be paramount. Some men may wish to just stay alive for as long as possible; others may say that they will happily sacrifice a few months of life to have a better quality of their remaining life.
The “New” Prostate Cancer InfoLink believes that the trial conducted by Dr. Hussain and her colleagues is a very important trial, and congratulates the investigators (and all the participants) on their 17 years of hard work. What it has shown us is that (yet again) what we hope and expect to be true may not turn out to be the case. However, what it also does not do is establish the idea that all men with metastatic, hormone-sensitive prostate cancer should be placed on CAD as opposed to IAD. It tells us simply that a patient and his doctor, in considering their options for the treatment of metastatic, hormone-sensitive prostate cancer today, need to discuss carefully the risks and benefits of CAD and of IAD. Yes, we now have evidence that IAD is less effective at extending survival than CAD in these men, but the decision whether to sacrifice quality of life for a few months of additional survival is one that only a fully informed patient and his family are capable of making — with appropriate guidance from a fully and well-informed clinician.