Maha Hussain’s keynote lecture from the GU Cancers Symposium

A detailed report on Dr. Maha Hussain’s keynote lecture at the Genitourinary Cancers Sysmposium in San Francisco — on the management of hormone-naive, progressive prostate cancer — is now available on the UroToday web site. This may well be of interest to many readers. You do have to register as a member of UroToday to read this.

9 Responses

  1. Recent studies (2015) have concluded that for men with high-grade, high-risk prostate cancer at diagnosis, or with known metastases at diagnosis, or found to have moved to metastasis despite surgical removal or radiation, early intervention with chemotherapy accompanied by androgen deprivation medications provide longer subsequent survival by as much as a median of 18¾ additional months from the time of beginning this treatment. But, important to keep in mind, studies for this protocol involved mainly men with a median age of 63 years of age. Thus for the most part, trial participants were healthier than many older patients. With this in view, in her above-mentioned, wide-ranging and comprehensive review at the ASCO Genitourinary Cancers Symposium, Dr. Hussain urged caution in the selection of patients for this protocol, stating it is important they be “fit” in order to reasonably weather the side effects involved in chemotherapy treatment.

  2. UroToday Report on Maha Hussain’s “Hormone Naïve Prostate Cancer” Talk — Interesting Nuggets of Insight Among Some Unrefined and Misleading Ore, Needing Two Filters

    There are interesting nuggets in the linked report, mostly indications of what one of the great leaders in prostate cancer oncology thinks about current and investigational approaches regarding androgen deprivation therapy (ADT). Dr. Maha Hussain has a CV a mile long, including a number of influential studies; among many influential roles, she has served as chair or co-chair of the FDA’s Oncology Drug Advisory Committee (ODAC), which reviewed a number of important drugs during her tenure, including Provenge.

    Her observations cover various aspects of standard of care involving androgen deprivation therapy (ADT) as well as promising advances. According to the report, she touched on combined and “maximal” ADT (vs. single agent), continuous versus intermittent therapy, improved survival for metastatic patients and possibility of chronic rather than lethal disease for such patients, problematic side-effects of some powerful bone density protecting drugs, good news about using chemo-ADT therapy up front for advanced patients (already reported on this site, as are the other topics, though without Dr. Hussain’s specific imprimatur), treating oligometastatic disease, needed research, personalizing treatment, survival figures (some misleading in in the view of some researchers/clinicians), and an optimistic view of progress. But two filters are needed in considering this UroToday article.

    The first filter — considering the reporter’s knowledge base and perspective: There is some seriously misleading information in the report, not stemming from Dr. Hussain’s remarks, but clearly a result of the UroToday’s reporter missing some important context in interpreting her comments in the field of ADT, which can be tricky for those not familiar with the twists and turns. Perhaps the most misleading statement comes almost at the beginning, where the reporter wrote that “But many will go on to progress to castration-resistance, with a median survival in the PSA era of roughly about 4 years.” Whew! Talk about the importance of context! That figure of 4 years may be appropriate for men with metastatic prostate cancer that is already castrate resistant, and perhaps that is what the reporter meant, rather than counting time from the beginning of ADT. However, it is extremely off the mark if it is taken as a generalization about all patients starting ADT, and that view still seems fairly common among urologists. A more accurate view emerged some years ago, based on research from Memorial Sloan Kettering Cancer Center, among some others. The well-known prostate cancer medical oncologist Dr. Mark Scholz, MD, summed up the ADT success picture as about 10 to 11 years before resistance for many men, with indefinitely long resistance for some others. Of course, post-resistance therapy extends survival beyond the resistance point, especially with the slew of medications approved in recent years, so survival is considerably longer if not til other causes of death ultimately claim the patient.

    Second filter — understanding the “trialists” view: Later, near the end of the article, the reporter writes: “We have come a long way in this disease,” Dr. Hussain observed. The promise of better therapies is real in metastatic hormone naïve prostate cancer. Androgen deprivation continues to be the backbone of treatment, with median survival in the PSA era of about 4 years, and the remarkable 10-year estimated survival of 17%.”) The context here is that Dr. Hussain was talking about metastatic men, and she may have been considering only those who were castrate resistant. We need to understand that Dr. Hussain is a prominent, very well published clinical trial manager/investigator — a trialist — and that trialists have a strong inclination to trust only results from well-done clinical trials as reliable. Trialists also get very used to some conventions commonly used to help make trials practical, at times representing those conventions as reality. Specifically, here, they often count survival time from the time of a patient’s enrollment in a trial, an event which can be well documented, rather than from the true date of the actual event. For example, here, the actual date when a test first showed a patient was castrate-resistant is typically different from the date of enrollment of a trial that counts survival from the nominal point of castrate resistance, which is often trial enrollment. It is easy to visualize that the difference in the real and conventional date can be quite large, in which case the length of survival as measured by the trial is much shorter than actual survival from the point of castrate resistance, which is what matters to us patients.

    Some years ago three researchers (Oefelein et al.) from Case Western Reserve University near Cleveland — well known for its prostate cancer research role — became disturbed that the relatively short survivals of 12 to 18 months that they were hearing about from fellow researchers for men with castrate-resistant prostate cancer were far short of what they were generally seeing in their clinics. Here is the key line from their results of a chart review they conducted (among 254 men) and published in 2004: “Median survival after hormone refractory prostate cancer developed in patients initially staged with and without skeletal metastasis was 40 and 68 months ….” Perhaps Dr. Hussain’s figure of 4 years was a rough average, but, based on the progress that has been made since 2004, I’m thinking that the trialist’s filter is still leading to an overly short estimate of survival.

  3. Continuous versus Intermittent ADT (IADT) – Perhaps Reporter Did Not Understand that Metastases Make a Huge Difference

    It is clear from the report that Dr. Hussain finds intermittent ADT attractive – “near and dear to my heart.” However, the report expands that statement with her statement that spot lights an important recent trial that is not favorable to intermittent ADT, while mentioning another trial with similar results.

    The problem is that the reporter does not make clear that Dr. Hussain is then talking about continuous versus intermittent ADT in metastatic men. Here is the statement in the report: ‘… In both trials, (recently discussed in a JCO article) continuous therapy was associated with better median survival compared to intermittent therapy. The largest of the trials, SWOG 9346, demonstrated a median survival difference of approximately 8½ months in favor of continuous treatment. This outcome was associated with “modest at best” improvement in quality of life that, Dr. Hussain added, was, unfortunately, short-lived. Still, she added, “…from a hormonal perspective, continuous androgen deprivation is the standard of care on grounds of optimal survival outcomes.”’

    For years I followed closely developments in intermittent ADT. SWOG 9346 is consistent with what I believe has been for many years a strong consensus: continuous ADT is better for men with metastatic disease; all men in that trial had metastatic disease. However, the reporter should have noted that Dr. Hussain was talking about metastatic patients in relating the results of these trials. For so many of us who have not reached the metastatic state, intermittent ADT has been supported by a number of trials indicating no loss of efficacy against the cancer compared to continuous ADT while improving quality of life. IADT is also favored by prominent guideline groups for non-metastatic men. As a side observation, unfortunately even continuous ADT in metastatic men is not effective for more than one to a few years, in sharp contrast to typical success for more than a decade or indefinitely long with IADT for men who are not metastatic.

    (I was on IADT3 for 14 years for a once life-threatening case, doing very well. My situation had improved so much by 2013 that I was eligible for a curative attempt with radiation, with results still encouraging at this point. I’m convinced I am far better off regarding side effects than I would have been on long-term continuous ADT.)

  4. Jim,

    Going on permanent (intermittent or continuous) ADT without evidence of metastases, or at least some evidence that detectable metastases are imminent (high and rapidly rising PSA), is highly controversial. There is no evidence of any survival benefit to early use in its absence.

  5. Allen,

    If by “survival benefit” you mean cure, then I agree, though there is some low quality, limited evidence that it may be curative for a few men. But I take your meaning to be broader, covering added survival time.

    I’m reminded of that sage advice that those who say something cannot be done should not interfere with those who are doing it, the “it” in this instance being extending survival with ADT. I have been aware of the view you relate almost from the time of my diagnosis 16 years ago. I consulted several times at Johns Hopkins back then, not realizing that Dr. Walsh was leading a loud chorus there with the message: don’t use hormonal therapy until a man has symptoms, as it does no good. (There are certainly those at Johns Hopkins who don’t share that view now, and probably they were also present in early 2000, but “Johns Hopkins” as an institution was known for shying away from early use of ADT.) Keep in mind that, as someone who opposed early ADT, Dr. Walsh had very little if any experience with its early use.

    Fortunately for me, I came across physicians who were highly experienced in using ADT, were achieving extraordinary success with it, were aware of ongoing research, and knew how to handle its side effects.

    There is actually an abundance of evidence that early ADT holds the cancer back for many years for many men, though a gold standard clinical trial to prove a survival benefit has not been done as far as I know, and trying to mount such a trial now would be both impractical and unethical, the latter in view of the known benefits of early ADT. Despite that, it’s not hard to resolve this question with a logical analysis.

    Try this thought experiment. Consider that men at high risk of dying from prostate cancer — the ones at ground zero of our efforts to help — often have short PSA doubling times (PSADT), especially PSADTs of 3 months or fewer, in fact down to doubling every couple of weeks. Many of these men are going to have fairly substantial PSAs at diagnosis, as I did (113 ng/ml), but let’s start our thought experiment with a PSA of just 20 and a PSADT of 3 months, with no treatment. Three months after diagnosis the PSA would be 40, would be 80 in 6 months, 160 in a year, 320 in 15 months, 640 in 18 months, 1,280 in 21 months (almost surely symptomatic by now), and 2,560 at 2 years. While some men do not survive with PSAs that high, some do. However, at 27 months that PSA would be 5,120, just 3 months later at 30 months would be 10,240, by 33 months would be 20,480, and by 3 years would be 40,960, assuming the patient were still alive, which is extremely unlikely. The highest PSA I’ve heard of was 25,000 something (Dr. Eugene Kwon’s patient), but most men are doing amazingly well if they are alive with PSAs of several thousand to 10,000. Now consider all the men in trials with short doubling times who have survived more than 3 years on ADT. Obviously, the ADT is extending their survival.

  6. Jim,

    As I said, and perhaps you missed, the benefit of lifelong ADT has only been shown in men who have detected metastases or “at least some evidence that detectable metastases are imminent (high and rapidly rising PSA).” Your PSA of 113 ng/ml certainly fits that category, and your “thought experiment” only proves what I wrote. If you’ve seen an “abundance of evidence” that starting on early lifelong ADT has a survival benefit for men with no metastases and low or slowly rising PSA, let’s look at it — I haven’t seen it.

  7. Interestingly, we have seen early use of hormonal ablation in cases that had no metastasis — men that were detected via digital rectal exams and had radical prostatectomy with orchiectomy in the pre-PSA era. It certainly is a form of continuous ADT. Unfortunately I don’t believe anyone was tracking outcomes in that era.

  8. Allen,

    I’ve reread your initial post and realize I missed your clear emphasis of “at least some evidence that detectable metastases are imminent (high and rapidly rising PSA)”. I tend to think about the short PSA doubling times rather than whether metastases have been detected, though the latter is obviously very important, and I think that’s why I missed it.

    I too do not know of evidence of a survival benefit for men with no metastases and low or slowly rising PSA, though there are, no doubt, a few cases in trials for men with short PSA doubling times who have been tested at the times early in the disease course when their PSAs are still low, the PSA level happening to be captured in that brief interval before it becomes much higher.\

    There is some evidence, from at least one clinical series (by Leibowitz and Tucker), that a one-time course of ADT3 for generally low-risk men can knock the cancer back and keep it back for years, though the questions remain (1) whether the cases were generally so mild that not even that treatment was necessary, and (2) whether there was a survival benefit. You can get the abstract at and the complete paper via a link at that URL. The paper was published in 2001. Unfortunately Dr. Leibowitz suffered a bout of debilitating disease during which his patients sought care with other doctors, and Dr. Leibowitz was unable to track his group effectively enough for publication after returning to practice. He has published a number of informal papers — not peer reviewed — that update his results, but the quality of follow-up appears somewhat shaky. The 2001 publication was in the days prior to any publication on active surveillance, and no doubt many of the patients in the group would have qualified for AS and done well throughout their lives with no conventional treatment. Most of his patients were on the treatment for 13 months, and many of them, as I recall, remained on finasteride indefinitely as maintenance.

    I remain grateful to Dr. Leibowitz as he was one of a very few pioneers of ADT3 with finasteride continued as maintenance. This is the therapy that worked so well for me for 14 years, through the time I took a shot at a cure with radiation, which is looking successful at this point.

    Another prominent practice using primary androgen deprivation therapy, also ADT3 with either finasteride or Avodart maintenance, is now led by Dr. Mark Scholz, and results of the Scholz, Lam, Strum and colleagues team on primary ADT was published in 2011 under the title “Primary Intermittent Androgen Deprivation As Initial Therapy for Men with Newly Diagnosed Prostate Cancer” (PMID: 21993252). I have a copy of the complete paper. This chart review from the practice covered 15 low-risk, 38 intermediate-risk, and 20 high-risk men.

    Another important piece of evidence regarding primary ADT is the Japanese study published in 2007. (PMID: 17965423 -– link to complete free paper. Primary ADT is much more accepted in Japan than in the US.)

  9. Dear Jim:

    Numerous studies have shown that early, primary ADT is associated with a significant risk for short- and longer-term cardiovascular and other metabolic complications and side effects (up to and including death). It is beyond me why, today, any patient with low- or intermediate-risk prostate cancer and no evidence of actual or probable metastatic or micrometastatic disease would be started on first-line treatment with any form of ADT. The studies you refer to are of low quality in the first place and provide no comparative data against which to judge the outcomes of the patients treated with ADT or IADT.

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.

%d bloggers like this: