Focal HIFU in men with localized prostate cancer — data from a small, initial, UK trial


A report just published on line in The Lancet Oncology provides data from a study of the use of focally directed (as opposed to whole gland) high-intensity focused ultrasound (HIFU) in the treatment of a small series of men with localized prostate cancer between 2007 and 2010. The data are interesting but follow-up to date is short.

According to this article by Ahmed et al., the research team recruited a cohort of 42 men with localized prostate cancer, all of whom met the following eligibility criteria:

  • PSA level ≤ 15 ng/ml
  • Gleason score ≤ 4 + 3 = 7
  • Clinical stage ≤ T2
  • No prior treatment for prostate cancer (including no prior androgen deprivation)
  • Able to safely undergo multiparametric MRI and receive general anesthesia

All 42 patients agreed to be treated by focal HIFU, directed to all identified prostate cancer lesions (and to  a margin of normal tissue) identified on multiparametric MRI, template prostate-mapping biopsies, or both. Additional information about the study design and patient eligibility is available on the  ClinicalTrials.gov web site.

The results of this trial are reported as follows:

  • The age range of the 42 patients enrolled was from 45 to 80 years.
  • A single patient died (from pneumonia, unrelated to his treatment) 3 months after treatment; he was excluded from data analyses.
  • The following short-term complications were potentially associated with treatment.
    • 1 patient was hospitalized for acute urinary retention post-treatment.
    • 1 patient had interventions for stricture that required hospital admission.
    • 9/41 patients (22 percent) had mild to moderate, intermittent, self-resolving pain on urination (median duration, 5.0 days).
    • 14/41 patients (34 percent) reported urinary debris with a median duration of 14.5 days.
    • 7/41 men (17 percent) had an infection of the urinary tract.
  • On average (median), International Index of Erectile Function-15 (IIEF-15) overall scores were similar at baseline (prior to treatment) and at 12 months post-treatment (p = 0.60).
  • Significant reductions were observed between baseline and 12 months post-treatment for IIEF-15 erectile (p = 0.042) and orgasmic function (p = 0·003).
  • 31/35 patients with good baseline function (89 percent) had erections sufficient for penetration 12 months after focal therapy.
  • Median UCLA Expanded Prostate Cancer Index Composite (EPIC) urinary incontinence scores were similar at baseline and at 12 months post-treatment (p = 0.045).
  • Lower urinary tract symptoms, assessed by International Prostate Symptom Score (IPSS), improved at 12 months post-treatment compared to baseline levels (p = 0·026).
  • IPSS quality of life scores showed no difference between baseline and 12 months post-treatment (p = 0.655).
  • All 38 men with no baseline urinary incontinence were leak-free and pad-free at 9 months post-treatment.
  • All 40 men who were pad-free at baseline were pad-free again at 3 months post-treatment and remained pad-free at 12 months post-treatment.
  • No histological evidence of cancer was identified in 30/39 men (77 percent) biopsied at 6 months and 36/39 men (92 percent) were free of clinically significant cancer.
  • 4/41 patients (10 percent) required retreatment.
  • After retreatment of the above-mentioned  4 patients, 39/41 (95 percent) had no evidence of disease on multiparametric MRI at 12 months.

The authors conclude that, “Focal therapy of individual prostate cancer lesions, whether multifocal or unifocal, leads to a low rate of genitourinary side effects and an encouraging rate of early absence of clinically significant prostate cancer.”

Now let us first state clearly that Ahmed and his colleagues are to be congratulated, once again, on the thoroughness with which they have conducted this study. The degree of detail is impressive and gives a very clear appreciation of the immediate post-treatment and the 12-month follow-up data on outcomes of all types related to this study.

However, there are a number of key points that we would make in our evaluation of this study:

  • The follow-up period of just 12 months is very short. There are good reasons to believe that some of these patients may exhibit recurrence with longer follow-up (most particularly among those patients with Gleason 4 + 3 = 7 disease).
  • We are not sure that we agree that this study demonstrates that focal HIFU has “a low rate of genitourinary side effects.” Erectile and orgasmic function were clearly seriously affected, and “erections sufficient for penetration” may have been meaningful for the 80-year-old man in this study by significantly less satisfactory if it also applied to the 45-year-old.
  • This is a small study in a series of carefully selected and motivated patients. Such patients tend to be prejudiced to see their outcomes in a positive light.

These comments should not be seen as being “critical” of the study. Rather, they are intended to point out issues that the thoughtful reader should take into account when assessing these data.

Additional information about this study is available on the Bloomberg.com web site based on an interview with Dr. Ahmed. Dr. Ahmed is clearly excited by these results, but more study is clearly going to be needed.

The problem we continue to see with the clinical use of HIFU in the USA is that there are still no data that provide us (let alone the US Food & Drug Administration) with a comparison of outcomes after HIFU (let alone focal HIFU) to any other form of recognized first-line treatment (e.g., brachytherapy). Absent such data, it continues to be unlikely that HIFU is going to be an approved form of first-line treatment for localized prostate cancer in the USA any time in the near future.

16 Responses

  1. Thanks for posting this. Today, two of my Facebook friends posted articles about this study on my page. One text merely stated that the study concerned “early-stage” prostate cancer. The other had a similar claim, but I forget it. In neither was any risk-group mentioned. In both cases I told the poster that early-stage *does not* mean low-risk, and that at least in this respect the articles are misleading and too optimistically stated. Well, now I can tell them more.

  2. Thanks for pointing out this attempt to extend focal therapy to HIFU. Here are my thoughts from a patient’s perspective.

    It seems that HIFU trials show encouraging results until around the 4- or 5-year point, by which time recurrence rates climb well above levels achieved for surgery and radiation. A glass-half-empty perspective for this trial is that 10% recurred early and were retreated within the short 3-year follow-up reported, with an additional 5% also recurring but not retreated during the reporting period, for a total recurrence of 15% within the period. Moreover, focal HIFU must be inherently more risky than HIFU for the entire prostate.

    On the other hand, the risk level for this 41 patient group is substantial, with 63% with intermediate risk and 10% at high risk according to NCCN guidelines. That sets a lower success threshold for recurrence rates for comparison with other therapies. Of course it would be great to have a head-to-head comparison trial, but short of that, we patients can at least get some indication of comparative success from the recurrence rates for risk levels.

    My layman’s impression is that the Sonablate 500 system used in this study is enjoying better results than the Ablatherm system.

    The patients in the study were not given preparatory TURPs. Aren’t such TURPs typical with the Ablatherm system?

    The patients did go through an initial TRUS biopsy followed by later template prostate mapping (TPM) biopsy that averaged 46 cores, as well as a follow-up biopsy at 6 months. That’s a substantial staging load on the patient.

    It will be interesting to see what the snap shot success rate is at the 5-year point, or later.

  3. On the basis of this early study, there is no ability to recommend this therapy as a reasonable option for men with early stage disease. Even in 10 years, the information necessary is likely to be lacking.

  4. Reasonable is relative. Deplorable is not an unfair evaluation of the documented results of traditional therapy. That appears to be changing, but is no more well documented than this study.

    I would take a higher probability of 5 good years over the probability of 20 decent years. That choice is based on the total state of health and life. Not fear, not avoidance.

    I understand not recommending a relatively untested therapy. Every patient should be aware of all therapies and risks, even choices you cannot recommend (or have access to).

  5. It would be great if Dr. Chodak could expand on his analysis.

  6. Two points I would raise are:

    (1) Is there an upper limit in prostate size for this treatment?

    (2) Many patients in the treatable group must be thinking, even if this is not yet a proven treatment, is it better than vigilant surveillance?

  7. First, vigilant surveillance would (arguably) not have been an appropriate form of management for any man in this study with a Gleason score of 3 + 4 = 7, and few people would think it was an appropriate form of management for men with a Gleason score of 4 + 3 = 7 (unless their life expectancy was a factor in their need for treatment).

    Second, if the patients were appropriate candidates for some form of vigilant surveillance, then why wouldn’t they want to do that until there was clear evidence that treatment was necessary? … at which point treatment of this type might be an appropriate option (if there is good outcome evidence from long-term follow-up).

    I would note that the side effects of treatment in this study were not inconsiderable, and we have no idea as yet whether there may be longer-term side effects and disease recurrence.

  8. Clarifying my comment of 4/17 4:26 pm re follow-up time …

    The 3-year span I mentioned was from the start of the study through the cut-off date for the report. Median follow-up for the group of patients in the study would have been much shorter, as Sitemaster indicated in the original article.

  9. HIFU AS A “DISPROVEN” THERAPY, FROM MY VIEWPOINT

    Hi William. I’m responding to your post of 4/19, 3:39 pm.

    Sitemaster and others have already raised serious concerns about this study, but your describing HIFU as “not yet a proven treatment” led me to realize I’m now skeptical to the point of viewing HIFU as disproven until new evidence indicates otherwise. If you look at the published results of several international studies, you see that all results for low-risk patients for HIFU are clearly substantially inferior in avoiding PSA recurrence compared to results for radiation and surgery studies for low-risk patients at about the 5-year point. (I’m not counting older radiation studies where a dose of radiation was typically employed that is now known to be insufficient.) While it is true that well over a majority of low-risk HIFU patients have avoided recurrence at about the 5-year point, the success rates are low enough that they resemble the long-term success rates for active surveillance. That suggests that most of those avoiding recurrence after HIFU probably had indolent prostate cancer and did not need any treatment. It is also discouraging that the success rates for HIFU studies are on a fairly steep downward slope as the years tick by.

    Arguably HIFU may have a role as a salvage therapy, and we can always hope for a breakthrough that will be reported in the future. However, if a friend asked me what I thought of HIFU as a first-line therapy, even for low-risk prostate cancer, I would explain the facts and say that I was highly skeptical.

  10. CHARACTERIZING SUCCESS RESULTS FOR TRADITIONAL THERAPY

    Hi Mike,

    I’m responding to your post of 4/18 at 8:09 am in which you characterized the results of traditional therapy as “deplorable” and the documentation as “no more well documented than this study.”

    You are in for a hefty dose of encouragement about traditional therapy — a real treat. What you need to do is actually take a look at the studies that have been done. You can do that at the site run by the US National Library of Medicine, known as PubMed (for Public Medicine), http://www.pubmed.gov. Right off you will see that follow-up time after therapy is far longer than in this HIFU study. The main obstacles are that so many studies of traditional therapy have been done, and details of study protocols vary considerably.

    However, for an overview that graphically presents comparative recurrence avoidance results of all therapy types by years of median follow-up in color-coded symbol clarity, take a look at the on-going work of the Prostate Cancer Results Study Group. The Group’s role was to set up criteria for including studies, and the implemented criteria went a long way toward an apples-to-apples comparison. Granted, their product is not the quality of evidence we would have from head-to-head, prospective, randomized studies, but, for a number of reasons, such studies are extremely hard to execute successfully; therefore, we do not have such studies as guides. For me as a patient, the evidence summarized by the Group is helpful in considering what works and what does not.

    There have been many long-term studies demonstrating high rates of success in avoiding recurrence. I suppose “high” is in the eye of the beholder, but I’m personally impressed. To me the results are “encouraging” rather than “deplorable.” In addition, for a substantial proportion of patients who do recur, evidence suggests the recurrences are mild enough that follow-up treatment is not needed.

  11. So, Jim, you’re not dismissing the potential for all forms of focal therapy, just HIFU?

  12. Hi Tracy,

    I’m replying to your comment of 4/19 10:38 am that asked if I’m dismissing the potential for all forms of focal therapy or just HIFU.

    Actually, I’m not dismissing the potential for any kind of focal therapy; it would be a wonderful advance if a focal therapy approach achieved a high success rate!

    However, after having hope several years ago that whole-gland HIFU and focal cryotherapy would show signs of success, I’m especially discouraged by the results being reported for HIFU, and I’m not yet confident in the focal cryo approach. For HIFU, I’m skeptical about the focal version as the whole-gland version has not achieved success, in my view, as I detailed earlier. It seems logical that focal HIFU would likely be even less successful than whole-gland HIFU.

    For focal cryo, there are two recognized leaders that I’m aware of who are reporting results, as you may know. Dr. Duke Bahn and colleagues published his results this year with a median follow-up of 3.7 years. He has a reputation as one of the foremost practitioners of cryo for prostate cancer, so his research is a worthy indicator of the state of focal cryo. Unfortunately, the recurrence rate reported was 25% at the 3.7 years mark. That is not encouraging to me. However, the abstract I read did not contain a breakout of low-risk versus intermediate-risk patients, and his series had many of the latter patients. In other words, this is a series with a substantial amount of higher risk, and therefore we should not expect success to be as good as for low-risk patients. It would be interesting to see the level of success currently achieved for the low-risk patients in the series.

    Dr. Gary Onik is another well-known physician/researcher working with cryo surgery for prostate cancer. In 2008 he and colleagues published results for 48 men, half with intermediate- and high-risk cancer, who had a minimum of 2 years of follow-up and a mean follow-up of 4.5 years. The success level in that series was impressive to me, based on 94% of patients achieving stable PSAs and 100% achieving negative biopsies among the patients with regular follow-up biopsies.

  13. I am surprised no one is asking nor sharing what clinical studies for both focal and full HIFU have been performed in Japan, Australia, and parts of Europe where this procedure is used extensively.

  14. Dear Bob:

    If you search this site for HIFU using the search system, you will find commentaries on several articles dealing with the use of this form of treatment. Frankly, there are still very few really thorough research studies published on either topic. The most thorough appear to be those by Ahmed, Edmonds, and their colleagues in the UK.

  15. I see that — why? Something is missing here.

    Thanks Bob

  16. Bob:

    If you are asking why there are so few good studies, the answers appear to fall into two groups. In the first place, the manufacturers of HIFU equipment have done a very poor job of convincing the respected urologic research community to carry out high quality clinical trials using this technology (in my opinion). Second, the small number of urologists who have treated large numbers of patients with HIFU (such as Dr. Scionti, who has now supposedly treatment > 1,000 patients) have not published any data on their work. I have no idea why, but we saw the same thing happen with the early work on proton beam therapy. By comparison, data from the early clinical use of brachytherapy and stereotactic body radiation therapy have been widely published.

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