Three generations of Sonablate HIFU equipment … the data from Japan


Over the weekend, one of our regular commentators brought to our attention a newly published, retrospective analysis of data on the risks and benefits of treatment of localized prostate cancer with three successive generations of high-intensity focused ultrasound (HIFU) equipment from the company now known as Sonocare Medical.

This new paper by Uchida et al. is long and complex. Unfortunately it is only going to be the abstract of the paper that is available to the majority of our readers, and so we have tried to boil down some of the extensive data in this paper — having had the opportunity to read the entire text. However, this is still going to be a long post to read.

Uchida and his colleagues are highly experienced users of the Sonablate HIFU technology in the management of localized prostate cancer. Their experience dates back to 1999 and the current paper reviews results from 918 patients treated between 1999 and 2012, all of whom were followed for at least 2 years after first-line therapy.

The patients treated are categorized into three groups based on the generational improvements of the Sonablate equipment over time:

  • Group A: 408 patients treated between 1999 and 2006 with “early” forms of Sonablate 200 and Sonablate 500 technology
  • Group B: 239 patients treated between 2005 and 2009 with version 4 Sonablate 500 technology
  • Group C: 271 patients treated between 2007 and 2012 with Sonablate TCM technology

This is, by far, the largest number of patients treated using the Sonablate HIFU technology on which data has been made available to date. What is more, all of these patients were being treated under an investigational protocol, with full disclosure of the risks associated with treatment, and prior informed consent on the part of the patients. However, …

It needs to be made very clear up front that 540/918 patients in this cohort (58.8 percent) had received neoadjuvant androgen deprivation therapy (ADT) of some type for an average (median) of 3 months before they ever arrived at Dr. Uchida’s clinic in Tokyo, and this single fact complicates the interpretation of the available data because it clearly means that > 50 percent of the patients were actually treated with neoadjuvant ADT + HIFU and not with HIFU alone. We should also note that 137/918 patients (14.9 percent) were given a TURP 1 month prior to HIFU (“to diminish prostate volume or remove large prostatic calcifications”).

So … let’s look at the outcome data reported by Uchida et al., broken down whenever possible by type of Sonablate technology being used.

  • Number of HIFU sessions required for treatment:
    • 154/408 patients (37.7 percent) in Group A had more than one session (with 33 patients receiving three, four or five sessions)
    • 51/239 patients (21.3 percent in Group B had more than one session (with 5 patients receiving three sessions)
    • 13/271 patients (4.8 percent) in Group C had more than one session (with just 1 patient receiving three sessions)
  • The results of post-HIFU biopsies were as follows:
    • 758/918 patients actually received a post-HIFU biopsy.
    • 296/367 patients (80.6 percent) in Group A had a negative post-HIFU biopsy.
    • 182/195 patients (93.3 percent) in Group B had a negative post-HIFU biopsy.
    • 184/196 patients (93.9 percent) in Group C had a negative post-HIFU biopsy.
  • The biochemical progression-free survival (bPFS) data were as follows when broken down by treatment group:
    • 48.3 percent for patients in Group A at 5 years
    • 38.4 percent for patients in Group A at 10 years
    • 62.3 percent for patients in Group B at 5 years
    • 82.0 percent for patients in Group C at 5 years
  • bPFS data were as follows when broken down by D’Amico risk group:
    • 63.2 percent for all low-risk patients at 10 years
    • 51.5 percent for all intermediate-risk patients at 10 years
    • 32.1 percent for all high-risk patients at 10 years
    • 95.0 percent for low-risk patients in Group C at 5 years
    • 80.9 percent for intermediate-risk patients in Group C at 5 years
    • 71.9 percent for high-risk patients in Group C at 5 years
  • Salvage therapy data (for 254 patients who clearly failed HIFU) were as follows:
    • 10/254 patients (3.9 percent) received a radical prostatectomy.
    • 75/254 patients (29.5 percent) received radiation therapy.
    • 169/254 patients (66.5 percent) received ADT.
    • 154/408 patients (37.7 percent) in Group A required salvage therapy.
    • 74/239 patients (30.9 percent) in Group B required salvage therapy.
    • 26/271 patients (9.6 percent) in Group C required salvage therapy
  • Overall survival at 10 years of follow-up for all patients in the cohort was 88.6 percent.
  • Prostate cancer-specific survival at 10 years of follow-up for all patients in the cohort was 97.4 percent.
  • With respect to complications and side effects of treatment:
    • 181/918 patients (19.7 percent) had a urethral stricture after a first HIFU session.
    • 52/263 patients (19.5 percent) had a urethral stricture after a second HIFU session.
    • 57/918 patients (6.2 percent) had acute epididymitis (pain and swelling in the epididymis at the back of the testicles) after a first HIFU session.
    • 10 patients (3.8 percent) had acute epididymitis after repeat HIFU.
    • 21/918 patients (2.3 percent) had stress incontinence after a first HIFU session.
    • 5 patients (1.9 percent) had stress incontinence after repeat HIFU.
    • Erectile dysfunction was recognized among
      • 77/134 patients (57.5 percent) at 6 months of follow-up
      • 65/128 patients (50.8 percent) at 12 months of follow-up
      • 37/106 patients (34.9 percent) at 24 months of follow-up
    • Erectile dysfunction at each time period was not statistically different by treatment group.

So … what to make of all of these data?

First, The “New” Prostate Cancer InfoLink wants to be very clear that we thank Dr. Uchida and his collaborators for finally providing us with data on a large cohort of Sonablate patients followed for an extended period of time and carefully broken down by generation of the technology used.

Second, we have some very clear observations:

  • Sonablate HIFU (even using the most recent generational technology) is clearly associated with a very significant risk for erectile dysfunction at 6, 12, and 24 months post-treatment.
  • The Sonablate technology is associated with a significant (about 20 percent) risk for urethral stricture, regardless of generation of the technology.
  • It is regrettable that just 134/918 patients in this cohort (14.6 percent) were followed with regard to erectile function post-treatment; data from the entire cohort might have given us much better perspective on risk for ED.
  • The potential of HIFU (up to and including Sonablate TCM HIFU) in high-risk patients appears to be limited … although we do need to see data from the Group C patients at 10 years; the 10-year data from patients in Groups A and B are clearly not good.
  • Overall 5-year bPFS using the Sonablate TCM technology in low- and intermediate-risk patients appears to be notably higher than with earlier forms of Sonablate technology … but we still have no idea whether such data are significantly better than the outcomes that might be achieved with active surveillance (especially for the low-risk patients).

Third, we need to reiterate a major caveat that is important to the interpretation of all these data. More than half of these patients were, in fact, treated with neoadjuvant ADT + HIFU and not with HIFU alone. The extent to which this fact affects the interpretation of these data is impossible to ascertain at this time.

 

 

10 Responses

  1. Thank you for taking the considerable time to look past the polished surface. Hopefully the new MRI-guided HIFU trials will bear more fruit.

  2. This was an extraordinarily respectful, clear, and well-organized summary of an important dataset. Thank you!

  3. Thank you for the hard work in reviewing this data and for your thoughtful perspective and insights (as always and often!). I have also had access to the complete paper and will try to carry the baton forward.

    I have registered some thoughts about this paper in the previous article on HIFU, but here are some additional comments.

    BREAKTHROUGH STUDY FOR HIFU? Many of us were quite interested in HIFU a decade or so ago but lost enthusiasm when study after study at locations around the world reported comparatively rather low biochemical disease-free survival (bDFS, essentially keeping PSA down) compared to other therapies, particularly surgery and radiation. Previous published success rates for the Uchida team were among those disappointing results, until this study. Finally, though groups A and B — the older technologies — still register unimpressive results, the group C results do look competitive with well-done surgery and radiation, at least for low- and intermediate-risk patients, keeping in mind Sitemaster’s well-taken point about the likely success of active surveillance for low-risk patients.

    Moreover, the flatness of the bDFS line — the level of success — at 5 years for all three risk groups for group C is encouraging. In fact Figure 3 shows those PSA success lines are flat — no longer declining — through the last time point graphed for Group C, 78 months, or 6.5 years! In fact the line for the low-risk group goes flat for Group C at about 40 months, nearly 2 years earlier than the lines for intermediate- and higher-risk for Group C. In contrast, the much less encouraging lines for the three risk groups for the previous (Group B) technology don’t appear to flatten until around the 72- to 84-month points, and even the low-risk group for the earliest technology — Group A — is still declining at about the 11-year point (with just approximately 50% success at that point).

    COMPETITIVE HIFU SUCCESS IS APPARENTLY QUITE DEPENDENT ON THE EQUIPMENT OR HIFU PROTOCOL

    Therefore, this study clearly is not demonstrating generalized success for HIFU. Rather it appears to demonstrate clear inferiority of earlier HIFU technology/protocols to the latest Group C technology, and, especially in view of the long-term follow-up, clear inferiority of earlier HIFU technology to well-done radiation and surgery (even inferiority to not so well-done surgery and radiation). It was not clear to me from the complete paper whether the Group C equipment — SB 500 TCM — was accounting for the difference, or a change in the way physicians used the equipment (especially what might be less nerve sparing, based on a markedly higher ED rate for Group C), or a mix of both.

    The similar issue of “operator variability”, in other words, the skill and experience of the doctor, was raised a number of times at last week’s FDA hearing on Ablatherm HIFU. Dr. Eric Klein, a well-known expert urologist from the Cleveland Clinic, raised this issue a number of times. EDAP, the Ablatherm company (main competitor to Sonablate technology), took the position that skill and experience does not make much of a difference after brief training, company support as needed, and about just 10 treatment experiences. It is worth noting that the FDA advisory committee panel was not overly impressed by the success levels presented by EDAP for its technology. On the other hand, the data represented treatments given some years ago, and the latest generation of Ablatherm technology (assuming there is one) may be considerably better. However, there are no published studies that indicate such improvement.

    SUCCESS IN GROUP C IS ASSOCIATED WITH A MUCH HIGHER RATE OF ED AT 2 YEARS COMPARED TO GROUPS A AND B

    While erectile dysfunction at each follow-up period was not statistically different, as Sitemaster reported, I suspect that is due to the rather small numbers that seem to have been tracked out of the entire group (about 40 in Group A, about 35 in Group B, and about 61 in Group C if I’m interpreting Table 4 correctly). I’m a little puzzled by the presentation; why are those numbers so small compared to the totals in each group for this important side effect? That said, at 2 years the table shows 26 patients of 50 (52%) in Group C with ED compared to just 6 of 29 in Group A (20.7%), and 5 of 27 in Group B (18.5%), blending into 34.9% for all three groups. If those numbers, those small samples of the entire groups, should turn out to represent the very much larger overall Groups A, B and C, it indicates that the impressive success in Group C may be due at least in part to more aggressive treatment of the areas of the prostate near the nerves. That’s not a bad thing, but it would mean there was a higher “cost” in side effects to be paid for the substantially higher success in curing and controlling the cancer.

    HIFU technology allows doctors to spare nerves associated with erectile function by managing the temperature gradient created by the equipment. As described at last week’s FDA hearing, and as is well known with other technologies, the trade-off for nerve sparing is greater risk of cancer recurrence.

  4. Jim, is it not true that Sonablate requires more involvement by the surgeon (which quite a few people consider a plus) compared to Ablatherm, which has more automated features?

    Was surprised to find out that the FDA included some prostate cancer survivors, rather than just medical professionals. The panel actually voted against approval, correct?

  5. HIFU SUCCESS LIKELY NOT LIMITED TO JAPANESE POPULATION

    Men leading a Japanese lifestyle, particularly consuming a typical Japanese diet, have long been known to be far less at risk for lethal prostate cancer. In fact, one of the intriguing facts of research on diet and prostate cancer is that Japanese men who migrate to the US and adopt a Western diet increase their risk to a level that is typical in the US.

    It might be argued that the HIFU results in this latest Uchida team study — results comparable to well-done surgery and radiation in the US — are substantially due to the fact that the men in the study are Japanese, and particularly that they therefore are likely to be consuming a typical Japanese diet.

    Indeed, at the recent July 30 FDA hearing on EDAP (Ablatherm’s) HIFU approval application, some of the best of the evidence presented was from the Long Term Refined Cohort that overwhelmingly involved treatment by a prominent hospital in Lyon, France, the same location that is world-famous for its heart-healthy diet work, particularly the Mediterranean diet. It’s a reasonable question whether a substantial proportion of men in studies that are associated with diets considered beneficial against prostate cancer do well just because of their diets, at at least in part because of their diets.

    However, it strikes me that we have fairly decent comparison groups here for the impressive Sonablate 500 TCM technology; those groups are the A and B groups using earlier and much less effective generations of Sonablate technology, but using it on men from the same Japanese population. The strikingly better success of the Sonablate 500 TCM technology leads me to think the technology is mainly behind the improvement.

    (Regarding the quality of evidence at the July 30 hearing: the quality was poor, as noted in other articles and comments. Even the Long Term Refined Cohort group involved a heavy degree of patient selection that seriously would have compromised the generalizability of results. FDA slides 21-27, available on the FDA website for advisory committee materials, provide more detail.)

  6. Wolfram:

    FDA advisory panels almost invariably provide the opportunity for patients and other consumers to testify at such hearings, and most FDA advisory panel also include a consumer representative as a voting member of the panel. Yes, the panel very definitely voted against approval, but it is up to the FDA itself to make any final decisions.

  7. Hi Wolfram,

    I’m responding to your post, on August 14, 2014 at 11:57 am, which Sitemaster has already addressed in part.

    I’m curious about your mention that there may be greater physician involvement with Sonablate than Ablatherm HIFU, but I simply do not know. I’m at the early part of the learning curve for HIFU because study results prior to this paper have been so discouraging, leading me to think, prior to this paper, that the technology had not yet matured to the point that it could be competitive with established therapies or even that it had demonstrated minimal benefit to patients.

    If you have some knowledge about the differences, please share it. I’m trying to sort out why Sonablate 500 TCM in this latest Uchida study is so superior to other versions. The study notes that improvement is due to “technical, imaging, and technological advancements” (at the end of the Results section of the abstract), but it does not say a lot about those advancements. However, the TCM (tissue change monitor) is emphasized in the paper, and the “STACK”, is also mentioned in the discussion related to the improvement in biochemical disease-free survival (BDFS): “This improvement may be due to the STACK and TCM features, which can change the treatment region more accurately and allow power intensity control for maintaining appropriate temperature at each focus lesion even during treatment.”

    The authors give little other insight into the technology.

  8. POSTSCRIPT AND CORRECTION — RESPONSE TO WOLFRAM

    Hi again Wolfram.

    I’m claiming “publisher’s license,” kind of like “poetic license” except that it means you notice errors right after publishing something, which is embarrassing and inconvenient, rather than before. The Uchida team actually devotes several sentences and a reference footnote to the equipment. Here it is, from the “Materials and Methods” section, sub-topic “Devices”:

    “Many improvements have been made to the SB device to shorten the operation time and improve clinical outcomes.13 Briefly, the cycle time has been reduced from 16 sec to 6 sec per focus lesion. The focus volume has also enlarged from 2.0 x 2.0 x 10 mm (0.04 cc) to 3.0 x 3.0 x 12 mm (0.108 cc). SB devices incoporate additional safety features, including reflectivity measurements, stacking, and TCM systems.13 The stacking system can refine the treatment plan before or during the procedure. The TCM system quantifies tissue changes based on comparisons of radiofrequency ultrasound pulse-echo signals at each treatment site and monitors lesion temperatures by color changes.13

    Footnote reference 13 is as follows: Uchida t, Nakano M, Hongo S, et al. High-intensity focused ultrasound therapy for prostate cancer. Int J Urol 2012; 19:187. Here’s the link to the abstract.

    I have recently learned that the areas of the prostate that are heated up by each cycle are the “focus lesions.” I believe reflectivity measurements are used to detect undesirable movement by the patient during treatment.

  9. SURVIVORS (AND OTHERS) AT HEARINGS BY FDA ADVISORY COMMITTEES

    Wolfram,

    Sitemaster has already addressed this, but here’s a little more detail. The hearing announcements are published on the FDA’s website in advance, and you can view the hearing calendar by using the button for advisory committees and selecting the calendar. The announcements will normally give notice that members of the general public may give statements of limited duration at hearings, usually five or ten minutes, and the notices provide detail about how to make arrangements. Of course, members of the public may also attend as audience members who do not give any statement. The FDA will also project slides provided in advance by public speakers.

    At this hearing, statements were given by:

    — Dr. Anna E. Mazzucco, PhD, Harvard, representing the Cancer Prevention and Treatment Fund, who stressed the need for solid evidence for new treatments

    — Me, expressing skepticism based on EDAP’s evidence and some evidence from trials, coupled with my own experience and awareness of the extended length of metastasis-free survival for many patients

    — Dr. Pascal Rischman, MD, from France, Toulouse University Hospital, who favored HIFU and said his site was now moving from HIFU for low-risk patients to intermediate-risk patients as well. He claimed that erectile function was preserved in more than 90% of patients by using nerve-sparing techniques

    — Mr. Joseph Arbogast, a patient from western North Carolina, who strongly favored HIFU based on his own experience with a HIFU trial at Duke University

    — Dr. Jessica Foley, the Scientific Director for the Focused Ultrasound Foundation, who favored HIFU of course and emphasized the patient choice aspect, and

    — Mr. Jeremy Stiener (spelling?) who expressed gratitude for his HIFU treatment but mentioned his severe post-HIFU incontinence

    At the end of time for speakers who had requested time, the chairman asked if anyone else in the audience wanted to make a statement, but no one responded and he closed the session.

    Speaker remarks and all other remarks during the day will be published within a few months based on a court-reporter type of transcript.

  10. TRANSCRIPT OF FDA HEARING ON ABLATHERM HIFU APPLICATION NOW AVAILABLE

    The full 253-page transcript of the July 30, 2014 advisory committee hearing is now available.

    It was posted August 27, 2014. My own contribution is on pages 128-130, and I am happy to see that my words came out pretty much as I had intended them. For anyone still reading this thread, I will be happy to answer questions if there are any. I was reacting to earlier parts of the hearing, such as the map showing widespread acceptance of HIFU in developed countries, and what I said may not be clear without the context. While transcripts are excellent, in some ways they fall short of capturing the actual experience at these hearings.

    The transcript is searchable, so it is easy to move to specific speakers or sub-topics. Here’s one comment from Dr. Patrick Walsh (on page 243) just for kicks: “So I firmly believe that someday surgery will be supplanted by some other technique …” Of course the flip side of that is an implication that it has not yet been supplanted.

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