5-year follow-up after focal therapy with HIFU for localized prostate cancer


A new paper from the Emberton-Ahmed group in the UK has reported 5-year follow-up data from a cohort of > 600 patients with clinically significant, localized prostate cancer, all treated with focal forms of high-intensity focused ultrasound (HIFU).

The entire text of this new paper by Guillaumier et al. is available on line in European Urology. There is also a write-up about this paper on the Cancer Therapy Advisor web site.

The paper reports data from a total of 625 consecutive patients, all treated at one of nine “secondary care” institutions in England between January 1, 2006, and December 31, 2015, and followed prospectively.

All patients were evaluated, prior to treatment, by the use of multiparametric MRI (mpMRI) scans together with targeted and systematic biopsies or transperineal mapping biopsies. To be eligible for evaluation, patients had to have been followed for a minimum of 6 months after initial treatment. Follow-up monitoring included the use of PSA testing, mpMRI scans, and additional biopsies as necessary.

Of the patients actually treated,

  • 599/625 (96 percent) met the criterion for 6 months of follow-up.
  • 505/599 (84 percent) met criteria for diagnosis with intermediate-risk (n = 316) or high-risk (n = 189) prostate cancer

Treatment was administered focally by either hemiablation or by wide area ablation to at least a quarter of the prostate for each patient (see Fig. 1 in the full text of the paper). All treatment was carried out using Sonablate 500 HIFU equipment. The primary endpoint for this study was failure-free survival (FFS), defined as freedom from any one of radical or systemic therapy, prostate cancer metastasis, or prostate cancer-specific death.

Patients could be given more that one HIFU treatment if necessary:

  • 504/625 patients (80.4 percent) received a single HIFU treatment.
  • 112/625 patients (17.9 percent) received one repeat HIFU treatment.
  • 9/625 patients (1.4 percent) received two repeat HIFU treatments.

Here are the basic results reported by Guillamier et al.:

  • Average (median) follow-up was 56 months (nearly 6 years).
  • The average (median) age of the patients was 65 years.
  • The average (median) pre-treatment PSA level of the patients was 7.2 ng/ml.
  • Failure-free survival levels were
    • 99 percent at 1 year of follow-up
    • 92 percent at 3 years of follow-up
    • 88 percent at 5 years of follow-up
  • For the entire patient cohort, at 5 years of follow-up,
    • Metastasis-free survival was 98 percent.
    • Prostate cancer-specific survival was 100 percent.
    • Overall survival was 99 percent
  • Among the patients who had a progression event on follow-up
    • 8 were give a subsequent radical prostatectomy
    • 36 were given salvage external beam radiation therapy
    • 1 was given androgen deprivation therapy (ADT)
  • No patients had any bleeding post-treatment that required intervention.
  • 53/625 patients (8.5 percent) had a urinary tract infection within 6 months of treatment.
  • 12/625 patients (1.9 percent were observed to have epidydymo-orchitis (an inflammation of the epididymis and/or the testicles) within 6 months of treatment.
  • 2 patients (0.3 percent) has recto-urethral fistulae

A total of 247 patients returned validated quality-of-life questionnaires at 2-3 years of follow-up, showing that

  • 241/247 men (98 percent) achieved pad-free urinary continence.
  • No patient required more than 1 pad per day.
  • 156/195 men (80 percent) reported that they were pad-free and leak-free at this time point.

Disappointingly, the study does not report any data on levels of erectile function over time.

The authors conclude that

Focal therapy for select patients with clinically significant nonmetastatic prostate cancer is effective in the medium term and has a low probability of side effects.

Now it does need to be noted that 5 years is still a relatively limited follow-up period for any type of treatment of localized prostate cancer, and we assume that these patients will continue to be followed until at least 10-year follow-up data are available.

On the other hand, this is by far the largest series of patients treated by focal HIFU to date, and the results are probably better than many of us might have initially expected.

In the very same issue of the same journal, there is another full text article, by van der Poel et al., entitled, “Focal therapy in primary localised prostate cancer: the European Association of Urology position in 2018”.

This article presents a much less enthusiastic review of the role of focal therapy (of any type) in the treatment of localized prostate cancer, stating explicitly that

… the available data regarding all forms of focal therapy are still poor and inconclusive. Consequently, due to both the lack of clear results associated with focal therapy and the difficulties in detecting all cancerous areas of the prostate, focal therapy should be considered an investigational modality only.</span

It should be noted that the data presented in the article by van der Poel et al. do not include the data presented by Guillaumier et al. in the first article referred to above.

The bottom line appears to be that the role of focal therapy (at least in Europe) remains a controversial one. Focal therapy advocates will certainly be disappointed by this. However, Edmonds, Ahmed, and their colleagues in the UK continue to produce most of the only really well documented studies on non-standard forms of treatment for localized prostate cancer. If some other groups were providing data on their patients with a similar level of quality, we might have a clearer picture by now as the the value of these types of therapy (focal types of HIFU specifically included).
 

7 Responses

  1. Combination of HIFU AND multiparametric MRI Used Here and Achieving Impressive Results for Focal Prostate Cancer Therapy

    What impressive results for these basically intermediate- and high-risk patients! Indeed, that stunning 88% failure-free survival average for all three risk categories at 5 years stands up even when risk-level is accounted for, with 88% of intermediate-risk patients hitting that same mark and even 84% of high-risk patients free from failure (Table 3)! (Naturally, the low-risk patients, a small proportion of study participants, had a super high success rate at 5 years.) The only subset not doing well was the 11 patients with Gleason scores of 8 or higher, 59% of whom were failure-free at 5 years. While patient selection plays a key role (mpMRI), this study suggests that at least one expert institution is able to achieve such successful selection, thereby reducing side effects, which means a real advance in improving the benefits-to-harms ratio.

    This also looks like a long-awaited breakthrough for focal therapy generally.

    It is really important for us to note that patients were very carefully selected in this clinical series. In September 2016, Dr. Emberton presented on focal therapy (basically) at the PCRI/Us TOO Conference on Prostate Cancer in Los Angeles. I was fascinated by Dr. Emberton’s explanation and illustration of mpMRI in assessing patients for eligibility for focal therapy. While these patients were mostly diagnosed with intermediate- and high-risk prostate cancer, many such patients were likely ruled out because of unfavorable anatomy, such as tumors at the edge of the prostate. Essentially, Dr. Emberton and colleagues are peeling off a subset of higher-risk patients whose mpMRI images indicate that, from a focal therapy viewpoint, the risk is substantially lower than for the average intermediate- and high-risk patient. This enables them to achieve excellent cancer control while also achieving excellent continence and other results, as noted above.

    (It is worth noting that Dr. Emberton gave up doing HIFU for the whole prostate gland around 2008.)

    Thanks for calling attention to this study!

  2. Dear Jim:

    Let me please just emphasize that these data do not come from “one expert institution”. They come from a group of nine different hospitals around England that have been involved in trials of HIFU for some time now, so that (as one might expect) the skill levels of the clinicians actually doing the itemized procedures and evaluating the available data have increased over time. Several of those hospitals are not what one describe as “tertiary care” centers associated with major academic research universities; they are just major “secondary care” level hospitals in a particular NHS region

  3. Thanks.

  4. Sitemaster:

    I would very much appreciate clarification of residual cancer after 5 years.

    For the Focal HIFU trial by Emberton, Ahmed, et al, I recall previous reporting of 37% residual cancer after 2 years on about 400 patients. I think I recall this analysis on your site. Am I correct?

    The 5-year follow-up from the study above does not report rates of residual cancer. Instead we read FFS results: “(FFS), defined as freedom from any one of radical or systemic therapy, prostate cancer metastasis, or prostate cancer-specific death.”

    So, let’s assume a patient initially had a Gleason score of 7 (3 + 4) and had focal HIFU; 5 years later he was still Gleason 7 (3 + 4) without mets/radical/systemic treatment, then the patient would be FFS.

    Is this correct? Thanks!

  5. Dear John:

    See this link for the relatively recent Emberton/Ahmed group’s data on 5-year survival after focal HIFU in treatment of (mostly) intermediate-risk prostate cancer.

    Their failure-free survival rates are given as:

    — 99 percent at 1 year of follow-up
    — 92 percent at 3 years of follow-up
    — 88 percent at 5 years of follow-up

    In other words, only 12% of these 625 patients had failed at 5 years of follow-up.

    However, I don’t think it is actually possible to accurately compare the data provided by the Ahmed/Emberton group with any degree of accuracy to the data provided by Meier et al. above for several reasons:

    — They were using different types of treatment (HIFU vs. SBRT), and the Emberton/Ahmed data used focal therapy whereas the Meier et al. group was using whole-gland therapy.
    — The precise definitions of “failure-free” seem to be slightly different between the two trials, since the men in the focal HIFU trial could have had as many as three cycles of HIFU, but it is only possible to give one “cycle” of SBRT.

    What I think we can say is that — based on these data — 88% or more of each patient cohort appears to have had very good outcomes at 5 years with relatively limited risk for complications and side effects … but there are some failures in each cohort and there are some significant complications and adverse events in each cohort too.

  6. Sitemaster: Thank you for your response. It depends on what “failed” means. I am not trying to nitpick, but of the 88% “successful” patients, a significant number may still have prostate cancer — it just has not been reported in the 5-year follow-up report.

    Please note the definition of FFS in the UK Focal HIFU study: “(FFS), defined as freedom from any one of radical or systemic therapy, prostate cancer metastasis, or prostate cancer-specific death.” So, FFS is not the same as “free from residual cancer”. I confirmed this at the recent PCRI meeting at the Sonablate booth. Robert Pugach, MD, Western States HIFU Medical Director confirmed that FFS is not the same as free from cancer. For example, if a patient had Gleason 7, then had focal HIFU, and still has Gleason 7 (without metastasis or radical or systemic treatment), then he is included in FFS. The previous report revealed 37% still had residual cancer after 24 months. The 5-year follow-up report does not reveal the percentage that still has residual cancer.

    What else is important? The UK study relied on a mapping biopsy to identify what needed to be ablated on 70% of the patients (avoiding the co-registration error that is inherent in MR-US Fusion guidance). Also, patients have not been uniformly biopsied post-procedure, so there is no definitive protocol for determining whether a patient is truly cancer-free. And patients were selected to not need a prior TURP.

    In summary, I conclude that the high FFS percentage is easily misunderstood as “free from cancer”. And I question whether the study’s outcomes are transferable to the US market where saturation/mapping biopsies are not the norm, and a TURP is needed on many patients.

  7. Dear John:

    The clear distinction between the precise meanings of such terms as failure-free survival (FFS), progression-free survival (PFS), and disease-free survival (DFS) is an important one. And anyone who is under the impression that these three categories of survival might mean the same thing has certainly misunderstood the relevant terminology.

    However, it is also important to appreciate that there are less evident distinctions between exactly how any one group of researchers might define each of these terms in a particular trial, depending on the nature of the trial, how patients were treated, and what can be measured before and afterward.

    I would also note that it is almost impossible to be able to measure disease-free survival with accuracy since we know that there are small numbers of prostate cancer patients who have been treated surgically — apparently entirely successfully — but then have recurrences as late as 25 years post-surgery. In other words, such patients show all the signs of disease-free survival for 20+ years and then recur despite the lack of a prostate. Clearly, such patients can’t have been entirely disease free after all. But prostate cancer can be a very slowly growing disease. They might have had only a couple of remaining prostate cancer cells somewhere in their body after surgery … and it might have taken 25 years for those cells to re-grow to the point that a rise in PSA levels became evident.

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