Similar long-term outcomes after treatment with HIFU or LDR brachytherapy

The chances that we will ever see a large, randomized, comparative trial of high-intensity focused ultrasound (HIFU) and low-dose-rate (LDR) brachytherapy in the treatment of localized prostate cancer are near to zero. But we do have some new comparative data that are, at least, suggestive of what happens in the “real world”.

A new paper by Aoun et al., which is available as a full-text article on line in Advances in Urology, provides data from a “matched pair” analysis of the outcomes of 212 men who were treated at one or other of two academic medical centers in Belgium between September 2001 and December 2012. All 212 patients received whole gland primary therapy with curative intent for organ-confined prostate cancer; had a PSA level of < 20  ng/ml; had a Gleason score of  ≤ 3 + 4 = 7; had clinical stage T1-2N0M0 disease; and had a follow-up of > 12 months. All HIFU patients were treated by a single surgeon using Ablatherm technology. All LDR brachytherapy patients were treated by the same radiation oncologist and radiation physicist with the support of one or other of two surgeons.

In this “matched pair” analysis, each of the 106 patients treated by LDR brachytherapy was matched 1 : 1 with a patient who received whole gland HIFU in the same year. The matching procedure was blinded to the outcome to avoid selection bias, and the matching criteria, in order of priority, were: Gleason score, PSA level, clinical tumor stage, D’Amico risk, and age.

Now a matched pair analysis is not the same as a randomized clinical trial, and so one has to interpret the results with a level of caution, but here is a summary what the authors state that they found:

  • LDR brachytherapy was associated with fewer incontinence problems and less frequent acute urinary retention than HIFU (p < 0.05).
  • Median oncologic follow-up was 83 months (range, 13 to 123 months) in the HIFU cohort and 44 months (13 to 89 months) in the LDR brachytherapy cohort.
  • Median time to PSA nadir was significantly shorter in the HIFU cohort than in the LDR brachytherapy cohort.
  • The rate of biochemical recurrence-free survival was significantly higher in the LDR brachytherapy cohort compared to the HIFU cohort (68.5 vs 53 percent, p < 0.05).
  • There were no statistically significant differences between the two groups with respect to metastasis-free, cancer-specific, or overall survival.

The authors conclude that HIFU and brachytherapy are both safe and minimally invasive options for the treatment of organ-confined prostate cancer that have different short-term complications but similar long-term functional outcomes. They state that their data suggest similar 5-year metastasis-free, cancer-specific, and overall survival rates for these two different types of treatment.

Now it should be noted that, in the time period from 2001 to 2006 the form of HIFU being used was a “first-generation” form of Albetherm HIFU which was later superceded by more sophisticated technology, but it is equally true that there have been improvements in techniques for planning and implantation of brachytherapy seeds over a similar time period.

What is interesting from a “real world” perspective is that Aoun et al. are basically telling us that, at least at their institutions, there was no real difference in long-term outcome between the men treated by HIFU and the men treated by LDR brachytherapy — but there were some differences in the short-term side effects. However, most of these differences were seen in association with the use of the first-generation HIFU technology.

Among the 43 patients treated by HIFU who were potent pre-treatment

  • 5/43 (11.6 percent) had documented erectile dysfunction post-treatment
  • 27/43 (62.8 percent) had erections satisfactory for sexual intercourse with or without pharmacotherapy.

Unfortunately, however, there is no data available on the impact of LDR brachytherapy on erectile function in men who were potent pre-treatment, so we are unable to determine whether HIFU had a significant advantage with respect to erectile/sexual function post-treatment.

So there are two ways to look at these data depending on one’s perspective:

  • Either, HIFU is just as good as LDR brachytherapy for the treatment of localized prostate cancer.
  • Or, LDR brachytherapy is just as good as HIFU for the treatment of localized prostate cancer.

We really would need a large, well-designed, randomized trial to sort that question out … and, as indicated above, the chance that such a trial will ever be implemented is very small indeed.

11 Responses

  1. My conclusion would be to get neither therapy at that institution. Naturally, the metastases and mortality rates are low and similar with only 5 years of follow up on favorable-risk patients. The HIFU recurrence rates were significantly lower (almost half had biochemical recurrence!) than for their LDR brachytherapy, and their LDR brachytherapy outcomes were unusually poor for favorable-risk patients. (A third had biochemical recurrence.) I have always contended that the only doctors who get superior outcomes from LDR brachytherapy are the ones with a great deal of experience — the learning curve seems to be quite steep.

    LDR brachytherapy is infamous for its acute urinary side effects, yet HIFU was significantly worse on almost all those dimensions. Especially troubling was that over a quarter of the men getting HIFU had long-term urinary strictures, for which many (1 in 5) required surgical intervention.

    It is beyond me how the authors can conclude whole-gland HIFU was “safe”, or that the functional or oncological outcomes were similar.

  2. Allen:

    That was the whole point about “the real world.” Belgium is not a large country. If you lived there you might not have a lot of choice.

  3. Really Strange Stark Difference in Follow-Up Periods (83 vs. 44 months)

    While the two comments posted are spot on, the difference in median follow-up times (83 months for HIFU vs. 44 months for brachy) is great and perplexing for a study in which, per text in the study as also reported by Sitemaster, “Patients treated by brachytherapy were matched 1 : 1 with patients undergoing whole gland HIFU in the same years.” How can follow-up possibly be so different under that protocol? The great difference makes no sense. I suspect an error in the paper as the various graphs in the paper appear to reflect similar follow-up of roughly 80 months depending on the patient/treatment group and the outcome being reported.

  4. Dear Jim:

    The follow-up periods given are correct as medians. This is the real world. It wasn’t a trial with a protocol.

  5. Still Trying to Understand the Difference in Follow-up

    Yes, using the word “protocol” was nagging at my mind even before reading your comment. Thanks. I should have used “method” or “procedure”. But I did understand that the follow-up results were medians, and I’m still trying to figure out how you could get so great a difference – 83-44=39 months, which is more than 3 years.

    It seems the difference should be small. As you match patients in the same year, the greatest difference at the outset would be rounded to 12 months (picking one patient in early January and one in late December; however, unless there is a systemic gap in matching (such as perhaps due to selection of the first patient always from one of the two hospitals with a subsequent match from the other hospital after a lag for record search and matching of case characteristics), one would think the differences would average out to a small net difference for all matched patients.

    If so, then the remaining large difference in the medians could be due to just two factors: death, and loss of follow-up with patients (at which point the follow-up time would be “censored” – as reflected by a “+” sign in the graph for such censored patients. Right?

    Apparently overall survival was roughly similar (97.5% for brachytherapy and 88% for HIFU per “overall survival rates in Table 3 in the study), and in favor of brachytherapy, so that would not account for shorter follow-up for HIFU. So if a big difference in survival does not account for the big difference in follow-up, that leaves just a big difference in loss of follow-up with patients as the answer, which seems possible but unlikely. Figures 1 and 2 in the study have some numbers, perhaps for “patients-at-risk”, at the bottom of the graphs, but I’ll acknowledge I’m not strong on interpreting those figures. They may hold the answer. Or perhaps I’m missing something else here.

  6. Dear Jim:

    As you sometimes do, you are vastly over-analyzing these data. There is a much simpler explanation, which is that most of the patients getting one form of therapy did so over a much shorter time frame and were followed for a shorter period.

    As I stated very clearly at the beginning of the commentary above, at best these data are “suggestive” of what goes on in the real world.

  7. Regarding your response of 9:45 am, if your explanation is the right one for this planned, prospective study, I am disappointed in the research team. If I were on a panel reviewing proposals and such a method were specified (shorter follow-up for one of the arms, especially just 44 months as a median, which is well short of 4 years), I would recommend against funding the study.

    My own hunch is that the study was led by researchers at the HIFU hospital and that the hospital doing the brachy was either not as enthusiastic or their enthusiasm for the study lagged for some period during follow-up, resulting in the loss of contact with patients. However, the list of authors leads to the opposite explanation, with most of the authors, including the first and last, from the institution doing the brachytherapy. I remain puzzled. I also remain committed to analysis.

  8. Dear Jim:

    Who ever said anything about this being a “planned, prospective study”? It wasn’t. It was a planned retrospective study based on data collected prospectively from the patients who were treated with the two forms of therapy — which is a completely different animal.

  9. Regarding the planning of the study and another thought on analysis –

    I find the authors’ wording confusing, don’t you? The first three sentences in the Methods and Materials section reads as follows: “Patients scheduled to undergo brachytherapy or HIFU for organ confined prostate cancer in our two academic hospitals were prospectively enrolled between September 2001 and December 2012. Pooled prospectively collected data were retrospectively analyzed. Institutional review board approval was obtained from the two centers.”

    Regarding “retrospectively analyzed,” how else do you analyze data other than retrospectively? If they are able to “prospectively” analyze data, they are really good! Perhaps the word “retrospectively” was added by the translator rather than by the authors. They do speak of “prospective enrollment” and “institutional review board approval”, both of which make this sound like a prospective trial.

    Realizing that the researchers are all Belgian, perhaps they would appreciate our observation of seeming inconsistencies, particularly the differences in follow-up times, as their legendary detective was so fond of using the “little grey cells,” n’est-ce pas?

  10. Dear Jim:

    I am sorry but this all seems perfectly clear to me. And while the author’s English may not be quite perfect, I don’t think either you or I are in a position to be critical (unless of course your mastery of Flemish and/or Walloon — the two languages spoken in Belgium — is near perfect).

  11. My knowledge of Belgian language is limited to what I’ve learned from Mr. Poirot, and I suspect that is mostly French, interpreted by Mrs. Christie for us English speakers who know no better, mon ami.

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