Salvage HIFU as a treatment for radiorecurrent localized prostate cancer

Although there has been some exploratory work in this area, the available data on the outcomes of patients treated with high-intensity focused ultrasound (HIFU) as a form of salvage therapy for men with biochemical recurrence after first-line radiation therapy are extremely limited.

Treatment options are not great for men who have biochemical recurrence of their prostate cancer after almost any form of first-line radiation therapy (IMRT, PBRT, SBRT, brachytherapy, you name it). It is usually not possible (or at least difficult) to give further radiation therapy to such patients; the risk is high for complications associated with salvage surgery in such patients (even if one can find a surgeon with an appropriate level of experience); and cryotherapy has until recently been the only other option, but that can also be associated with significant side effects.

Ahmed et al., a while ago, suggested (based on their experience in about 80 patients) that this type of therapy was a high-risk procedure (see here). And the US Food & Drug Administration was not willing to approve HIFU as a salvage therapy for men who had progressive disease after first-line radiation therapy on the basis of the data presented to them.

We now have data from a paper by Crouzet et al. based on a registry study that includes > 400 patients with biochemical recurrence after external beam radiation therapy treated at nine different centers in Europe (all or mostly in France as far as we can tell) between 1995 and 2009. Our suspicion is that all of these patients were probably treated with relatively early forms of the Ablatherm HIFU technology, and so these data also raises questions about whether newer forms of HIFU technology (either Ablatherm or Sonocare Medical) might be able to offer superior results.

The data described in the paper by Crouzet and colleagues can be summarized as follows:

  • The study included 418 patients with an average age of 68.6 ± 5.8 years.
  • The patients’ average PSA level prior to salvage HIFU was 6.8 ± 7.8 ng/ml.
  • The average (mean) follow-up after salvage HIFU was 3.5 ± 2.5 years.
  • Actuarial outcomes after salvage HIFU in these patients were:
    • A 7-year overall survival rate of 72 percent
    • A 7-year prostate cancer-specific survival rate of 82 percent
    • A 7-year metastasis-free survival rate of 81 percent
  • Biochemical recurrence-free survival rates at 5 years were
    • 58 percent among men who were low risk at their original diagnosis
    • 51 percent among men who were intermediate risk at their original diagnosis
    • 36 percent among men who were high risk at their original diagnosis
    • 67 percent among men with a pre-salvage PSA level of ≤ 4 ng/ml
    • 42 percent among men with a pre-salvage PSA level of 4 to 10 ng/ml
    • 22 percent among men with a pre-salvage PSA level of > 10 ng/ml

With regard to complication rates, the authors state that these “decreased after the introduction of specific post-radiation treatment parameters”:

  • From 32 percent to 19 percent for grade 2 and grade 3 incontinence
  • From 30 percent to 15 percent for bladder outlet obstruction and stenosis
  • From 9 percent to 0.6 percent for urethro-rectal fistula

What the authors mean by “specific post-radiation treatment parameters” is presumably explained in the full text of the paper, but we take this to mean that improvements in technique and patient selection over time reduced the risk for these complications and side effects (but risk for post-treatment incontinence, bladder outlet obstruction, and stenosis appear to have remained significant even after these improvements in technique and patient selection).

Crouzet et al. conclude that:

  • Salvage HIFU in men with biochemically recurrent prostate cancer after the failure of external beam radiation therapy as a first-line treatment is associated with 7-year prostate cancer-specific and metastasis-free survival rates of > 80 percent.
  • Such outcomes come “at a price of significant morbidity”.
  • Salvage HIFU should be initiated early after EBRT failure (if salvage HIFU is considered to be a valid form of therapy).

These data, once again, raise real questions about the value of salvage HIFU in  men with radiorecurrent prostate cancer:

  • Does the early data like this (based on the use of outdated HIFU technology) justify the use of more modern form of HIFU as salvage therapy in such patients?
  • When might we be able to see comparable data from the use of modern forms of HIFU technology as a salvage therapy in comparable patients?

There is no doubt that we need improved forms of salvage therapy for the treatment of men with radiorecurrent prostate cancer, but a compelling case for the use of such therapy is going to require better data than anything we have seen to date (in terms of both outcomes and complication rates), and ideally we need data from some form of trial that compares some form of modern salvage HIFU to modern forms of salvage cryotherapy if we are really going to appreciate whether one technique is any better than the other.

6 Responses

  1. I know that we have fewer studies of salvage treatment after radiotherapy than salvage treatment after radical prostatectomy. However, the problems for the two situations have much in common. I surmise that we have good studies that argue for start of salvage radiotherapy after radical prostatectomy where PSA has increased from unmeasurable to 0.1 ng/ml. Risk of a secondary biochemical recurrence is down in 10% for this group.

    For patients with biochemical recurrence after radiotherapy the criterion is PSA of 2 ng/ml above nadir PSA. Nadir PSA may be as low as 1 ng/ml, but very few patients with salvage treatment after radiotherapy start salvage radiotherapy at PSA levels below 3 ng/ml.

    I have not read the paper on HIFU but I believe that a study with many hundreds of patients might be able to analyse whether outcome was better for those with an early start at PSA of 3-5 compared with the same treatment at the same units where treatment was delayed for a starting PSA > 5 ng/ml.

  2. Dear Finn:

    There are hundreds of papers published about how and when to initiate salvage radiotherapy after first-line radical prostatectomy, and most really good surgeons will now recommend a consult with a radiation oncologist when the PSA starts to rise above PSA levels as low as 0.03 ng/ml.

    The situation with salvage therapy after first-line radiation therapy radiation therapy is very different for the simple reasons that: (a) men who received first line radiation therapy (at least until comparatively recently) tended to be older or to have had more advanced disease at the time of diagnosis and (b) the options for salvage therapy came (and still do come) with high risk for complications and side effects. In fact, it has long been customary for men to go straight to androgen deprivation therapy (ADT) as standard “salvage” treatment for radiorecurrent prosatate cancer. The question therefore has always been how early to initiate ADT as salvage therapy in such cases (based primarily on patients’ PSA doubling times).

  3. I am wondering how these researchers determined that the recurrence was really localized. Did patients have to have a positive TRUS-guided biopsy? That would seem to exclude the majority of patients who have rising PSA after primary radiation therapy.

  4. Dear Tom:

    It is impossible to make any type of absolute guarantee that any patient has localized prostate cancer. However, the baseline data for the patients in this study would suggest strongly that the vast majority did indeed (a) have localized prostate cancer at initial diagnosis and (b) that they had local recurrence.

  5. My thought was: If the patient didn’t have a positive TRUS biopsy after his radiation treatment, how would they have anything at which to target the HIFU?

  6. Dear Tom:

    We are having this conversation in a vacuum. I have only seen the abstract of this paper. If you were to read the full text of the paper, it probably answers several of the questions you are asking. You could probably get a copy of the full text if you were to e-mail Dr. Crouzet and ask him nicely for a PDF copy of the full text. There are all sorts of ways they might have tried to determine the areas they wished to treat, starting, as you note, with biopsies, but also by using MRI scans and other forms of scan. Alternatively, all patients may simply have received wide field HIFU to the prostate and the prostate bed. Since this study is based on a retrospective analysis of data from several centers, my bet is that slightly different decision parameters may have been used at the different centers.

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