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High-intensity focused ultrasound (HIFU) in treatment of early stage (localized) prostate cance

Posted Sep 17 2008 1:51pm

Some Background

The theoretical application of high intensity focused ultrasound or HIFU as a means of treatment of solid tumors like prostate cancer dates back to work in France in the late 1980s and early 1990s. From that point of view, HIFU is hardly an “new” technique. And in fact, HIFU is approved for the treatment of prostate cancer in many different countries (although not yet in the USA).

Prototype HIFU equipment first became available under the trade name Ablatherm® from a French company known as EDAP in 1999. According to one of their web sites, over 15,000 patients have now been treated with HIFU for prostate cancer with their equipment at about 180 centers around the world (mostly in Europe).

A second company to enter the field was Focus Surgery, developer of the Sonablate500® HIFU system. And other companies are now starting to investigate the opportunity to use focused ultrasound in treatment of prostate cancer (e.g., InSightec ), but to date their technology is not (as far as we are aware) in development for the treatment of early stage disease.

The first important thing to understand from a patient viewpoint is that the technology that is being used for HIFU today is significantly improved by comparison with the technology of the mid to late 1990s (”prototype” technology) and even over the technology first approved in the late 1990s (”first-generation” technology). Most centers that are seriously committed to HIFU are now using what we would describe as “second generation” technology. However, “third-generation” technology will presumably start to come available in the near future, and perhaps such technology will further enhance the potential of HIFU.

The Basics

HIFU is a method of focusing ultrasound waves in the same way as a convex mirror can focus the sun’s rays to set light to a piece of paper. Thus, focused ultrasound rays can be directed to highly specific areas of the prostate and be used to kill the tissue on which they are focused by heating them to temperatures of 80 to 100 °C — way higher than normal body temperatures. To this extent one can think of HIFU as the precise reverse of cryotherapy: instead of freezing the prostate cancer to death, one cooks it to death!

What are the immediate theoretical benefits of a technique like this for the treatment of early stage prostate cancer?

  • In the first place, there is no invasive surgery. The beam of ultrasound rays is delivered transrectally into the prostate, through the rectal wall closest to the prostate.
  • Second, ultrasound is not an ionizing form of radiation (which radiotherapy is). Therefore tissue along the entry path and the exit path of the ultrasound beam is not normally significantly affected.
  • Third, it is a single treatment, like brachytherapy. One day — in and out (at least in theory).
  • Fourth, it is a repeatable treatment. In other words, if you discover that you have a rising PSA after the first round of treatment, you can go back and have a second treatment.

But (based on the data available to date) there are also appear to be some downsides:

  • 5-year biochemical response rates appear to be less robust than those for radical prostatectomy (RP), external beam radiotherapy (EBRT), and brachytherapy.
  • There is an unexpectedly high level of side effects reported in the few long-term data available to date.
  • In the USA, approval of HIFU will depend on its ability to offer at least the same level of clinical outcomes as cryotherapy (as opposed to RP, EBRT, or brachytherapy)

The last point leads one to suspect that the manufacturers may have already accepted that (at least with current technology), HIFU is not as effective as some others forms of treatment.

The Details

There are two articles available on line that offer technical details about how HIFU works, and we do not intend to cover such details on this web site. For those who are interested, please see the following articles or visit the manufacturers’ web sites (given above).

What we do want to be clear about are the long-term data that are available from European studies to date. However, “patient-friendly” this technology may seem, it will be hard to justify widespead use unless it can provide similar levels of outcome as the currently available forms of treatment or offer other benefits yet to be established.

As of May 22, 2008, only two sets of prospective data appear to be available that offer significant long-term information about the clinical outcomes from treatment with HIFU.

Blana et al. initially published the first long-term, multi-center data in  European Urology. Their article reviewed experience with 140 patients, all diagnosed with T1-2N0Mx disease and treated between October 1997 and August 2001. Critical information from this trial was as follows:

  • All patients had a PSA < 15 ng/mL, a Gleason score (GS) &le; 7, and were treated with prototypes or first-generation Ablatherm® equipment.
  • Treatment failure was defined as biochemical failure (based on the Phoenix criteria of nadir PSA + 2 ng/mL) or a positive biopsy post-treatment.
  • The mean age of the 140 patients was 69.1 years and the mean follow-up was 6.4 years.
  • Post-treatment control prostate biopsies were negative in 86.4 percent of patients.
  • A median PSA nadir of 0.16 ng/mL was achieved at an average of 4.9 months, and a nadir PSA &le; 0.5 ng/mL was recorded in 68.4 percent of patients.
  • The actuarial biochemical failure-free survival rates at 5 and 7 years were 77 and 69 percent, respectively.
  • The actuarial disease-free survival rates at 5 and 7 years were 66 and 59 percent, respectively.

Let us be clear: these 140 patients were among the very earliest patients treated with HIFU (using prototype or first-generation equipment) for localized prostate cancer. At the 2008 annual meeting of the American Urological Association, presentations by Murat et al. and Blana et al.  provided additional information from this same study. The data revisions on efficacy were minor, but the data on safety, presented by Blana et al. are clearly of importance:

  • At last evaluation (mean 6.4 years) 94.3 percent of patients were continent and 5.7 percent of patients had grade I or grade II incontinence.
  • Also at last evaluation, 46 percent of patients were potent and “capable of intercourse,” 14 percent were capable of partial erection but not capable of intercourse, and 21 percent were impotent. (No data were available for the remaining 19 percent of patients.)
  • Other common adverse reactions reported included urinary infections (10 patients, 7.1 percent); urinary tract obstruction (19 patients; 13.6 percent); and transient pelvic pain (8 patients; 5.7 percent).
  • There were no cases of recto-urethral fistual, no cases of grade III urinary incontinence, no blood transfusions, and no treatment-related deaths.

In conclusion, Blana stated that overall 94.3 percent of patients reported no need for pads to manage urinary incontinence; 46 percent of patients claimed sexual function; and there were no unexpected late complications.

The second study (by Conant et al.) offer the results of the first French prospective study of HIFU in previously untreated patients with a mean 5 years (62 months) of follow-up. Their outcomes are based on 117 patients from eight different centers and the authors claim that, “This early prospective study … has shown HIFU to be efficient in 62 percent of the patients, and safe.” However, the interpretation of the data provided does not necessarily support the conclusions stated (although in part this is clearly a “language issue”). Let us be clear about the actual results:

  •  The authors claim that their patients were followed up for “a minimum of 5 years.” However, from the poster it is clear that this was actually a mean follow-up of 5 years. Only 55/117 patients were actually followed for at least 5 years, and only 41 of those patients (75 percent) had no adjuvant treatment.
  • For the 117 patients there were 179 sessions of HIFU. In fact, 61/117 patients (52 percent) required  two sessions of HIFU.
  • Nine patients died post HIFU (although none died of prostate cancer).
  • Twenty-four patients failed and went on to have other forms of salvage therapy (13 received radiotherapy; 10 received hormone therapy; and one received salvage radical prostatectomy).

These data (from patients treated over a 12-month period between January 2001 and January 2002) are again from the earliest patients treated with HIFU, this time using “first-generation” (Ablatherm®) equipment.

The final paper that is worthy of attention at this time is a systematic literature review finalized in November 2007 by the Association Francaise d’Urologie, published in 2008, and addressing all available data on the management of prostate cancer with HIFU as of the annual meetings of the European Association for Urology and the American Urology Association in that year. The full text of this paper is available on line. We believe it is worth summarizing the conclusions of this review:

  • The ideal patient for HIFU is one over 70 years of age with clinical stage
    T1-2N0M0 prostate cancer, a Gleason score of < 7, a PSA level of > 15 ng/mL, and a prostate volume of < 40 mL, in particular if they refuse or are unsuitable for radical therapy.
  • In such patients, HIFU results in short-term cancer control, as shown by a high percentage of negative biopsies and substantially decreased PSA levels.
  • Median term disease-free survival data (with the Ablatherm device) seem promising.
  • With the continuous development of the Ablatherm device and the use of transurethral resection of the prostate (TURP) before HIFU, the rate of HIFU-related complications has decreased.
  • Recent studies show that HIFU is well tolerated, with a low rate of complications that compares favorably with those after established therapies.
  • Longer-term follow-up studies are needed to further evaluate cancer-specific and overall survival rates.
  • The efficacy and safety of HIFU as primary therapy should be further evaluated in randomized controlled trials comparing it with other (minimally invasive) therapies and watchful waiting. 

Some Conclusions

it would not be reasonable to expect the sorts of outcomes currently available from radical surgery, external beam radiotherapy, or brachytherapy with prototype and first-generation HIFU technology. However, we suspect that these results are actually somewhat disappointing for the advocates of HIFU as a first-line treatment for localized prostate cancer.

The “New” Prostate Cancer InfoLink believes that the summary information provided by the Association Francaise d’Urologie offers a fair assessment of the current situation, and this assessment would also appear to reflect some of the apparent concerns of the US Food & Drug Administration regarding approval of HIFU in the USA. Their questions appear to be clear: “Is this technology at least as good as cryotherapy? If it isn’t do we need it?”

The “New” Prostate Cancer InfoLink also suggests that US-based patients who are really interested in having HIFU consider enrolling in one of the current clinical trials of this technology. Patients in other countries where HIFU may already be available would be well advised to read the current French guidelines with care and weigh their options with equal care.

Patients should appreciate that this does not, nor does it intend to provide, a complete list of every possible risk associated with high intensity focused ultrasound. If you decide to work with a physician who intends to use this procedure, you should be sure to review these and other risks — infertility, infection, injury to other organs, pain, recurrence — with that surgeon prior to your operation, and you will certainly be asked to sign a relevant consent form prior to surgery.

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