NEWS

High-Intensity Focused Ultrasound Makes Its Debut

Judith Randal

When an American living in France learned he had early-stage prostate cancer, he was advised that any of the classic treatments for it—radical prostatectomy, radiation, or watchful waiting—would be a reasonable choice for him. But at 68 years old and otherwise healthy, the thought of watchful waiting made him uneasy, and the considerable risk of life-altering changes the other options posed did, too. So when he heard about Ablatherm, a French system for prostate cancer treatment that reportedly had a lower side-effects profile than the surgery or radiation, he looked into it further and then put himself in the hands of a Paris physician experienced in its use.

Ablatherm uses a technique known as high-intensity focused ultrasound (HIFU). The method is still too new (less than a decade old) to tell how it will stack up against the more established alternatives, but reassuring to him was that it, unlike radiation and prostatectomy, can be repeated and that it does not preclude later use of standard approaches. Also a bonus was that it requires no incision.



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At the focal point of the high-intensity focused ultrasound beam, the sharp temperature increase creates a lesion that causes irreversible necrosis of the tissue. (Image courtesy of EDAP-Technomed)

 
HIFU destroys targeted tissues by heating them to temperatures approaching 80 to 85 °C. Because the HIFU device has both ultrasound imaging capability and computer guidance software, its sound wave beam can be focused with great precision with little or no impact on neighboring and intervening structures.

With the patient lying on his right side and under spinal or general anesthesia, the HIFU probe is placed in the rectum and advanced until it is parallel to the prostate. The surgeon uses the probe’s ultrasound imaging component to map the gland before switching on the probe’s firing head, which generates the HIFU beam. Each shot of HIFU is followed by a 5-second delay, during which the system’s computer slightly shifts the beam’s focal point. Repeated firings, therefore, can destroy the entire gland, provided that its back-to-front distance is not too great.

If the front portion of the gland cannot be reached, HIFU will miss any tumor that may be there. However, because the initial HIFU treatment reduces the size of the prostate, a repeat session can often finish the job. It is also possible to shrink the gland with a hormonal drug such as leuprolide before the initial session. In addition, a modification of the system’s firing head that extends the reach of the beam is under evaluation.

The Ablatherm system grew out of research begun in 1989 by Albert Gelet, M.D., of the Edouard Herriot Hospital in Lyon, France, and his colleagues in collaboration with INSERM, the French government’s National Institute for Health and Medical Research. In 1993, the Gelet team also began the first clinical trial of the system—a phase I/II study in 50 patients with localized prostate cancers who were not candidates for surgery.

Multicenter trials followed that led to the official award of a CE mark for the system in 1999 to EDAP-Technomed of Lyon, which sells the $500,000 system. This mark is the European Union’s equivalent to U.S. Food and Drug Administration approval in the United States. According to EDAP-Technomed’s medical director Annie-Claude Benichou, M.D., Ablatherm is commercially available wherever the CE mark is recognized.

U.S. Trial

Also in 1999, the FDA gave the firm permission to sponsor a U.S. trial of Ablatherm for localized recurrence after radiation therapy in patients who, because they had no evident metastatic disease, were theoretically curable. However, accrual at the participating hospitals—Georgetown University in Washington, D.C., Baylor College of Medicine in Houston, and the University of California at San Francisco—was so slow that the company suspended the trial last year.

Peter Scardino, M.D., of Memorial Sloan-Kettering Cancer Center, New York, was the trial’s monitor. He said he was impressed by the fact that the patients’ PSA levels typically fell dramatically after HIFU—and stayed that way—and that their subsequent biopsies were clean.

Baylor’s Brian Miles, M.D., one of the study’s principal investigators, further explained that in two-thirds of the trial’s 29 patients given HIFU, PSA levels became undetectable.

"You have to realize [that] these were patients who are exceptionally hard to treat—the kind you ordinarily try to salvage with radical prostatectomy and then have a 50% to 60% success rate only in those having a PSA level of less than 10 and a Gleason score less than or equal to seven," he said. (PSA is a measure of prostate-specific antigen in the blood; a Gleason score is a measure of prostate cancer stage.)

By contrast, he said, many of the men who responded to HIFU had a PSA reading in the 15 to 20 range and Gleason scores of eight or nine prior to treatment. Miles is optimistic that these patients will fare well. "Sure, we’ll need to have more patients to see whether this will really pan out," he said. "But I have to say it’s been very exciting so far."

Miles is scheduled to meet with officials at the National Cancer Institute to discuss the possibility of resuming enrollment of men into the U.S. Ablatherm trial who have failed radiation therapy and also opening the trial to newly diagnosed patients. Pending that, he has, at the patients’ request, sent three American patients with early-stage disease to Germany to be treated by Stefan Thuroff, M.D., of the Harlaching Krankenhaus (hospital) in Munich. "They did fine," he said. "Stefan has the world’s largest experience in the HIFU treatment of prostate cancer."

Thuroff has treated about 600 of the roughly 2,000 patients worldwide who had been treated with the Ablatherm device as of March 2002. In a phone interview, he said that about 80% of them were newly diagnosed patients and, because of advanced age and/or co-existing health problems, were not candidates for radical prostatectomy, which he regards—other things being equal—as the best treatment for localized disease.

Another 10% of Thuroff’s patients had primarily recurrent localized disease—some after prostatectomy, some after either external beam or brachytherapy (interstitial radiation with implants of radioactive seeds), and still others after hormonal treatment.

Also among them were some patients who at the time of diagnosis already had metastases. For them, Thuroff explained, the idea is to use HIFU as "adjuvant treatment to debulk the primary tumor mass." Although he concedes that the practice is controversial, he is confident that the meticulous database he is keeping will vindicate it over time.

Now and again, he also sees patients—typically those in their 50s—who would ordinarily be candidates for radical prostatectomy, but strongly resist the drastic surgery because of the incontinence and impotence that may accompany it. Provided that they understand that the operation would be a safer choice, Thuroff settles for partially destroying the gland with HIFU.

Other HIFU Systems

As all this suggests, European prostate cancer patients undergoing HIFU have been a far more diverse lot than the much smaller number of their counterparts in the United States. In Japan, a system called Sonablate, a competitor to Ablatherm, is approved for treating benign prostate enlargement and has had promising results in small trials there for early prostate cancer and localized tumor recurrence after radiation therapy.

A trial of the Sonablate system, sold by Focus Surgery of Indianapolis, Ind., for both of these cancer indications has started in Indianapolis at the University of Indiana and will start soon in Cleveland at Case Western Reserve University. A lot is riding on whether Ablatherm or Sonoblate wins the race for FDA approval and so gets first crack at the lucrative U.S. market, where prostate cancer is already a $50 billion-a-year enterprise and, given the aging of the baby boom generation, will only grow.

Many U.S urologists, meanwhile, are taking a wait-and-see attitude about how well HIFU will stack up against other treatments. As Alexis Te, M.D., director of the Brady Prostate Center at the Weill Cornell Cancer Center, New York, put it, "if you ask me whether it’s HIFU time for prostate cancer in this country, I have to say no," although he acknowledged that the therapy is still in its infancy.

"I think it has a lot of promise," he continued, "but I also think that it needs to go through appropriate studies in this country. In my experience, these are usually more rigorously conducted here than they are where—as in Europe—there tends to be such a mix of different types of patients in a given study that the true picture is hard to sort out."

Finally there is the matter of the procedure’s safety. In Europe, it is now routine to perform a transurethral resection (TUR) on patients before HIFU treatment because TUR has been found to prevent urinary retention caused by obstruction of the urethra with the necrotic tissue created by the heat of the ultrasound. Pretreatment with TUR seems not to lead to incontinence, but reversing the steps—i.e. doing the HIFU first—is more likely to.

In addition, certain protective features have been added to the Ablatherm equipment: continual cooling of the applicator, for instance, to minimize the chance of rectal burns, and sensors that stop the applicator in its tracks or correct its aim when they detect the slightest patient movement. Nonetheless, HIFU is very much a work in progress and further improvements are to be expected.



             
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