FDA panel recommends against approval of ultrasound therapy for early prostate cancer

GAITHERSBURG, MD. – A Food and Drug Administration advisory panel agreed that a device that thermally ablates the prostate gland using high-intensity focused ultrasound should not be approved for treating men with localized prostate cancer now, because of issues that included no proof of efficacy and a high rate of adverse events for a noninvasive treatment.

At a meeting on July 30, the FDA’s Gastroenterology and Urology Devices Panel voted 8-0, with one abstention, that the benefits of the high-intensity focused ultrasound (HIFU) therapy did not outweigh the risks for the proposed indication, the primary treatment of prostate cancer in subjects with low-risk, localized prostate cancer. Available in Europe for 15 years, the Ablatherm integrated imaging device is manufactured by EDAP TMS, a French company. The components of the computer-controlled device include a treatment module, a control console, and an endorectal probe that is inserted rectally, heating the target tissue to therapeutic levels, while the patient is under general or spinal anesthesia. The company describes HIFU therapy as a "minimally invasive treatment during which the Ablatherm device precisely focuses ablative energy on the prostate gland while avoiding damage to sensitive adjacent anatomy."

But in separate questions, the panel unanimously voted that there was not reasonable assurance that the device was effective for the proposed indication. The vote on the safety issue alone was mixed, with panelists voting 5-3, with one abstention, that there was not reasonable assurance that the device was safe for the indication.

The company had problems completing enrollment in the U.S. pivotal trial, which compared HIFU treatment to cryotherapy, and provided several other analyses, including comparisons of the results with data from a registry and other clinical trials. The FDA reviewers raised multiple issues with the data, and panelists agreed, citing issues with safety and efficacy, including the efficacy endpoint used in the pivotal trial.

"I don’t think the potential benefits outweigh the risk," said Dr. Eric Klein, chairman of the Glickman Urological and Kidney Institute, at the Cleveland Clinic. His negative vote on the efficacy question, he noted, "relates mostly to the fact that patients with low-risk prostate cancer are at low risk for progression andbeing harmed by their disease and there are other management strategies that have lower risk than this proposed therapy."

Dr. Patrick Walsh, professor of urology, Johns Hopkins University, Baltimore, said that "at the present time, I do not believe there’s any evidence that efficacy, which has not been proven, outweighs what I look at as significant side effects." Describing a noninvasive treatment that has a 41% rate of serious adverse events as safe was "excessive," he added. (In the pivotal study, the rate of severe adverse events was 41%.)

Another panelist, Dr. Marc Garnick, professor of medicine, Harvard Medical School, Boston, said that he appreciated the technologic advance that HIFU represents and acknowledged the difficulties involved in studying the treatment in the low-risk population. However, as a practicing physician who counsels many patients with early-stage, low-risk cancer trying to make a decision about primary therapy versus active surveillance, he said it "would be very, very difficult for me to make a recommendation for HIFU therapy if one takes a look at the metastasis-free survival and the cancer-specific survival in patients with low-risk features that basically don’t get any therapy and compared that to some of the vagaries of the safety considerations that they would be subjected to with HIFU."

The U.S. pivotal study was a nonrandomized, multicenter prospective study comparing HIFU to cryotherapy in patients with low-risk, localized prostate cancer (a prostate-specific antigen level of 10 ng/mL or less, clinical stage T1 to T2a cancer, and a Gleason score of 6 or less). But the study was not completed because of problems enrolling patents, and only 135 patients were enrolled in the HIFU arm and 5 in the cryotherapy arm, instead of 205 patients in each arm, as planned.

Among the 135 HIFU-treated patients, the primary endpoint, biochemical relapse-free survival (based on the Phoenix criteria for biochemical recurrence, the nadir PSA level plus 2.0 ng/mL) at 2 years was 90.5%, and the cumulative positive biopsy rate was 28%.

Other analyses provided by the manufacturer included a comparison of long-term follow-up data on a subgroup of 227 patients from a European registry of patients treated with Ablatherm HIFU, who met the criteria of those on the pivotal study, with outcomes among 148 patients with low-risk prostate cancer in the radical prostatectomy arm of the U.S. Veterans Affairs PIVOT (Prostate Cancer Intervention Versus Observation Trial). PIVOT investigators compared radical prostatectomy with observation among men with clinically localized prostate cancer; the trial was conducted between 1996 and 2002. Metastases were reported in 3 of the 227 HIFU-treated patients (1.3%) and in 6 of 148 (4.1%) of those in PIVOT. The cumulative risk at 8 years was similar in both groups, 1.1 % among those treated with HIFU and 1.4% among the low-risk PIVOT patients.

In the pivotal study, almost all of the patients (97%) treated with HIFU had an adverse event; 82% had a moderate or severe adverse event. Adverse events included erectile dysfunction in 67%, urinary retention in 49%, urinary incontinence in 39%, urinary stricture in 35%, urethral injury in 15%, and bowel dysfunction in 21%. Most of these adverse events resolved in most patients over time, but at 24 months, 44% of the treated patients still had erectile dysfunction.

The FDA reviewers said that it was unclear whether HIFU therapy provides a benefit for patients with low-risk prostate cancer, and said that they were concerned about the 28% positive biopsy rate in the pivotal trial. Based on the evidence provided, "we can conclude that a single whole-gland HIFU treatment session does not get rid of all the cancer within the prostate gland in a significant percentage of patients," said one of the FDA reviewers, Dr. Jonathan Jarow of the FDA’s office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research. The FDA has never approved a treatment for prostate cancer based on PSA results, he pointed out.

Panelists generally agreed that the biochemical survival rate at 2 years using the Phoenix criteria could not be used to show the treatment was effective for a nonradiation treatment in patients with low-risk prostate cancer, pointing out that the criteria had not been validated with this technology. Several panelists said that the device might be effective but that it was not possible to determine that with the available data.

In a statement issued by EDAP after the meeting concluded, Marc Oczachowski, the company’s chief executive officer, said that the company "will continue to work diligently with the FDA as it carefully completes its final review" of the Ablatherm HIFU application.

The device has been used to treat about 40,000 patients with low-risk disease worldwide, according to EDAP.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts.

[email protected]

GAITHERSBURG, MD. – A Food and Drug Administration advisory panel agreed that a device that thermally ablates the prostate gland using high-intensity focused ultrasound should not be approved for treating men with localized prostate cancer now, because of issues that included no proof of efficacy and a high rate of adverse events for a noninvasive treatment.

At a meeting on July 30, the FDA’s Gastroenterology and Urology Devices Panel voted 8-0, with one abstention, that the benefits of the high-intensity focused ultrasound (HIFU) therapy did not outweigh the risks for the proposed indication, the primary treatment of prostate cancer in subjects with low-risk, localized prostate cancer. Available in Europe for 15 years, the Ablatherm integrated imaging device is manufactured by EDAP TMS, a French company. The components of the computer-controlled device include a treatment module, a control console, and an endorectal probe that is inserted rectally, heating the target tissue to therapeutic levels, while the patient is under general or spinal anesthesia. The company describes HIFU therapy as a "minimally invasive treatment during which the Ablatherm device precisely focuses ablative energy on the prostate gland while avoiding damage to sensitive adjacent anatomy."

But in separate questions, the panel unanimously voted that there was not reasonable assurance that the device was effective for the proposed indication. The vote on the safety issue alone was mixed, with panelists voting 5-3, with one abstention, that there was not reasonable assurance that the device was safe for the indication.

The company had problems completing enrollment in the U.S. pivotal trial, which compared HIFU treatment to cryotherapy, and provided several other analyses, including comparisons of the results with data from a registry and other clinical trials. The FDA reviewers raised multiple issues with the data, and panelists agreed, citing issues with safety and efficacy, including the efficacy endpoint used in the pivotal trial.

"I don’t think the potential benefits outweigh the risk," said Dr. Eric Klein, chairman of the Glickman Urological and Kidney Institute, at the Cleveland Clinic. His negative vote on the efficacy question, he noted, "relates mostly to the fact that patients with low-risk prostate cancer are at low risk for progression andbeing harmed by their disease and there are other management strategies that have lower risk than this proposed therapy."

Dr. Patrick Walsh, professor of urology, Johns Hopkins University, Baltimore, said that "at the present time, I do not believe there’s any evidence that efficacy, which has not been proven, outweighs what I look at as significant side effects." Describing a noninvasive treatment that has a 41% rate of serious adverse events as safe was "excessive," he added. (In the pivotal study, the rate of severe adverse events was 41%.)

Another panelist, Dr. Marc Garnick, professor of medicine, Harvard Medical School, Boston, said that he appreciated the technologic advance that HIFU represents and acknowledged the difficulties involved in studying the treatment in the low-risk population. However, as a practicing physician who counsels many patients with early-stage, low-risk cancer trying to make a decision about primary therapy versus active surveillance, he said it "would be very, very difficult for me to make a recommendation for HIFU therapy if one takes a look at the metastasis-free survival and the cancer-specific survival in patients with low-risk features that basically don’t get any therapy and compared that to some of the vagaries of the safety considerations that they would be subjected to with HIFU."

The U.S. pivotal study was a nonrandomized, multicenter prospective study comparing HIFU to cryotherapy in patients with low-risk, localized prostate cancer (a prostate-specific antigen level of 10 ng/mL or less, clinical stage T1 to T2a cancer, and a Gleason score of 6 or less). But the study was not completed because of problems enrolling patents, and only 135 patients were enrolled in the HIFU arm and 5 in the cryotherapy arm, instead of 205 patients in each arm, as planned.

Among the 135 HIFU-treated patients, the primary endpoint, biochemical relapse-free survival (based on the Phoenix criteria for biochemical recurrence, the nadir PSA level plus 2.0 ng/mL) at 2 years was 90.5%, and the cumulative positive biopsy rate was 28%.

Other analyses provided by the manufacturer included a comparison of long-term follow-up data on a subgroup of 227 patients from a European registry of patients treated with Ablatherm HIFU, who met the criteria of those on the pivotal study, with outcomes among 148 patients with low-risk prostate cancer in the radical prostatectomy arm of the U.S. Veterans Affairs PIVOT (Prostate Cancer Intervention Versus Observation Trial). PIVOT investigators compared radical prostatectomy with observation among men with clinically localized prostate cancer; the trial was conducted between 1996 and 2002. Metastases were reported in 3 of the 227 HIFU-treated patients (1.3%) and in 6 of 148 (4.1%) of those in PIVOT. The cumulative risk at 8 years was similar in both groups, 1.1 % among those treated with HIFU and 1.4% among the low-risk PIVOT patients.

In the pivotal study, almost all of the patients (97%) treated with HIFU had an adverse event; 82% had a moderate or severe adverse event. Adverse events included erectile dysfunction in 67%, urinary retention in 49%, urinary incontinence in 39%, urinary stricture in 35%, urethral injury in 15%, and bowel dysfunction in 21%. Most of these adverse events resolved in most patients over time, but at 24 months, 44% of the treated patients still had erectile dysfunction.

The FDA reviewers said that it was unclear whether HIFU therapy provides a benefit for patients with low-risk prostate cancer, and said that they were concerned about the 28% positive biopsy rate in the pivotal trial. Based on the evidence provided, "we can conclude that a single whole-gland HIFU treatment session does not get rid of all the cancer within the prostate gland in a significant percentage of patients," said one of the FDA reviewers, Dr. Jonathan Jarow of the FDA’s office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research. The FDA has never approved a treatment for prostate cancer based on PSA results, he pointed out.

Panelists generally agreed that the biochemical survival rate at 2 years using the Phoenix criteria could not be used to show the treatment was effective for a nonradiation treatment in patients with low-risk prostate cancer, pointing out that the criteria had not been validated with this technology. Several panelists said that the device might be effective but that it was not possible to determine that with the available data.

In a statement issued by EDAP after the meeting concluded, Marc Oczachowski, the company’s chief executive officer, said that the company "will continue to work diligently with the FDA as it carefully completes its final review" of the Ablatherm HIFU application.

The device has been used to treat about 40,000 patients with low-risk disease worldwide, according to EDAP.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts.

[email protected]

GAITHERSBURG, MD. – A Food and Drug Administration advisory panel agreed that a device that thermally ablates the prostate gland using high-intensity focused ultrasound should not be approved for treating men with localized prostate cancer now, because of issues that included no proof of efficacy and a high rate of adverse events for a noninvasive treatment.

At a meeting on July 30, the FDA’s Gastroenterology and Urology Devices Panel voted 8-0, with one abstention, that the benefits of the high-intensity focused ultrasound (HIFU) therapy did not outweigh the risks for the proposed indication, the primary treatment of prostate cancer in subjects with low-risk, localized prostate cancer. Available in Europe for 15 years, the Ablatherm integrated imaging device is manufactured by EDAP TMS, a French company. The components of the computer-controlled device include a treatment module, a control console, and an endorectal probe that is inserted rectally, heating the target tissue to therapeutic levels, while the patient is under general or spinal anesthesia. The company describes HIFU therapy as a "minimally invasive treatment during which the Ablatherm device precisely focuses ablative energy on the prostate gland while avoiding damage to sensitive adjacent anatomy."

But in separate questions, the panel unanimously voted that there was not reasonable assurance that the device was effective for the proposed indication. The vote on the safety issue alone was mixed, with panelists voting 5-3, with one abstention, that there was not reasonable assurance that the device was safe for the indication.

The company had problems completing enrollment in the U.S. pivotal trial, which compared HIFU treatment to cryotherapy, and provided several other analyses, including comparisons of the results with data from a registry and other clinical trials. The FDA reviewers raised multiple issues with the data, and panelists agreed, citing issues with safety and efficacy, including the efficacy endpoint used in the pivotal trial.

"I don’t think the potential benefits outweigh the risk," said Dr. Eric Klein, chairman of the Glickman Urological and Kidney Institute, at the Cleveland Clinic. His negative vote on the efficacy question, he noted, "relates mostly to the fact that patients with low-risk prostate cancer are at low risk for progression andbeing harmed by their disease and there are other management strategies that have lower risk than this proposed therapy."

Dr. Patrick Walsh, professor of urology, Johns Hopkins University, Baltimore, said that "at the present time, I do not believe there’s any evidence that efficacy, which has not been proven, outweighs what I look at as significant side effects." Describing a noninvasive treatment that has a 41% rate of serious adverse events as safe was "excessive," he added. (In the pivotal study, the rate of severe adverse events was 41%.)

Another panelist, Dr. Marc Garnick, professor of medicine, Harvard Medical School, Boston, said that he appreciated the technologic advance that HIFU represents and acknowledged the difficulties involved in studying the treatment in the low-risk population. However, as a practicing physician who counsels many patients with early-stage, low-risk cancer trying to make a decision about primary therapy versus active surveillance, he said it "would be very, very difficult for me to make a recommendation for HIFU therapy if one takes a look at the metastasis-free survival and the cancer-specific survival in patients with low-risk features that basically don’t get any therapy and compared that to some of the vagaries of the safety considerations that they would be subjected to with HIFU."

The U.S. pivotal study was a nonrandomized, multicenter prospective study comparing HIFU to cryotherapy in patients with low-risk, localized prostate cancer (a prostate-specific antigen level of 10 ng/mL or less, clinical stage T1 to T2a cancer, and a Gleason score of 6 or less). But the study was not completed because of problems enrolling patents, and only 135 patients were enrolled in the HIFU arm and 5 in the cryotherapy arm, instead of 205 patients in each arm, as planned.

Among the 135 HIFU-treated patients, the primary endpoint, biochemical relapse-free survival (based on the Phoenix criteria for biochemical recurrence, the nadir PSA level plus 2.0 ng/mL) at 2 years was 90.5%, and the cumulative positive biopsy rate was 28%.

Other analyses provided by the manufacturer included a comparison of long-term follow-up data on a subgroup of 227 patients from a European registry of patients treated with Ablatherm HIFU, who met the criteria of those on the pivotal study, with outcomes among 148 patients with low-risk prostate cancer in the radical prostatectomy arm of the U.S. Veterans Affairs PIVOT (Prostate Cancer Intervention Versus Observation Trial). PIVOT investigators compared radical prostatectomy with observation among men with clinically localized prostate cancer; the trial was conducted between 1996 and 2002. Metastases were reported in 3 of the 227 HIFU-treated patients (1.3%) and in 6 of 148 (4.1%) of those in PIVOT. The cumulative risk at 8 years was similar in both groups, 1.1 % among those treated with HIFU and 1.4% among the low-risk PIVOT patients.

In the pivotal study, almost all of the patients (97%) treated with HIFU had an adverse event; 82% had a moderate or severe adverse event. Adverse events included erectile dysfunction in 67%, urinary retention in 49%, urinary incontinence in 39%, urinary stricture in 35%, urethral injury in 15%, and bowel dysfunction in 21%. Most of these adverse events resolved in most patients over time, but at 24 months, 44% of the treated patients still had erectile dysfunction.

The FDA reviewers said that it was unclear whether HIFU therapy provides a benefit for patients with low-risk prostate cancer, and said that they were concerned about the 28% positive biopsy rate in the pivotal trial. Based on the evidence provided, "we can conclude that a single whole-gland HIFU treatment session does not get rid of all the cancer within the prostate gland in a significant percentage of patients," said one of the FDA reviewers, Dr. Jonathan Jarow of the FDA’s office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research. The FDA has never approved a treatment for prostate cancer based on PSA results, he pointed out.

Panelists generally agreed that the biochemical survival rate at 2 years using the Phoenix criteria could not be used to show the treatment was effective for a nonradiation treatment in patients with low-risk prostate cancer, pointing out that the criteria had not been validated with this technology. Several panelists said that the device might be effective but that it was not possible to determine that with the available data.

In a statement issued by EDAP after the meeting concluded, Marc Oczachowski, the company’s chief executive officer, said that the company "will continue to work diligently with the FDA as it carefully completes its final review" of the Ablatherm HIFU application.

The device has been used to treat about 40,000 patients with low-risk disease worldwide, according to EDAP.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts.

[email protected]