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An FDA panel on Thursday endorsed a cryoablation system as an alternative to surgery for some early breast cancer patients.

By a 9-5 vote, the agreed the benefits of the ProSense cryoablation system in combination with adjuvant endocrine therapy outweigh the risks in early-stage, low-risk breast cancer.

"The benefit-risk profile is acceptable," said Kelly Hunt, MD, of the University of Texas MD Anderson Cancer Center in Houston.

In explaining her vote in support of the minimally invasive device, which destroys tumors by freezing them, Deborah Armstrong, MD, of Johns Hopkins Kimmel Cancer Center in Baltimore, said she came down on the side of "not letting the perfect, or the ideal, be the enemy of the good."

While the panel recognized that patients and their doctors are looking for an effective, less-invasive option to surgery, members still expressed concerns that the supporting evidence lacked certainty regarding recurrence rates and that the proposed indication from sponsor IceCure Medical may be too broad -- specifically, that eligible patients would include those as young as 60 years, whose cancers could be more aggressive.

"I'm not convinced there is sufficient safety data for a 61-year-old who may have a life expectancy of 28 years to consider this procedure as an alternative to a standard lumpectomy," said Harold Burstein, MD, PhD, of the Dana-Farber Cancer Institute and Brigham and Women's Hospital in Boston, who voted against the device, though he also said he might have voted "maybe" if that was an option.

"What we need to do is define low-risk breast cancer because that's where it's just all over the map," said Hunt. "Giving clinicians very specific data on what is low risk, and whether that includes genomic data or not, that to me is an important factor in the overall risk-benefit of this, in lieu of lumpectomy."

Primary support for the cryoablation system came from the ICE3, a single-arm trial involving more than 200 patients with early-stage breast cancer treated with the device instead of lumpectomy.

In data presented by IceCure, the 5-year rate of ipsilateral breast tumor recurrence (IBTR) was 4.3%, and the trial met statistical criteria for positivity. However, FDA analyses including some with patients excluded by the study's data safety monitoring board calculated IBTR rates of 6.2% (95% CI 3.2-11.7) to 8.7% (95% CI 5.2-14.5).

For the indicated population, the FDA's assessed IBTR rate was 2.3% (95% CI 0.6-9.0) based on the 120 patients who also received adjuvant endocrine therapy in ICE3.

"I'm still not sure whether the actuarial risk of recurrence with this procedure is close to 10% at 5 years from the intent-to-treat analysis, or more like 2% to 3%," said Burstein. "We've all sat down at moments with patients and said here are the tradeoffs -- there is an x% risk with this and a y% risk for that, and you can make an informed choice."

Murad Alam, MD, of Northwestern University in Chicago, questioned why the sponsor chose to conduct a small nonrandomized study in a population where the risk of recurrence is so low, and without consultation with FDA. "There's no way to tell -- as far as I can see -- that [ProSense] is comparable to the prevailing standard of care," said Alam. "I think that's what some of us are struggling with in trying to compare this to the historical data."

"If we could go back a decade we would have consulted the FDA -- that would have been a smart thing to do," said ICE3 investigator Richard Fine, MD, of the West Cancer Center and Research Institute in Germantown, Tennessee. "The volume of data that exists on the gold standard in terms of ipsilateral breast tumor recurrence -- that data has tens of thousands of patients and we felt like that would be a good historical comparator."

"We have a lot of information on the control side," agreed panelist Toan Nguyen, MD, of Westchester Medical Center in Valhalla, New York. "There is numerous data out there, and whether [the recurrence rates are] 2%, 4%, or 6%, that's the range and I'm not sure what a control arm would add."

Several panel members suggested it would be extremely difficult to conduct a randomized trial involving the ProSense device considering it is already in use. The cryoablation system has received clearance in the U.S. for general minimally invasive cryoablation applications, including kidney, liver, and benign breast tumors, and is offered at several U.S. centers. It is approved for treating malignant breast tumors in Europe, China, and other countries.

"To do a randomized trial when the experimental arm is out there and available is what is the difficulty," said Armstrong, adding that patients are unlikely to participate in such a trial unless they were going to be treated with the ProSense device. "I think that we all agree that the ideal would have been a randomized trial, but I think it's not really feasible because the treatment is available."

While the FDA is not required to follow the advice of its advisory committees, it typically does.

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