Health

‘Missing Data’ on Prostate Test: Good Science or Marketing War?

Ten paragraphs into an article in STAT News about a scientific squabble involving a prostate cancer blood scan, I sat up straight in my recliner.

At that point, author Eric Boodman disclosed that the test in question was the Prostate Health Index, or phi. The story took on a sudden personal significance — for the three past years, I have been on phi to monitor my low-risk (Gleason 6) prostate cancer and determine whether I need a biopsy. My results have been great, but the debate could undermine one’s confidence in the test.

As a medical journalist, I have written my share of stories warning patients about risks and failings of various diagnostic tests and treatments. Now I was getting a taste of my own medicine. It’s not a pleasant experience.

Jeannine Holden, MD, medical director of Beckman Coulter, which makes the phi test, told me about the PSA: “Many patients with an elevated PSA don’t have cancer, and many patients [who] don’t have an elevated PSA do have cancer. So it’s almost a coin toss essentially.”

As a result, several companies have been in a race to develop new and improved tests to forecast how aggressive a prostate cancer is and whether patients need or can defer those disagreeable biopsies.

STAT‘s Boodman wrote a well-researched story on the case of the “missing data.” It was a pissing match between two groups of researchers. As a patient and a medical journalist, I followed the reporter’s work and managed to land some interviews he didn’t.

I am left uncertain which side is correct. For every researcher, it seemed there was an equal and opposite researcher.

Are you ready to rumble?

In one corner: six researchers from four major urology practices and six others from Beckman Coulter who published a study in Prostate Cancer and Prostatic Diseases last year involving about 1,000 men. About half of them had undergone the phi scan to help determine the need for a biopsy. The authors said the main point was that phi testing reduced the rate of biopsies in men in the PSA gray zone of 4-10 ng/mL and nonsuspicious digital rectal exams. In those tested with phi, 36% underwent biopsies versus 60% of the control group who hadn’t had phi tests. So it appeared that the phi test was sparing lots of men from unnecessary biopsies. That’s a big deal for the phi guys.

And in the other: Memorial Sloan Kettering Cancer Center (MSKCC) researchers Behfar Ehdaie, MD, a urologist, and Sigrid Carlsson, MD, PhD, an epidemiologist, who wrote a letter in 2018 raising some thorny questions about the phi paper. They did their own math and concluded that the phi study was missing vital data. They demanded that the authors release the missing numbers.

They said the phi test had a high-miss rate — one in three cases of high-risk prostate cancer.

The MSKCC authors urged the phi researchers to “justify recommending the routine use of a test with a 1-in-3 miss rate.” As a patient, that miss rate sounded alarming.

Stephen Freeland, MD, editor of Prostate Cancer and Prostatic Diseases, asked lead author Jay White, PhD, then an epidemiologist at Carolina Urology Partners in Huntersville, North Carolina, if he and his co-authors wanted to write a rebuttal.

Two did, White and Ronald Tutrone, MD, of Chesapeake Urology Associates in Towson, Maryland. They wrote in response that the investigators had enrolled men with PSAs in the range of 4-10 ng/mL and nonsuspicious DREs — the target of the phi test. They said they expected to find few patients with high-grade cancers. But they stressed that their study was not “powered” to answer questions about more aggressive cancers of Gleason 7 and above.

Mark Reynolds, PhD, Beckman Coulter’s global director of health economics and outcomes research and a co-author of the phi study, opted out of responding to the MSKCC pair’s criticism. He told me he felt that his group was “very transparent in our paper about all these questions that were raised by those authors, and we frankly didn’t agree with their math. But we didn’t want to dispute it either because we didn’t believe we had enough data to answer that question. So we allowed our urologist co-authors to decide how to respond.”

Reynolds added, “I’m sorry that our study wasn’t designed to answer [questions raised by the MSKCC team]. It’s a perfectly valid question to ask about higher-grade Gleason pathologies.” He said the best he and his colleagues could do to respond was to cite in the discussion section other published studies that were statistically powered enough to address issues about men with more aggressive cancers.

Then, STAT weighed in with comments from other experts, including medical ethicists, who called on Beckman Coulter to release the missing data — data Reynolds claimed were not missing.

One of those calling for Beckman to release the data was Andrew Vickers, PhD, a biostatistician at MSKCC.

Vickers argued it was simply good science to release all the data. He told STAT News: “That’s normally what happens in science. You do an experiment and release the results. That’s exactly why I wrote to them and said, ‘What are your data?'”

Beckman felt it had shown its hand.

But things are more complicated. It turns out Vickers may be more than a curious scientific do-gooder seeking missing data. He has a conflict of interest, one he freely discloses. He co-holds the key patent for the 4Kscan test made by OPKO Health in Miami. In effect, Vickers is competing with the phi test in helping urologists predict the aggressiveness of prostate cancers. As a patent holder, Vickers gets a royalty payment from each 4Kscan performed.

I called Vickers, whom I had interviewed in another article for MedPageToday last year on anxiety experienced by men on active surveillance for prostate cancer. We spoke briefly off-the-record this time. He indicated he would have MSKCC public affairs get back to me. They didn’t.

Instead, Vickers sent me an email begging of an interview and offering this statement as the final word: “In the interest of delivering the best possible patient care for men with prostate cancer, several physicians and scientists including myself have requested what has been identified as missing data points from phi’s study related to high-grade cancers. That data has not yet been made public, so I can’t comment on it. Additionally, I’ve properly disclosed my personal financial relationship with the 4Kscore test.”

Others at MSKCC have a similar personal financial relationship with OPCO, including the former head of urology. I recall asking my urologist three years ago in a general way about why he ordered a phi test rather than the 4Kscore. He was skeptical about the conflicts of interest.

I also was curious about the motivation behind the letter from the MSKCC researchers after reading a quote in STAT from Patrick Bossuyt, a University of Amsterdam epidemiologist. He told STAT: “The unwillingness to release data, that happens. But many articles never get a letter to the editor — most actually.”

So why did Ehdaie and Carlsson raise questions? In a statement, they told me: “We wrote the letter to the journal because as physician/researchers who specialize in prostate cancer we wanted to better understand the data. This is typical when the data isn’t published in a journal paper.”

I asked them about any conflicts on their part and MSKCC’s. They said: “Neither we as individuals nor Memorial Sloan Kettering have any financial relationship with OPKO or the 4K Score test.”

I thought maybe Freeland, the journal editor and a urologist at Cedars-Sinai Cancer Institute in Los Angeles, might sort this out. Instead, he passed my query on to public relations at Nature, the publisher of his journal.

Michael Stacey, spokesman for Nature, sent me a statement saying, “Prostate Cancer and Prostatic Diseases is looking into this issue. This process is ongoing and we do not comment on individual investigations. It can take time to undertake and report on investigations, and once we have the information necessary to make an informed decision we will take action, if appropriate, to ensure the integrity of the scientific record.”

The integrity of the science is important. No doubt. But what about patients? What does this flap mean to us?

Is this fuss just a tempest in a teapot? Does it matter to patient care? Should patients be worried? Is all this just a marketing battle to win the hearts and minds of the urologists and insurance companies?

An inquiring patient and reporter and, I imagine, my fellow patients want to know.

1969-12-31T19:00:00-0500

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