Advances in Urology

Dr. Jim C. Hu

Jim C. Hu, MD, MPH, Director of the LeFrak Center for Robotic Surgery at NewYork-Presbyterian/Weill Cornell Medical Center, has recently been awarded more than $7 million in funding from the Patient-Centered Outcomes Research Institute (PCORI) for two studies on outcomes of prostate cancer biopsy and treatment. He has also received $2.5 million from the National Cancer Institute to study prostate biopsy. With close to $10 million in federal funding for comparative effectiveness research into better ways to diagnose and treat prostate cancer, Dr. Hu will continue to advance the groundbreaking work that has defined his career and informed progress in the prostate cancer care paradigm – from screening to diagnosis and treatment. His work has had a leadership role in identifying the value of PSA screening for detection of prostate cancer.

PSA Screening: Redefining the Debate

In 2012, the United States Preventive Service Task Force made a monumental decision to no longer recommend prostate-specific antigen (PSA) screening after evaluating data from two trials: one in Europe, which showed a benefit to PSA screening, and one in the United States, which did not show any differences between a control group screened with PSA compared to a cohort of men not assigned to screening. As a result of their data assessment derived primarily from these two trials, the Task Force recommended against PSA screening. In 2016, Dr. Hu and Jonathan E. Shoag, MD, a urologic oncology fellow at Weill Cornell at the time, uncovered flaws in the U.S. study that turned the Task Force decision on its head.

“These two randomized studies – one from Europe and one from the U.S. – looked at the benefit for men who had a PSA screening,” says Dr. Hu. “Essentially the two outcomes differed. The study from Europe showed that there was a benefit to PSA screening, whereas the randomized trial from the U.S. did not.”

The European study found that PSA screening resulted in a 21 percent relative reduction in prostate cancer mortality, providing evidence to support using PSA screening to prevent deaths. Drs. Hu and Shoag discovered that PSA testing in the control arm of the U.S. study, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, was substantially higher than previously recognized, leading to a misinterpretation of the trial results and invalidating the data used to rule against PSA screening.

“We found that during the study, because PSA screening was already so widely disseminated among internists and so forth, there was upwards of 85 to 90 percent contamination, meaning that the men randomized to the unscreened group still got PSA screening,” explains Dr. Hu. “Instead of comparing apples to oranges in a randomized trial, the study was really comparing apples to apples. So, it’s not surprising that you would not see any difference in mortality between a population of men actively screened with PSA evaluations and those who already had PSA testing as standard care.”

“I think those two factors, the first being that one of the pillars of evidence against PSA screening was very flawed, and the second that decreased PSA screening has become associated with an increase in metastasis at diagnosis, started overturning the conception that PSA screening is not beneficial.”

— Dr. Jim C. Hu

The implications of the PLCO study were far-reaching, with several major U.S. organizations subsequently advising against screening, leading to declines in PSA screening rates nationally and a shift toward fewer prostate cancer diagnoses.

Dr. Jonathan E. Shoag

“Following the introduction of PSA screening in the early 1990s, prostate cancer mortality had fallen by about 50 percent,” says Dr. Shoag. “After the PLCO study, PSA screening decreased dramatically, and we diagnosed many fewer prostate cancers. Now, unfortunately, we’re seeing more men whose cancer is metastatic. Before it was very uncommon to see men with metastatic disease as their initial presentation. So obviously we’ve been missing a lot of important cancers.”

“I think those two factors, the first being that one of the pillars of evidence against PSA screening was very flawed, and the second that decreased PSA screening has become associated with an increase in metastasis at diagnosis, started overturning the concept that PSA screening is not beneficial,” adds Dr. Hu, who with his Weill Cornell colleagues, was among the first to provide evidence of the upswing in prostate cancer metastasis as an initial diagnosis.

With the revelation by Drs. Hu and Shoag of the contradictory results between the two studies and the reasons behind their opposing outcomes, the United States Preventive Service Task Force revised their recommendation against PSA screening to placing that decision in the hands of providers and their patients.

“We were glad to be able to influence that change, but I think that as urologists, we need to be the advocates for PSA screening,” says Dr. Shoag. “Not every man needs a PSA every year such as men with limited life expectancy or over age 70, but we recommend that every man in their fifties should have a baseline PSA screening. Based on that test, we can stratify next steps accordingly.”

“We need to screen men, but how do we minimize the downside and optimize the upside? This is the follow-up question to be addressed. But the message needs to be out there that PSA screening saves lives, and we need to do it.”

— Dr. Jonathan E. Shoag

A defining moment in the debate over PSA screening, the work of Dr. Hu and Dr. Shoag was first presented in the October 18, 2016 issue of the Journal of Clinical Oncology, which was followed with their reevaluation of the plausible long-term effects of PSA screening using the most current data available in the June 18, 2020 issue of The New England Journal of Medicine.

Dr. Hu and Dr. Shoag have since shifted their attention to maximizing the benefits of PSA screening, while minimizing the limitations and drawbacks of the test, such as overdetection and associated treatment-related complications. Says Dr. Shoag, “We need to screen men, but how do we minimize the downside and optimize the upside? This is the follow-up question to be addressed. But the message needs to be out there that PSA screening saves lives, and we need to do it.”

Maximizing Care, Minimizing Harm

In recent years MRI, with or without targeted biopsy, has become an alternative to standard transrectal ultrasonography-guided biopsy to detect prostate cancer in men with an elevated PSA. “Among the concerns cited for PSA screening was that it leads to a biopsy and its associated discomfort, pain, and risk of infection, and that it resulted in an overdiagnosis of cancers that were not significant or that would not go on to cause problems,” notes Dr. Hu. “The addition of MRI has curbed many of these issues.”

Dr. Hu, along with Daniel Margolis, MD, a foremost diagnostic radiologist specializing in prostate cancer at NewYork-Presbyterian/Weill Cornell, participated in a landmark study published in The New England Journal of Medicine that showed men with an elevated PSA should now get an MRI instead of going straight to biopsy. “This strategy has been adopted more widely,” says Dr. Hu. “If the MRI is not suspicious, the patient can avoid a biopsy. If it is suspicious, the MRI can guide the biopsy so that it’s more accurate and less likely to miss a cancer.” The international, multicenter trial showed that there was less diagnosis of indolent cancer and more diagnosis of clinically significant cancers in the MRI targeted group.

Dr. Hu, Dr. Margolis, and faculty in the Department of Urology at Weill Cornell Medicine, also were major participants in a multicenter study to improve detection of clinically significant prostate cancer in men who had elevated PSAs but had not undergone a biopsy. The study, which evaluated 247 men with PI-RADS ≥ category 3 lesions who underwent MRI-targeted biopsy, found that 22 percent were diagnosed with clinically significant prostate cancer and that higher PSA density, lower prostate volume, and lower apparent diffusion co-efficient values were associated with this diagnosis. Based on these results and the work of others in this area, the authors note that they now base their recommendations whether to biopsy men with PI-RADS 3 lesions primarily on PSA density. The study was published in the July 2020 issue of Urologic Oncology.

According to Dr. Hu, the MRI approach also minimizes the complication of infection associated with transrectal prostate biopsy. “Sepsis following this type of biopsy occurs in 2 to 5 percent of cases and the risk is increasing because of greater resistance by bacteria to the commonly used antibiotics,” explains Dr. Hu. “The other biopsy method, which avoids the rectum thereby reducing the risk of infection, is painful and therefore requires general anesthesia. We are one of the few places that now combines MRI to help target the area for the biopsy with a local anesthesia, making the procedure safer. We can also do focal therapy, if indicated, and both can be performed in the office.”

With the funding from the PCORI and the NCI, Dr. Hu and his colleagues will be leading a trial to evaluate transperineal biopsy in men who have had a previous negative biopsy but continue to have a suspicious PSA or they need a monitoring biopsy on active surveillance, and a second trial for men undergoing a first-time biopsy. “If the risk of infection is less with the transperineal approach, it would represent a safer way to perform biopsies. But we also need to make sure the cancer detection rate doesn’t drop off using it.”

Validating Outcomes of Novel Treatments

To substantiate the value for focal therapy and other new image-guided treatment platforms, Dr. Hu also leads an effort with the Food and Drug Administration of a nationwide, multicenter patient registry that is capturing outcomes for the new prostate ablation technologies.

“Compiling data through a prospective, multicenter coordinated registry network enables us to responsibly determine the performance and substantiate the validity of novel prostate ablation technologies,” says Dr. Hu. “We know that MRI-guided biopsy can optimize the diagnosis of prostate cancer. Focal therapy, which is derived from image-guided biopsy, has the potential to maximize its treatment.”