U.S. debate on transperineal vs. transrectal drags on despite randomized trials

By Howard Wolinsky 

Last April, I thought that by this point in 2024, the American Urological Association (AUA) might have been on the verge of endorsing transperineal (TP) biopsies as a safe choice to replace germy transrectal (TR) biopsies with its rare but real risks for deadly and disabling sepsis.

Boy, was I wrong.

In announcing new guidelines, Daniel Lin, MD, MPH, of the University of Washington, vice chair of the AUA’s Early Detection of Prostate Cancer Guidelines Committee told me in Medscape Medical News last year that the AUA itself was waiting for the results of two randomized trials before finally deciding what to do.

The smart money was on the results coming from two ground-breaking randomized controlled trials (RCTs) of TP vs. TR.

RCTs are considered the gold standard in finding “the truth,” reliable research results you can bank on.

RCTs are as as rare in the surgical world as, say, the dazzling green C/2022 E3 (ZTF) comet, which last year made its first trip near Earth since the Stone Age. Well, I’m getting hyperbolic. But most of us won’t want to participate in a RCT for surgery.

Two RCTs —one at multiple centers and one at a single center—were published earlier this year.

I don’t think either of them delivers a definitive answer on superiority of TR vs. TP. One based at Albany Medical College, saw TR and TP in a tie; the other based at Weill Cornell in New York saw some advantages to TP, but didn’t find them statistically significant.

The European approach—pro-TP

I have been campaigning for TP for about five years based on the experience with the technique in Europe and Australia.

Last year, I served as patient advocate, representing the AnCan Foundation and I hope my fellow AS patients, in reviewing the proposed AUA/SUO guidelines for early detection. I made the case for adoption of guidelines promoting transperineal, the safer insertion of biopsy needles through the skin of perineum—the area between the scrotum and the anus—vs. through rectum in a transrectal biopsy.

The European Association of Urologists in 2021 designated TP as the preferred biopsy.

The EAU stated that transperineal prostate biopsies should be performed "due to the lower risk of infectious complications." EAU described the evidence as strong: A meta-analysis of seven studies that included 1330 patients showed that for patients undergoing transperineal biopsy, infectious complications were significantly reduced.

AUA/SUO took a radically different approach in its analysis, giving a “C” to TP.

The groups said: "Clinicians may use either a transrectal or transperineal biopsy route when performing a biopsy. (Conditional Recommendation; Evidence Level: Grade C)." Grade C is the lowest grade of acceptance the guideline committee could issue.

However, AUA/SUO did put TP on a par with TR, a first in their guidelines.

AUA/SUO vs. EAU: vive la difference?

What’s the difference anyway? EAU made its decision out of concern over sepsis and infections, whereas AUA and SUO based theirs on the ability of the methods to detect cancer early.

Advocates for transperineal procedures cite several studies that show that the rate of infection, including sepsis, with such biopsies is virtually zero.

The death of a patient from sepsis linked to a transrectal prostate biopsy was front-page news in Norway and led to an overnight switch there to TP and later to the endorsement of TP by tthe EAU.

Norwegian researcher urologist Truls Bjerklund Johansen reported last year that annually on average 20 deaths occur after transrectal biopsy in Norway, which has a population of 5.5 million people, corresponding to 1,230 deaths in the United States with a population of 325 million.

Deaths often are hidden in the statistics, Bjerklund Johansen told me. Many American urologists reject these numbers in disbelief.

For its part, AUA/SUO wanted randomized double-blind studies, which it considered the strongest evidence. So it picked up on one presented at its annual meeting last year. It was not ideal because it was conducted at a single center, Albany (N.Y.) Medical College by Badar Mian, MD. This study was published in the Journal of Urology in February.

The Albany study

The study is known as “Complications Following Transrectal and Transperineal Prostate Biopsy: Results of the ProBE-PC Randomized Clinical Trial.

Mian said his group started using TP because it sounded safer and was “trendy.” As he result, they organized a study. “We didn't have any randomized controlled trials. It was trendy. So, we were part of the trend; we started a program, just like many other people, thinking that [transperineal] might be better.”

Of the 763 randomized participants, 718 underwent either transrectal (351) or transperineal (367) prostate biopsy. A composite infectious complication event occurred in 9 participants (2.6%) in the transrectal and 10 participants (2.7%) in the transperineal group. None of the participants developed sepsis in either group so other infections were used as markers.

“What we found was that the rate of complications due to infection were 2.6% with the transrectal approach, and 2.7% with the transperineal. So, we did not find any difference. That was a bit surprising; we were expecting to find a difference, because [among] experts in the field, the impression was that there should be a difference,” he told Urology Times.

“Among men undergoing transperineal or transrectal prostate biopsy, we could not demonstrate any difference in the infectious or noninfectious complications. Both biopsy approaches remain clinically viable and safe.”

Mian told Urology Times his group plans to continue this research: “The topic of transrectal vs transperineal biopsy is still an interesting one. We have other things to look at. One of those is the difference of cancer detection rates amongst a procedure, whether we find more cancers or certain types of cancers if you perform one procedure vs the other.

“We have completed that trial also. We had to increase the sample size to over 800 patients to answer the second question, whether one biopsy technique is going to be superior than the other biopsy technique in terms of finding clinically significant prostate cancer. That study is completed. That manuscript is being written, so that work should be presented hopefully at this upcoming AUA meeting in San Antonio. That'll be interesting additional information that be useful to clinicians.”

The Weill Cornell study

There was also a lot of excitement over a double-blind study led by Jim Hu, MD, MPH, of Weill Cornell Medicine in NYC. The study is known as Transperineal Versus Transrectal Magnetic Resonance Imaging–targeted and Systematic Prostate Biopsy to Prevent Infectious Complications: The PREVENT Randomized Trial.” The study was published in January in European Urology.

This is the first multicenter randomized trial of its kind. Mian’s was the first randomized study in a single institution.

Hu et al. enrolled a total of 658 participants who were randomized. The study showed ZERO transperineal biopsy infections versus four (1.4%) transrectal biopsy infections. Patients were “naive” or first-timers undergoing biopsies. 

Hu said he encountered skepticism from reviewers of his research because his study had ZERO infections among those who underwent TP while the Mian group found just as many infections in the TP and TR groups.

I chatted about these studies with researchers who joked that patients seeking TPs might consider going to Weill Cornell over Albany to avoid infections and potentially sepsis.

Hu noted: “Importantly, detection of clinically significant cancer was similar (53% transperineal vs 50% transrectal.” 

Jeremy Grummet, MBBS, MS, FRACS, Urologic Surgeon and Prostate Cancer Specialist Deputy Director of Urology, Alfred Health, Melbourne and Clinical Associate Professor, Monash University, a biopsy researcher, said that though the conclusion reads "similar infection rates," the p-value was pretty darn close to statistically significant at 0.059 (i.e. TP less infection).

[Note: The smaller the p-value, the less likely the results occurred by random chance, and the stronger the evidence that you should reject the null hypothesis.]

Hu et al. concluded: “Office-based transperineal biopsy is tolerable, does not compromise cancer detection, and did not result in infectious complications. Transrectal biopsy with targeted prophylaxis achieved similar infection rates, but requires rectal cultures and careful attention to antibiotic selection and administration. Consideration of these factors and antibiotic stewardship should guide clinical decision-making.”

Uros down under really upbeat on TP

(Jeremy Grummet, MBBS)

Grummet felt the Hu group understated its findings: “The wording of the conclusion was so laughably soft considering the findings in favour of TP, I got the sense the authors might have been fearing a backlash from their colleagues if they wrote more strongly in favor of TP.”

Grummet maintained that though the conclusion reads "similar infection rates", the p-value [statistical significance] “was pretty darn close to statistically significant at 0.059 (i.e TP less infection) and that was even for the soft metric of ‘infection,’ some of which can be so minor as to be easily treated as an outpatient.” 

Grummet stressed that sepsis is the real concern here because it is deadly and costly. He said the Hu study “was hopelessly underpowered for what should have been the metric of sepsis.”

The researcher, formerly a panel member of the EAU Prostate Cancer Guidelines, added: “Nowhere near enough hoo-ha is made about antibiotic stewardship. Note that there were no infections in a procedure done with NO antibiotics versus some infections WITH antibiotics AND they were ‘targeted.’ This tells me that targeted prophylaxis remains inadequate (not surprising given the zoo that lives in the rectum). 

“But worse, that we are using antibiotics at all when they're not needed at all in the TP approach just shows how we continue to keep our heads in the sand regarding our massive overuse of antibiotics and consequent acceleration of antibiotic resistance. WE are contributing unnecessarily and harmfully to the rise of superbugs. This is just bad medicine.”

With a spotlight on sepsis and biopsies these days, I suspect American urologists are taking extra precautions in trying to avoid sepsis and using powerful antibiotics not only for transrectal but, unnecessarily, on transperineal biopsies.

Pain and TP?

One of the big debates amongst patients is whether to undergo transperineal procedures with just a local in an office or outpatient facility, or to get knocked out with general anesthesia in an OR.

More on this issue.

Participants in the Hu study were asked immediately and at seven days after biopsy to rate the amount of pain, discomfort, and anxiety they experienced on a scale of 0 to 10.

Hu said that participants in the transperineal arm experienced worse pain, but the effect was moderate and resolved by [day 7]” after the procedure,

Consider Hu’s comments on this:

Immediately following biopsy, men rated more pain and discomfort with the transperineal approach relative to the transrectal approach. In other words, for pain, for example, the difference was 3.6 vs 3.0 on that 0 to 10 scale. It was a smaller difference for discomfort, but that also reached statistical significance. But then when we reassessed at 7 days afterwards, through a patient-reported survey, there were no differences in pain, discomfort, and anxiety and no difference in anxiety at the time of the procedure.

So, there is a statistically significant difference in that transperineal approach had more pain and discomfort compared to transrectal. [More here.]

What’s next with the PREVENT TRIAL?

Hu said his group will continue to enroll patients for up to eight months and reanalyze the statistics to see if there is any statistical significance,

“We're also continuing to examine whether or not there's a difference in cancer detection rate,” he said.

Hu said his goal is to find out what is the best approach for patients.

Reimbursement rates for TP vs. TR

“Our hope is to really change the practice of medicine,” Hu said.

It needs changing with all the mixed incentives.

Money, money, money.

Money is one of the hang-ups in the adoption of TP. Urologists have to spend $40,000 or so to get trained in the technique and to upgrade office equipment.

Also, they and the associations that look out for their reimbursement rates, or “codes” used by Medicare and insurers, resent the fact that the codes thus far are the same for TP and TR, even though TP takes a few minutes more per procedure. Those minutes add up to dollars lost.

Hu said his research could result in changes in Medicare codes to increase payment of physician fees for transperineal biopsies.

Contrast this with Australia. In OZ, thanks to patient advocacy, urologists get double the fee for performing transperineal vs. transrectal biopsies.

Grummet said: “There's no doubt that, whether we like it or not, reimbursement patterns drive practice. But once you have evidence, you can change reimbursement, which is we did in Australia several years ago now with the following result: In Oz, TP biopsy went from 30% in 2015 to 85% in 2021. It will be even higher now.

“If reimbursement is backed by science, then all the better.”

Stay tuned. Meanwhile, tune into a discussion between Drs. Hu and Grummet at GU Cast:

TheActiveSurveillor Poll: Transperineal gaining traction with patients while most U.S. urologists lag behind

By Howard Wolinsky

Transperineal (TP) vs. transrectal (TR) biopsies. Where do you stand? What does your urologist think?

TPs can be hard to score in the U.S. But change is in the wind.

Many readers of TheActiveSurveillor.com are voting with their feet--and their prostates--in favor of transperineal procedures.

Turns out we’re very European: The European Association of Urology considers transperineal biopsy the preferred approach because it avoids potentially life-threatening sepsis and other infections. A top doc from EAU told me transrectal procedures are tantamount to medical malpractice in Europe.

Many American urologists disagree. They tend to think their infection rates are low—even if they haven’t checked them lately.

According to Mayo Clinic, the risk of sepsis with transrectal—some critics call them transfecal—biopsies is approximately one to two patients in 100.

Norwegian researchers estimate about 2 million transrectal biopsies a year are performed in North America and Europe, resulting in about 2,000 deaths, many of which were not linked to sepsis in the death certificate.

Many urologists don’t believe those numbers. They and patients’ families may not connect patient deaths from sepsis from a prostate biopsy performed a month earlier.

Ask your doctor his/her infection rate for biopsies before undergoing a biopsy and whether he/she offers you the option for TP, what his/her success has been with it, and how long they’ve done it.

Patients undergoing transperineal potentially also can avoid powerful antibiotics that contribute to the risks of antimicrobial resistance, which can unleash deadly “superbugs” that resist all antibiotics. “Antimicrobial stewardship” is a far bigger motivator in Europe than in the United States,

The transperineal procedure involves passing a biopsy needle, guided with ultrasound, through the perineal skin—the area between the scrotum and the anus—and into the prostate, rather than passing the biopsy needle through the contaminated rectum.

AUA in 2023 slightly promoted transperineal biopsies, putting them on par with transrectal biopsies.

(Read more about the debate in my article in Medscape Medical News: https://www.medscape.com/viewarticle/991496)

Meanwhile, my poll of 145 readers of TheActiveSurveillor.com showed that their most recent biopsies were transrectal (61%). That’s to be expected since transperineal procedures can be hard to find in the United States. The availability is scaling up as increasing numbers of urologists are training to offer the procedure.

What’s surprising is 36% said their last biopsy was a transperineal. That’s much higher than the national rate for transperineal of 10%, up from 5% two years ago, according to urologist Matthew Allaway, DO, founder of Perineologic, developer of the updated, less-invasive system of transperineal known as PrecisionPoint.

(About 3% of respondents to the survey were unsure what type of biopsy they had.)

Respondents to TheActiveSurveillor.com Poll are probably not typical prostate cancer patients. I suspect they are better informed about their options and are more willing to travel to get a TP.

This is reflected again in their plans for their next biopsy, only 11.4% said they expect their next biopsy to be transrectal while a majority of 53.8% expect to undergo transperineal procedures, 35.6% are undecided.

Change is slow because of the costs of physicians to be trained in the procedure and for them to set up their offices for transperineal.

What’s the price for safety?

I’m told it costs $40k to set up an office practice for TP.

(Dr. Matt Allaway, founder of Perineologic/PrecisionPoint.)

“We expect [TP] to surge over the next 18 to 24 months,” said Allaway, whose system is now used in an estimated 90% of transperineal cases.

The modern transperineal procedure was designed to be performed in a urology office with only local anesthesia. 

In the office? Or hospital OR?

The modern TP was designed for the urology office. But some men--not all--say the pain from transperineal before the local takes effect is unbearable. Some urologists, especially newbies to the procedure, prefer patients undergo general anesthesia in the OR so patients don’t squirm during the procedure. 

Of 116 respondents to the poll, the biggest number (41%) said they’d prefer to be knocked out for the transperineal procedure, while 30% said they prefer to be awake and 28% were unsure. Some experts estimated the proportion of office vs. OR TPs is about 50-50.

Men again are voting with their feet and their prostates.

The sleep option may be winning hearts and prostates. friends of mine describes it “as the best nap ever.” Other men shrug off the brief pain.

I covered this issue in a newsletter last year: “New debate for transperineal biopsies: ¿Despierto o dormido? Awake or asleep”

There’s a third choice emerging: laughing gas. Check out my article in Medscape.

Time’s almost up on ZERO Prostate Cancer’s Active Surveillance webinar March 12

As part of its annual virtual summit, ZERO Prostate Cancer will be holding an Active Surveillance support group at 11 a.m.-12 p.m. Eastern on Tuesday, March 12. Why not join me and AnCan AS moderators Jim Schraidt, Hugh Idstein and Garry Tosca.

Register: https://us02web.zoom.us/meeting/register/tZUsfuqgrjIoG9AWf7voMhzT_UjdqbQQbQPA