Optimal prostate biopsy comes into sharper focus

Practicing U.S. urologists show significant variability in their approach to prostate biopsy. An AUA workgroup, chaired by Samir S. Taneja, MD, was commissioned to develop recommendations on the optimal method to perform a prostate biopsy and handle specimens. In this interview, Dr. Taneja discusses these recommendations, how to minimize infection, and the role of imaging. Dr. Taneja is professor of urology and radiology at New York University’s Langone Medical Center, New York. He was interviewed by Urology Times Editorial Consultant J. Brantley Thrasher, MD, professor and chair of urology at the University of Kansas Medical Center, Kansas City.

What do you consider to be the best prostate biopsy algorithm right now for the practicing urologist?

Prostate biopsy has really evolved in clinical practice because there are lots of reasons that urologists do biopsies nowadays. Obviously we do them when we suspect prostate cancer in somebody who has an elevated PSA or an abnormal rectal exam. We do repeat biopsies very often when patients are negative on the first go-around and then we do biopsies for active surveillance, for staging of patients before therapy, and for monitoring premalignant causes like high-grade PIN or atypia. For that reason, the technique of biopsy might vary a bit with the indication.

We recently realized that there is tremendous variability in the practice of prostate biopsy in the United States. Urologists use different templates, different approaches, and different numbers of cores. For that reason, the AUA in 2012 commissioned an expert panel to develop a white paper on recommendations on the optimal way to perform a prostate biopsy, particularly in men who have never had a biopsy before.

Our panel was able to review the existing literature and ask fundamental questions related to cancer detection, which is one of the obvious goals of biopsy; avoiding over-detection of tiny indolent cancers, which is something that we get criticized for all the time; providing good clinical data that corresponds well to the radical prostatectomy pathology, ie, accurate prediction of grade and stage; and finally, avoiding false negatives-how many cores you need to be confident that a negative result is really negative. We concluded that there is no evidence that going above 10 to 12 cores on the first biopsy greatly increases the cancer detection rate or greatly improves the negative accuracy. It does increase the number of clinically insignificant cancers that you find.

So we made the recommendation that the ideal first biopsy is probably one that incorporates 10 to 12 cores. Interestingly, core location influences detection, so those cores ought to include sampling from the far lateral region of the prostate and they ought to include apical sampling, which is often the most predictive of stage or extracapsular extension at the time of the final pathology.

We advised against transition zone sampling because it doesn’t really add much to the biopsy. It increases morbidity on a first biopsy and the rate of cancer detection in the transition zone is very low.

One area of concern relates to the patient who has had multiple negative biopsies but who may still be at risk because his PSA continues to rise. In cases like this, some urologists are performing saturation biopsies in the operating room with as many as 40 cores. How do we increase the efficiency of our biopsy technique and avoid that?

We looked at this at NYU and found that the major indication for repeat biopsy is, as you described, rising PSA or worry that the PSA is still high. A patient who has a very high PSA for their age and a negative biopsy often doesn’t give us confidence. In those patients, many urologists will use different types of biopsies. In other words, they overcome sampling error by increasing their sampling; they might choose to do a transrectal biopsy with a lot more cores and might choose to do a transperineal biopsy with a lot more cores. Some will even use transurethral biopsies when they are really worried that they’re missing something.

Data would show that most cancers we miss on primary biopsy reside in the very far lateral peripheral zone, in the very anterior prostate along the anterior capsule on either side, or in some cases over the urethra. Those are difficult areas to approach transrectally. Our own data shows that if a man receives a repeat transrectal biopsy for whatever indication-whether it’s PIN, atypia, or rising PSA-he is very likely to get multiple repeat biopsies over the period of his life because very often the initial repeat biopsies aren’t able to find the cancer.

I would say the two optimal techniques of repeat biopsy are either some sort of saturation, transperineally, with which you can access the anterior gland well or, if you have the ability, an image-guided biopsy. There is growing evidence that, particularly in the subset of men with previous negative biopsies, an MRI might demonstrate an abnormality in the anterior prostate that can then be targeted. So you can overcome sampling error in two ways: You can either continue to increase your sampling through multiple repeat biopsies or saturation techniques, or you can localize with imaging, as we do in all other organs of the body. The problem is that the more you saturate and the more cores you sample, the more you increase the complication rate from the biopsy, escalate cost, and increase the likelihood of finding a clinically insignificant cancer.

Tell us about your imaging technique at NYU and how you use MRI.

The changes in MRI that have occurred in the last 5 years relate to the idea of using functional sequences to improve the specificity to reduce the rate of false positives. The typical MRI images that most of us may remember from our training were conventional T2-weighted MRI sequences with which you could often see cancers, but you also saw a lot of false-positive findings: atrophy, inflammation, and infarcts in the prostate. As such, they weren’t that accurate in predicting cancer location.

When functional sequences are added to the T2-weighted image, that improves the specificity and accuracy. The ones we choose to use are contrast enhancement sequences, or what’s called dynamic contrast enhancement, which provides rapid acquisition of sequences every 5 seconds over 5 minutes to depict the pattern of blood flow in and blood flow out. We also look at a sequence called diffusion-weighted imaging, which measures the random movement of water molecules. The less water molecules in the tissue move, the more dense the cellularity is. When you see restricted diffusion, that’s a good indicator of cancer in any organ, and in the prostate, it actually may correlate with Gleason score to some extent.

We use a combination of those three techniques. Various centers will do it in different ways. We don’t like the endorectal balloon just because it’s uncomfortable for the patient to have a balloon in the rectum for 30 or 40 minutes. You give up some resolution when you don’t use an endorectal balloon, but we think the quality of the images can be quite good just with standard phased array coils on the external surface of the body. We also utilize a stronger magnet of 3-tesla strength rather than the conventional 1.5 tesla.

We do prostate MRI now in many clinical scenarios, but particularly in patients who have had multiple negative biopsies but their PSA keeps rising. We are also exploring the use of pre-biopsy MRI in men who have never had a biopsy and in men on active surveillance for low-risk disease. The use of MRI in these particular scenarios has the potential to allow the biopsy to more accurately characterize the tumor as low risk or high risk. This means a better ability to counsel the patient regarding the best management approach to his disease.

Did the AUA panel find any difference in end-fire ultrasound versus side-fire devices? If not, what do you recommend?

Both the technique of biopsy-end-fire/side-fire and transrectal/transperineal approaches-and imaging were topics not addressed by the panel. They were beyond the scope of what we were trying to accomplish, but they are very relevant questions for clinical practice.

A reasonable amount of data suggests that there are places in the prostate you can reach with an end-fire device that you can’t get to with a side-fire needle because of the needle angle. When a needle comes out of the probe side-fire, it comes out at about 30 to 40 degrees and deflects in the tissue. As such, finding cancer in the extreme apex with a side-fire needle is difficult unless you traverse the rhabdosphincter, and that’s very painful for the patient. The other place is the extreme base near the seminal vesicle insertion site where we do often see cancers; you could easily miss that with a side-fire needle.

For many years, I used side-fire, and most urologists are trained to do side-fire biopsies. The ultrasonography aspect is quite simple because it involves just rotating the probe. About 5 to 6 years ago, I converted to end-fire biopsies, and I have been happier. Our data shows that we have higher cancer detection rates, and I think that translates into a lower likelihood of missing a significant cancer, particularly in the apex. It does require some training to understand how to move the probe and how to interpret the probe, because unlike a side-fire where you’re either looking in a straight sagittal or straight axial plane, on an end-fire, you could easily be in an oblique plane and that can create confusion about where you are in the prostate. There’s clearly a learning curve.

Does the added cost of MRI equate to a benefit to the patient in terms of avoiding further biopsies? Do you see MRI-guided biopsy providing a good cost-benefit ratio?

It’s an interesting question that really hasn’t been addressed in the literature, as the field of MRI-guided biopsy is somewhat in its infancy. But it’s a critical question, and the answer depends on how widely one might utilize MRI. If you’re using it in the case of repeat biopsy-and our national trends show that patients who undergo repeat biopsies often end up getting multiple, repeat, or saturation biopsies, which escalates pathology costs-I do think it would probably represent a savings because it might do away with those multiple biopsies. If we chose to do MRIs on patients who have one negative biopsy, it’s very likely we would have confidence in the results of the second biopsy and would reduce the core numbers. So I think it does represent an opportunity for cost saving.

MRIs vary geographically in their cost. That’s something a urologist has to figure out locally, particularly as we begin to ration health care. But over time, the cost of any test declines as its utilization and its efficiency increase, and we’re hoping that’s the case with MRI. We are also interested in looking at MRI’s role in active surveillance patients in reducing the number of biopsies they might need. I think an added benefit might be that you would be able to select patients who need treatment very early on, so that may also represent a cost savings.

The real question is, would you use it in every man who comes in with an elevated PSA? We’ve been very interested in doing some decision analysis modeling to determine if overall cost savings can be achieved if you could avoid a certain number of biopsies by setting a threshold for biopsy based upon the degree of suspicion on the MRI. This may reduce the over-detection of cancers that are considered indolent and reduce the number of secondary treatment-related side effects in those men.

Do you feel that with imaging, you can more accurately find cancer, such as a Gleason 6 cancer? In other words, are you correlating what you see on biopsy with what you saw on the MRI pretty accurately?

Absolutely. We’ve found in our studies over the last 3 or 4 years, in which we have correlated our MRI with radical prostatectomy, that we don’t see every cancer. There are factors that influence what you see and what you don’t see; in particular, grade, size, and the sparse or dense architecture of the cancer glands. Some cancers histologically look like little nests of cancer buried in a lot of benign stroma, and we tend not to see those. But we do see the densely packed ones.

When you correlate that with grade, it’s potentially beneficial in two ways. One is that you would identify most high-grade cancers, and you might not identify many of the smaller indolent cancers that we want to avoid. Our group presented a paper at the 2013 AUA annual meeting where we did computerized targeted biopsies of MRI abnormal regions, and we showed that in the same patients, systematic biopsy finds a lot more cancer. About 55% of our systemically sampled patients had cancer, but only about 35% of the MRI-guided biopsies were positive. However, when we looked at the rate of Gleason 7 or higher detection, it was identical between the two arms. Among the cancers we are missing, the vast majority seem to be small Gleason 6 cancer.

MRI quality is highly variable and depends on how the MRI is read and the experience of the radiology site. The other question that’s not answered is, how do you go about targeting those areas? We use a computerized technique now, but many centers just estimate the position and that’s fraught with potential for error as well.

Infection has been one of the primary concerns about prostate biopsy, and we are seeing a significant elevation of fluoroquinolone-resistant E. coli in this country and others. What antibiotic coverage do you commonly useat NYU, and do you have particular patient populations you cover differently because they are at higher risk of infection?

We have observed that among patients coming into our emergency room with community-acquired pneumonia, about 25% have quinolone-resistant organisms. The quinolones are becoming of less and less value to urologists as prophylaxis for procedures and invasive surgical interventions. For that reason, we have altered our overall antibiotic regimen.

The literature is pretty consistent in showing a growing rate of post-biopsy sepsis, from what used to be less than 1% to as high as 3% to 4% in recent years. People at high risk are health care workers, who are exposed to resistant organisms; people who return from international travel; and those who have had multiple health care procedures. If a patient tells you that he just got out of the hospital from a cardiac bypass or had complications from a colectomy and was in the hospital on antibiotics for several weeks within the last year or 2, that probably has left him with resistant organisms.

One has to obtain a better history before the biopsy to understand an individual’s infectious risk, and there are two approaches you can take. One is to individualize antibiotic therapy. That is done by taking a swab from the rectum, streaking it on an agar plate, and letting it grow to see if there are resistant organisms there. In my experience, that requires communication with your lab because obviously a rectal swab grows out a lot of organisms; it’s typically a polymicrobial swab, and the lab is going to ask what you want them to do with this. The other problem with that approach is that it’s a burden on the workflow in many offices; that is, who is going to do it, when will the patient come into the office, and do you have room in your waiting room for all these people coming in a week ahead for a culture?

The other approach might be to consult your local infectious disease doctors and ask for what’s called an antibiogram. Typically an antibiogram is a survey of infections that have occurred within the community or within a health care system, and it reflects how often we see resistant organisms and what they might be sensitive to. We did that at our Manhattan VA in previous years, and we noted an increasing rate of post-biopsy sepsis in our veteran patients undergoing prostate biopsy. Over a 3-year period, our rate of sepsis increased from roughly 1% to about 4%. We had some near-death sepsis events.

Looking at the local antibiogram at our VA hospital, we did away with quinolones and converted our prophylaxis to a single dose of gentamicin and a single dose of ceftriaxone at the time of the biopsy. In the 3 years that followed that, our readmission rate for sepsis among 450 men receiving that regimen was zero. We dropped the rate from 4% to zero. In our private offices, we continue to utilize quinolones; we use them in combination with ceftriaxone as a single injection based on the antibiogram at our private center. I think that’s an effective strategy with a lower workload. Many would argue that over time, you will just draw out resistance to those antibiotics. As a result, it has to be a dynamic process in which you revisit the local antibiogram every year or 2 to readjust your prophylaxis regimen and use as minimal a regimen as possible.

Because of the concerns you described, some urologists in the United Kingdom have elected to stay out of the rectum and have gone back to using transperineal biopsies. Do you see us changing techniques to avoid infectious complications?

Transperineal biopsy certainly will lower the infection rate because skin colonization doesn’t seem to greatly influence the risk of prostate biopsy infection after sampling. The problem with it is twofold. First, there are major practical issues involving workflow and the patient’s comfort. We do at least a million biopsies a year in this country, and given the number of biopsies most urologists do in their office, it’s difficult for me to believe they would find a comfortable workflow where they could sedate a patient or put him in a proper OR suite or other location to do a transperineal biopsy.

Second, I am not sure that transperineal biopsy is as good a method for sampling the peripheral zone as transrectal biopsy. I don’t think the imaging suggests that it gets to the same regions of the prostate. I will be interested to see how that would influence primary prostate cancer detection as these series from the UK evolve.

Is there anything else you would like to add?

I would conclude by saying that most of the time, we focus on whom we should biopsy and we tend to indict oversampling of men with low PSA as the cause of over-detection, but the technique of biopsy has a lot to do with that as well. Once you’ve decided who you are going to biopsy, I think it’s worthwhile to have a strategy in mind that balances all the elements we talked about: maximizing cancer detection, avoiding repeat biopsies, and avoiding oversampling, which will identify lot of these smaller cancers. If we can do that across the country, I think that will correct a lot of the ills of prostate cancer detection and will put us in a better position to prove that we are really helping patients.UT

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