Dr. Thrasher, a Urology Times editorial consultant, is professor and chair of urology at the University of Kansas Medical Center, Kansas City.

J. Brantley Thrasher, MD

The non–muscle invasive bladder cancer treatment BCG remains in short supply, with Merck currently serving as the sole supplier of the medication in the US. In this interview, 

discusses current recommendations for managing patients during this shortage, what the FDA is doing to resolve the problem, and a SWOG trial testing a new strain of BCG.

Lerner is professor of urology, Beth and Dave Swalm Chair in Urologic Oncology, director of urologic oncology, and director of the multidisciplinary bladder cancer program at Baylor College of Medicine, Houston, Texas. He was interviewed by 

 executive director of the American Board of Urology, Charlottesville, Virginia.

Disclosures: Dr Lerner has conducted clinical trials for Endo, FKD Therapies, JBL Science, Roche/Genentech, UroGen Pharma, Vaxiion Therapeutics, Viventia Bio Inc; is a consultant/advisor for FerGene, Genentech, Merck, Pfizer/EMD Serono, QED Therapeutics, UroGen Pharma, Vaxiion Therapeutics, and Verity Pharmaceuticals; has received honoraria from Grand Rounds Urology and UroToday; and holds a patent for The Cancer Genome Atlas Classifier.

This goes back several years. For a long time, there were 2 manufacturers of BCG in the United States and Canada. In 2012, Sanofi Pasteur in Canada, which manufactured the Connaught strain, went offline because of some inconsistencies in their manufacturing. In 2017, they shut down production completely. Merck, which makes the TICE strain, is the sole supplier of BCG not only in the US and Canada, but for 70 countries worldwide. Over the years, Merck has really stepped up, but they too had brief periods of challenges in the manufacturing process in the last several years. Having solved these, they ramped up production by, according to their numbers, 100% over the course of about 12 to 18 months. That solved a lot of the problem, but demand has essentially outstripped supply. In a recent press release,

 Merck has committed to building a new manufacturing facility for BCG that will take up to 6 years to complete and triple production of Tice BCG.

In February 2019, a group of stakeholders consisting of representatives from the American Urological Association, Society of Urologic Oncology, American Association of Clinical Urologists, the Urology Care Foundation, LUGPA, and the Bladder Cancer Advocacy Network (BCAN) met with representatives from Merck at the GU Cancers Symposium. We crafted a joint statement to try to help urologists manage patients during this shortage. We provided some guidelines to prioritize BCG for the patients who most needed it, such as patients with high-risk, high-grade non-muscle-invasive disease at their first diagnosis. Getting those patients through the induction and the first 3 months of maintenance treatments is critical. For patients who have already had a year or two of maintenance, we recommend curtailing that treatment.

With the statement, we were also trying to help urologists look for alternatives to BCG; namely intravesical chemotherapy for patients with intermediate-risk disease, where there’s less of a distinction about the superiority of BCG over chemotherapy. We’re trying to help urologists understand the AUA guidelines and where we think BCG can be most effective. But despite all of these efforts, the shortage persists, so we have to look for other strategies to help solve the problem.

What are the recommendations for urologists currently?

In high-risk patients for whom clinicians do not have access to BCG, we recommend a combination of chemotherapy drugs that can be delivered intravesically. We’re currently using gemcitabine and docetaxel. This combination was originated by Dr Michael O’Donnell at the University of Iowa, and a number of centers are using it quite successfully for patients for whom we don’t have BCG, or for patients who recur, after induction and one round of maintenance where they don’t necessarily need to go on to a cystectomy.

Another strategy is to extend the use of a vial of BCG by dividing it into 2 or even 3 doses. There’s actually a J code for that, but unfortunately, the payors haven’t given us a way to charge for that appropriately. This remains a challenge for many practices, and efforts are needed to resolve this with CMS and other payors. Another strategy is proper use of perioperative single-dose chemotherapy for low- and intermediate-risk patients to try to reduce the risk of recurrence and the subsequent need for BCG. A recent SWOG trial showed that a single dose of peri-operative intravesical gemcitabine, reduced the risk of recurrence by almost 50% at 4 years in patients with low-grade disease.2 In patients with intermediate-risk disease—patients with multi focal or recurrent Ta low grade cancer—an optimized regimen of mitomycin C first described in 2001 is easy to use and improves the efficacy of mitomycin.

What is the FDA doing to help address the shortage?

The FDA is being very proactive. They fully recognize and appreciate the importance of solving this problem. The group of stakeholders that met at the 2019 GU Cancers Symposium convened again at the 2020 symposium. There were 2 representatives from the FDA at that meeting, and they expressed a very strong interest in working with us and anyone else in the community to try to solve this shortage.

The reality of it is that we need to get new strains of BCG into the US market. They have to go through the standard FDA approval process. In the Southwest Oncology Group, we’re currently conducting a trial led by Dr Robert Svatek (NCT03091660). This is a 3-arm, 969-patient trial for patients who have high-risk, high-grade disease and are BCG naive. In the control arm, patients receive induction and maintenance TICE BCG, which is the current standard of care. We have a contract with Merck to guarantee the supply of Tice BCG for this trial. Patients in the other 2 arms receive the Tokyo-172 strain that was developed in Japan and has been around for decades. There are data suggesting that it is equivalent in efficacy to the Connaught strain and we will compare the efficacy of the Tokyo strain to Tice. We are also evaluating intradermal vaccination to prime the immune system prior to starting BCG treatment in order to improve the response rate. Failure-free survival at 1 year is the primary outcome measure. Two thirds of patients receive intravesical Tokyo-172, and half of those patients get vaccinated with Tokyo-172 BCG.

We’ve had multiple conversations with the FDA regarding the trial. They are very interested in looking at the patients with carcinoma in situ, who make up about one third of the patients in this trial. If the data support the efficacy of the Tokyo-172 strain for these patients, it’s a potential pathway for regulatory approval for this BCG strain.

Companies are looking at bringing other strains into the US market. One company is looking at the Russian strain, which is used mostly in Europe and other parts of the world. They will also have to go through a very strict FDA review and approval process.

Are there data to suggest a protective effect against bladder cancer in patients who have been vaccinated with BCG?

I’m not sure how well that’s been studied. We won’t be able to answer that question in our trial, because previous vaccination is one of the exclusion criteria. The trial design was based upon Dr Matthew Albert’s work from the Institut Pasteur.

 He and his colleagues compared induction BCG in patients who were previously vaccinated and those who were not, and the vaccinated patients seemed to do a lot better but that was with induction only and no maintenance BCG. Conceptually, the idea is that you prime the immune system with vaccination 3 weeks prior to intravesical BCG, so that, where it normally takes between 4-6 intravesical instillations during induction to reach peak cytokine induction, we think that that would happen much earlier, and by virtue of that, yield better outcomes in terms of failure-free survival.

You mentioned a couple of ways to potentially to relieve the stress on urologists who can’t obtain BCG. Is there a role for thiotepa, adriamycin, valrubicin, and some of the other agents that have been used in the past?

I think most urologists should be comfortable using mitomycin and gemcitabine. Here in Houston and the surrounding area, we’ve been very happy to guide clinicians in the use of intravesical chemotherapy drugs that they may not have a lot of experience with, particularly these combinations. I would say that if you don’t have experience, then simply reach out to your nearest academic urology department for guidance. These are really easy to use. We’re available for consultation, guidance, and treatment, if needed. I think most of us are in a situation where we currently have adequate BCG supply, but I’m still getting referrals for patients in my community from physicians who don’t have access to BCG.

You mentioned boosting the immune system. I understand that you are involved with a trial evaluating BCG vaccinations for COVID-19.

Yes, this is something that a number of us have become involved with. Infectious disease experts here in the US, the Netherlands and Australia have done a lot of work in this space, conducting research on BCG vaccination for tuberculosis globally. They observed that, epidemiologically, countries that had programmatic vaccination for tuberculosis from birth had about a ten-fold lower incidence of COVID-19 and about a ten-fold reduction in mortality rate compared with countries that did not have programmatic vaccination from birth.

 There is a fair amount of laboratory and experimental evidence to support why that might be. There are nonspecific immune effects of BCG vaccination that have been shown to reduce the risk of bacterial and viral respiratory infections, particularly yellow fever, which is another virally transmitted disease. The experimental evidence suggests that BCG causes epigenetic modification of immune cells that make them perhaps more alert to other foreign viruses; in this particular case, the novel coronavirus causing COVID-19.

As a result, the infectious disease community has put together randomized clinical trials comparing BCG vaccination to placebo, initially focusing on the highest risk health care workers, first responders and the elderly. The trial that I am involved with is a collaboration with Baylor College of Medicine, MD Anderson Cancer Center (Ashish Kamat, MD, is one of the principal investigators), Texas A&M University, Cedars-Sinai Medical Center, and Harvard University (NCT04348370). This was largely conceived of and led by the infectious disease community, but they logically tapped into the urologic community because we have experience with BCG. The primary outcome measure is incidence of COVID-19, and the secondary outcome measure is disease severity. We do not feel these trials will have a material negative impact on BCG supply as a single vial that is used for 1 treatment of BCG in a patient with bladder cancer can vaccinate up to 500 subjects.

Is there anything else you’d like to add?

I serve on the board of directors for the Bladder Cancer Advocacy Network (BCAN). They have been very active in calling attention to the BCG shortage and trying to develop strategies for patients who face many challenges navigating this complex situation.

As a community, we must always be sensitive to the needs of patients, and work very closely with them. Consider a patient who is out 12 or 18 months and never recurred, receiving their maintenance BCG and surveillance cystoscopies. Then their doctor tells them that, in order to manage this shortage, their treatment is being stopped. That can come as a big shock to patients, and it can create a lot of concern and anxiety. We can reassure them that they have already received most of the benefit and will continue close surveillance. In addition, we need to use BCG only for the highest risk patients. That will go a long way towards helping manage the shortage. Finally, we need to support clinical trials that could lead to getting new strains into the market as well as clinical trials evaluating other drugs that could be used to treat patients with alternative agents if shown to be as effective as BCG.

1. Merck announces plans to construct new facility in the united states to expand manufacturing capacity for TICE BCG. Press release. Merck. October 14, 2020. Accessed October 15, 2020. https://bit.ly/2HBYJhW

2. Messing EM, Tangen CM, Lerner SP, et al. Effect of intravesical instillation of gemcitabine vs saline immediately following resection of suspected low-grade non–muscle-invasive bladder cancer on tumor recurrence SWOG S0337 randomized clinical trial. 

 2018;319(18):1880-1888. doi:10.1001/jama.2018.4657.

3. Au JL, Badalament RA, Wientjes MG, et al. Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial. 

 2001;93(8):597-604. doi:10.1093/jnci/93.8.597

4. Biot C, Rentsch CA, Gsponer JR, et al. Preexisting BCG-specific T cells improve intravesical immunotherapy for bladder cancer. 

 2012;4(137):137ra72. doi:10.1126/scitranslmed.3003586

5. Hegarty PK, Sfakianos JP, Giannarini G, et al. COVID-19 and bacillus Calmette-Guérin: What is the link? 

 2020;3(3):259-261. doi:10.1016/j.euo.2020.04.001

Articles

In this interview, Seth P. Lerner, MD, discusses current recommendations for managing patients during the BCG shortage, what the FDA is doing to resolve the problem, and a SWOG trial testing a new strain of BCG.

The BCG shortage: What's being done—and what you can do

 Editorial Consultant, is executive director of the American Board of Urology, Charlottesville, Virginia.

Androgen deprivation therapy (ADT) has been a mainstay of treatment for advanced prostate cancer for decades and has been shown to provide long-term disease control and improve symptoms. However, there is evidence that ADT increases cardiovascular (CV) risk, especially in men with preexisting CV disease.

 Additional concerns for gonadotropin-releasing hormone (GnRH) agonists are delayed castrate levels of testosterone and the need for intermittent injections, among many others.

The recent results of a phase 3 randomized controlled trial investigating relugolix, an oral GnRH antagonist, vs leuprolide may change the landscape in the treatment of advanced prostate cancer (see article, page 8). HERO (NCT03085095) was a multinational, open-label trial that randomized 934 men 2:1 to treatment with relugolix (360 mg on day 1, then 120 mg po qd) or subcutaneous leuprolide injection 22.5 mg (11.25 mg in Japan and Taiwan) every 3 months. Eligible men had confirmed advanced prostate cancer defined as biochemical or clinical relapse, metastatic disease, or advanced localized disease. Additionally, the men had to have serum testosterone levels of 150 ng/dL or greater, serum prostate-specific antigen above 2 ng/mL, and require at least 1 year of ADT. Men with a history of ADT for more than 18 months, active liver disease, or significant CV risk were excluded. The primary end point for the study was sustained castrate levels of testosterone
(< 50 ng/dL) through the 48-week study.

The 2 groups were well balanced in their clinical characteristics. In addition, both arms met the primary end point with 96.7% of relugolix patients and 88.8% of leuprolide patients achieving sustained suppression of testosterone.

Key differences in secondary end points were a much quicker suppression to castrate levels (56% vs 0%, at day 4) and a quicker return to normal by day 90 (54% vs 3%) in the relugolix vs leuprolide arms, respectively. As expected, it took approximately 1 month for the leuprolide-treated patients to reach castrate levels. Known adverse events (AEs) such as hot flushes and fatigue were very similar in both groups, with more grade 1 or 2 diarrhea in the relugolix arm, but this did not result in study discontinuation. Major adverse cardiovascular events (MACE) were 2.9% in the relugolix-treated patients and 6.2% in the leuprolide-treated patients. The authors performed a Kaplan-Meier analysis of cumulative MACE incidence over the study period and found a 54% risk reduction in the relugolix group.

If further studies confirm the efficacy and lower CV adverse effects with this new oral GnRH antagonist, this could make a substantial impact on most urologists’ practices. Patients could avoid an injection, initial testosterone surge would be alleviated, and a significant reduction in CV events would be realized. However, several questions remain to be answered, among them the following: 1. What will be the cost of this new oral therapy? 2. Will third-party payers reimburse for the therapy with currently available injectables already on the market? 3. Will the quicker testosterone recovery make this a more appealing option for intermittent therapy? 4. Might we see more gastrointestinal AEs in a larger trial? 5. What will the AE profile look like when this drug is given in conjunction with nonsteroidal antiandrogens such as bicalutamide?

Although there remain several unanswered questions about this new drug, the initial report is very promising. This new therapy could change the landscape for the treatment of advanced prostate cancer.

1. Van Hemelrijck M, Garmo H, Holmberg L, et al. Absolute and relative risk of cardiovascular disease in men with prostate cancer: results from the population-based PCBaSe Sweden. J Clin Oncol. 2010;28(21):3448-3456. doi:10.1200/JCO.2010.29.1567

"This new therapy could change the landscape for the treatment of advanced prostate cancer," Thrasher writes.

Are phase 3 HERO results a game-changer for urologists?

	Active surveillance (AS) continues to gain traction as a management strategy for low-risk prostate cancer in the United States. However, barriers still exist and challenges remain for both the treating urologist and the patient.

	Marzouk et al evaluated 463 patients enrolled in AS from March 2000 through January 2016. A total of 413 patients completed a prostate cancer quality of life survey as part of the follow-up. Questions related to the anxiety associated with their prostate cancer. Estimating equations were used to test the association between the risk of anxiety and age, marital status, PSA, Gleason sum, number of positive cores, family history, overall state of health, and length of time on AS.

	The authors found that the risk of anxiety decreased over time, and those reporting high overall health scores had lower anxiety levels throughout their duration on AS. They conclude that although moderate levels of anxiety exist in patients on AS, it significantly decreases over time and this should be taken into consideration when counseling men.

	This study adds to a growing body of information on how men perceive AS, its effect on their emotional well-being, and reasons they might consider leaving an AS protocol. Berger et al interviewed a small sample of the 1,159 men on the Johns Hopkins AS program who self-elected to leave 

 The authors noted that those electing to leave the program had higher baseline PSA levels and younger age. They also noted that this subset of men continued to feel anxious about their cancer and viewed AS as a way to delay treatment rather than avoid it. Additionally, the attitudes and worries of family members and loved ones were potential influences on the decision to leave the AS program.

	The take-home for all of us who treat low-risk prostate cancer and use AS protocols is that we need to tailor our counseling to consider many of these factors. Family members and loved ones should be included, when possible, in the counseling session. Detailed counseling regarding the very slow growth rates of low-grade prostate cancer, the protocol for follow-up, and trigger points for further decisions/intervention should be covered and questions answered to minimize anxiety.

	However, further studies are needed in this patient population to answer numerous questions: What should a standard AS protocol look like? How should contemporary imaging and genetic testing be incorporated? Should older men or those with multiple comorbidities be counseled differently than younger, healthy men? And finally, how should family members and loved ones be integrated into AS protocols?

SNS vs. botulinum: Caveats, considerations

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“Active surveillance continues to gain traction as a management strategy for low-risk prostate cancer in the United States. However, barriers still exist and challenges remain for both the treating urologist and the patient,” writes J. Brantley Thrasher, MD.

Challenges remain for active surveillance in low-risk PCa

The role of biopsy in renal masses is evolving. For large renal masses in particular, new data suggest biopsy may change the management of patients with certain high-risk features, according to 

 assistant professor of urology at the University of Wisconsin School of Medicine and Public Health Madison. Dr. Abel discusses biopsy’s role in small and large renal masses, associated risks, and when patients can be safely observed. Dr. Abel was interviewed by 

 Editorial Consultant J. Brantley Thrasher, MD, professor and chair of urology at the University of Kansas Medical Center, Kansas City.

Let’s start by discussing the small renal tumor. In the past, conventional wisdom was that a biopsy doesn’t add very much information. If you’ve already decided that a tumor needs treatment based on imaging, then doing a biopsy will only potentially cause a complication or lead to an indeterminate result. In your mind, which patients should be offered percutaneous biopsy for small renal masses today?  

	That’s an excellent question. I do think we should at least discuss renal mass biopsy with the vast majority of patients who have small renal masses. The biopsy informs patients and improves the decision-making process for treatment. Biopsy ultimately provides more information that allows the surgeon to provide better informed consent for treatment.

Immunotherapy shows survival benefit in advanced RCC

	Given that about 20% of small renal tumors are benign in almost all surgical series, it’s difficult to make the argument that you can decide if a patient needs treatment based on imaging alone. Simply, biopsy allows identification of some patients with benign tumors, who may be spared unnecessary treatment. Biopsy is especially valuable for older patients with comorbidities or for patients who are poor candidates for nephron-sparing techniques.

	Finally, serious complications from percutaneous biopsy are rare in experienced centers, especially when compared to the possible complications from treatment.

Next: "Imaging has certainly improved the detection of lipid-poor angiomyolipomas but is not perfect."

Doesn’t improved imaging give us a better idea of whether a tumor might be an oncocytoma or angiomyolipoma, most of which are not renal cell cancers in the first place? Or do you still think there are places where we might benefit from biopsy for identifying benign versus cancerous masses?

	Lipid-poor angiomyolipomas and oncocytomas are two tumors that comprise the majority of benign tumors in surgical series. Imaging has certainly improved the detection of lipid-poor angiomyolipomas but is not perfect. If we can identify lipid-poor angiomyolipomas or oncocytomas from biopsy, contemporary studies have demonstrated that treatment can usually be avoided for these benign tumors. However, in younger patients with larger tumors, most experts would agree there’s less of a role for biopsy.

	Large renal masses demonstrate significant heterogeneity in radiological appearance. A multiquadrant technique samples cores from multiple enhancing areas in tumors, whereas standard technique obtains tissue from asingle location. (Source: Reprinted from the Journal of Urology, Vol. 194, page 887, Copyright 2015, with permission from Elsevier.)

How about women in childbearing years? Would you limit biopsy in those cases too?

	Biopsy is not appropriate for everyone and the decision should be made for each patient individually. However, I think it’s important to realize that biopsy is one way to avoid the morbidity associated with overtreatment of small renal masses. Overtreatment is associated with a decrease in renal function and increased cost of treatment. The potential risks associated with biopsy are very small, and it does provide more information to help patients make decisions.

What are those risks? When you’re doing informed consent with patients, what do you tell them?

	The risk is probably dependent on the institutional experience. In our last 700 patients, we’ve had less than 1% incidence of Clavien III complications-those requiring additional treatment. Most complications are related to bleeding and less than 1% of patients will require blood transfusion or angioemobolization.

Next: "The practice of urologists performing biopsies is encouraging."

Practicing urologists may be concerned about sending a patient to interventional radiology to do the biopsy and have the urologist take care of the complication. There’s also a concern about the radiologist doing cryotherapy or a percutaneous treatment right in the suite. Does this remain in our purview as urologists?

	Definitely. At our institution, we have a close relationship with our radiology department and communicate about patients frequently. Improving future patient outcomes is really dependent on cooperation across disciplines. However, it’s important that urologists continue to maintain ownership of these patients because we are trained to understand the tumor biology of kidney cancer and we follow these patients for years to observe the natural history of renal masses. The practice of urologists performing biopsies is encouraging.

	A gross pathology specimen demonstrates distinct pathologic diagnoses among different regions of large renal cell carcinoma. (Source: Reprinted from the Journal of Urology, Vol. 194, page 889, Copyright 2015, with permission from Elsevier.)

If you believe by imaging that you’re looking at a small, percutaneous tumor, how does biopsy help you risk-stratify patients?

	For the patient who has a very limited life expectancy and a very small tumor, it’s probably not helpful to identify whether or not a tumor is cancerous since it will not likely affect their life expectancy. In very young patients, biopsy is also probably not as helpful.

	But there are a lot of gray areas, since most patients with renal cell cancer are in their 60s or 70s and are healthy but have some comorbidities or borderline renal function. Patients may choose different treatments if they know that they have a benign tumor or a malignancy. If patients understand that they have cancer, some would feel more comfortable consenting to surgery.

Next: "I have had many patients in their 70s ask if a mass can be just followed instead of treating it. What do you tell them?"

I’ve had a few older patients who are not in great shape say that if they have cancer, they need to identify that for their cancer insurance policy; that’s one of the reasons to do a biopsy. Also, I have had many patients in their 70s ask if a mass can be just followed instead of treating it. What do you tell them?

	The minority of small renal masses will be aggressive tumors. But if you identify an aggressive tumor in an older patient, you may be more likely to treat it. If you identify a grade 4 or sarcomatoid tumor, even when it’s 2 or 3 centimeters, you may offer aggressive treatment to an older comorbid patient.

Patients also tell me they’ve read that aggressive cancer can actually spread cancer along the needle tract. What do you tell them?

	That is a very rare, almost theoretical risk with modern techniques. We struggle sometimes with explaining rare events because we can’t define the exact risk. We have not seen tumor seeding our institution in the last 20 years, and there have been very limited reports of it. It’s a theoretical concern, but we know that biopsy tract seeding is a rare event for any cancer that involves doing a biopsy, such as prostate cancer.

When you have an upper pole or lower pole tumor that may be extending into a calix or coming from the calix, do you use an endoscopic approach first before placing needles in those tumors?

	Yes. More central tumors and those we suspect are urothelial cancers are approached ureteroscopically rather than percutaneously.

Next: How do you see percutaneous biopsy fitting into the large heterogeneous class of renal masses?

How do you see percutaneous biopsy fitting into the large heterogeneous class of renal masses?

	In the management of locally advanced and metastatic renal cell cancer, there is not a lot of data to guide us how to use biopsy. For large, locally advanced but non-metastatic tumors, extended lymph node dissection certainly benefits some patients but may also be associated with increased morbidity.

RCC trials don’t mirror real-world experience

	Several groups have identified poor prognostic factors for patients who harbor lymph node metastases, including advanced clinical stage, high Fuhrman grade, clear cell renal cell cancer, necrosis in the specimen, and sarcomatoid features. If the primary tumor demonstrates these high-risk features from biopsy, the surgeon has that information prior to surgery, and you can discuss more aggressive surgery preoperatively with the patient.

	We know these large heterogeneous renal tumors frequently have areas with different tumor grades and rare aggressive pathologic features, such as sarcomatoid de-differentiation. Prior studies of large renal mass using a standard biopsy technique to obtain multiple cores from a single site may be prone to error from sampling. We presented data at the 2015 AUA annual meeting using a novel multiquadrant technique that obtains multiple samples from different sites in large tumors. Using this technique, we demonstrated a higher detection rate of sarcomatoid features, increasing sensitivity from 11% in prior studies to about 85%, and we had no higher rate of complications with this technique.

In patients with advanced disease, the medical oncologists are asking us to debulk the tumor before immunotherapy. In those cases, is there any reason to proceed with a biopsy?

	Even with newer therapies, there’s certainly a role for cytoreductive nephrectomy in many patients. However, we know from population-based studies that less than half of patients with metastatic disease undergo a cytoreductive nephrectomy; biopsy definitely has a role in identifying metastatic disease in those patients. Subtyping and getting those patients into appropriate treatment is important because some of the treatments work better than others for clear cell carcinoma.

	In patients with metastatic disease, renal mass biopsy using a multiquadrant technique demonstrated fewer non-diagnostic biopsies.

Study: High surgeon volume linked to post-RP outcomes

	In the future, biopsy may be increasingly utilized to identify metastatic renal cell cancer patients who are unlikely to benefit from nephrectomy. For example, metastatic renal cell cancer patients with sarcomatoid de-differentiation in the primary tumor are known to have exceptionally poor survival and may not benefit from cytoreductive surgery.

Next: "I think we need to continue to be aggressive with cytoreductive surgery."

At our institution, medical oncologists often question whether a patient is a good candidate for cytoreductive nephrectomy simply because their tumor is advancing so quickly. They advise watching it for another 3 to 6 months. Is biopsy helpful in those cases, or are you simply watching the biological growth of such a tumor?

	In metastatic patients, biopsy establishes a diagnosis for histologic subtype of renal cell cancer. In patients with non-clear cell subtypes for whom there are not great systemic treatments, surgery remains a viable option. I think we need to continue to be aggressive with cytoreductive surgery, including nephrectomy, metastasectomy, and lymph node dissection. Despite the development of newer and better systemic therapies, most patients continue to have very poor outcomes, and surgery will be important for the foreseeable future in the treatment of metastatic renal cell cancer.

One other argument against biopsying large masses is that, in many cases, it leads to non-diagnostic results. How often does that happen in your series?

	We presented another study at the 2015 AUA annual meeting evaluating patient and tumor characteristics that were predictive of non-diagnostic findings from biopsy. Factors that may increase non-diagnostic rate are: tumor size, radiologic enhancement, the presence of cystic features, and the distance from the tumor to the skin. We reported a non-diagnostic rate of about 15%, which is similar or less than other large series.

Study appears to refute obesity paradox in kidney cancer

	The lack of consensus definitions for “non-diagnostic” biopsy is a source of considerable variability in reported biopsy diagnostic rates. It is important to note that the definition of non-diagnostic should also include biopsies that have only normal renal tissue and have likely “missed the target.” These findings should not be interpreted as benign.

	In large renal masses with a standard biopsy technique (multiple cores from one site), approximately 10% to 11% of biopsies are non-diagnostic. Using the multi-quadrant technique to sample several sites within large tumors decreased the non-diagnostic rate to 0% in our experience.

Next: "I think biopsy is relevant to anyone who sees patients with incidental renal masses."

You work at a major institution where people are doing this a lot. How is this relevant to the average private practitioner in a community hospital?

	I think biopsy is relevant to anyone who sees patients with incidental renal masses, although experience is definitely helpful to get the best results. To maintain good quality of care, discussing the approach to renal mass biopsy with your abdominal or interventional radiologist is important. If the urologist is performing a biopsy in the office, I think it’s important to carefully plan the procedure and begin with less anatomically complex lesions. It’s certainly reasonable to expect good results with renal mass biopsy, just as we do with other complex office procedures.

We know that partial nephrectomies for small renal masses are not done very often by private practitioners. They’re simply doing a radical nephrectomy. If you’re going to approach that surgery laparoscopically, would there be a reason to do a biopsy at the time and potentially avoid a nephrectomy?

	I think we should always use nephron-sparing and minimally invasive approaches when feasible. If a urologist sees a patient with a small central renal tumor and feels that the patient will need a radical nephrectomy for treatment, biopsy can be especially helpful. In most patients with benign masses such as oncocytoma, active surveillance is a better choice compared to radical nephrectomy.

Next: "We really believe it’s an advantage to have the pathologic diagnosis before the procedure."

The average urologist might consider doing a biopsy laparoscopically prior to definitive treatment. Would you recommend that approach?

	We really believe it’s an advantage to have the pathologic diagnosis before the procedure. Unfortunately, frozen pathology is not always reliable and establishing the diagnosis in patients treated with ablation is critical so that we know how to follow patients afterward. Historically, many patients were treated with thermal ablation without a biopsy, which makes it difficult to follow these patients clinically afterward.

I’ve looked at some of the cryotherapy series and some radiofrequency ablation (RFA) series. It appears that results with cryo might be a little better than with RFA, but our interventional radiologists are doing RFA in their suite. Do you favor one or the other at your institution?

	It’s a difficult question because we don’t have head-to-head, prospective, randomized studies. We actually do a lot of microwave ablation. Microwave is similar to radiofrequency ablation, but it’s a little bit more powerful and it provides a bit of a coagulation effect. Institutionally, we favor microwave ablation and we have good results. Patients who are young with no medical comorbidities are not generally selected for ablation.

Next: "If you do ablation, how are you following those patients afterwards?"

If you do ablation, how are you following those patients afterwards?

	We do MRIs post ablation in most patients. Especially in younger patients, there’s a concern about limiting radiation exposure. There’s not high-quality, evidence-driven data guiding us on the best methods to follow patients post ablation, but we generally obtain abdominal MRI or CT, and obtain labs/chest imaging similar to patients after surgery.

If you have some rim enhancement in that lesion, are you going back and doing biopsies or just following?

	To ensure there is no viable tumor present after ablation, we may biopsy the ablation bed at about 9 months. With no viable tumor, we can extend the interval between surveillance MRI or CT. Another approach is to follow with serial imaging at shorter intervals.

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In this interview, E. Jason Abel, MD, discusses biopsy’s role in small and large renal masses, associated risks, and when patients can be safely observed.

J. Brantley Thrasher, MD

Articles

The BCG shortage: What's being done—and what you can do

Are phase 3 HERO results a game-changer for urologists?

Challenges remain for active surveillance in low-risk PCa

Renal biopsy may alter management in high-risk patients