Around the Practice is a monthly urologic virtual tumor board featuring live case review from multidisciplinary experts, presented by 

® in partnership with LUGPA. On January 20, 2021, a panel convened to discuss cases involving an incidentally discovered renal mass as well as upper tract transitional cell carcinoma. What follows is an edited portion of the panel’s conversation regarding the upper tract transitional cell carcinoma case.

The panelists included moderator Raoul S. Concepcion, MD, FACS; Jason M. Hafron, MD; Joelle Hamilton, MD; and Jeremy D. Handel, MD.

In this case, the patient is a 64-year-old White male who presents with a 3-day history of asymptomatic gross hematuria, no voiding complaints, and no history of stones. He was a 2-pack/day smoker for 25 years, and his medical history is otherwise noncontributory. He has a history of colorectal cancer with both his younger brother and father.

The exams are unremarkable. Cytology is nondiagnostic. Office cystoscopy is negative for any type of bladder lesions. The provider conducted an upper tract work-up per guidelines. CT imaging showed a big filling defect in the left renal pelvis. Dr Hamilton, is there a role for genetic testing in this patient?

Yes, there is. The first thing that comes to mind is Lynch syndrome. Lynch syndrome occurs when there is a germline mutation in mismatch repair genes, resulting in loss of mismatch repair proteins MLH1, MSH2, MSH6

PMS2, which can be detected by immunochemistry [IHC]. An abnormal test of any of these 4 proteins on IHC suggests possible Lynch syndrome.

Up to 15% to 20% of patients with Lynch syndrome will develop an upper tract urothelial cancer. The urologist can refer a patient to a genetic counselor or a medical oncologist to discuss germline testing if the immunohistochemistry stains suggest presence of Lynch syndrome or if the family history suggests Lynch syndrome. Genomic sequencing of the tumor can be done to assess for the presence of [microsatellite instability–high], but the IHC stains are a more cost-efficient and accessible test.

Regarding the patient’s family history, he likely fulfills the Amsterdam Criteria detailed in the National Comprehensive Cancer Network guidelines (brother and father with colon cancer). If the patient’s brother received a diagnosis of colon cancer prior to age 50, the patient would fulfill the Amsterdam Criteria for further evaluation of Lynch syndrome, which will frequently be covered by the patient’s insurance.

The most cost-effective and available form of testing is IHC of the original pathology. When Lynch syndrome is suspected by the family history as per the Amsterdam Criteria, genetic counseling can be done regarding germline testing. A third and less cost-efficient way is genomic sequencing.

Dr Hafron, from a diagnostic approach and a therapeutic approach, please walk us through how you would manage this patient.

My first step would be to do a ureteroscopy and take a biopsy of the lesion. You need to get tissue. Radiographic images are no longer adequate for any surgical resection. I typically biopsy with a basket. Tissue is king, and with a forceps biopsy, you really don’t get good tissue. I will also do a selective cytology. I think that’s critical, as well, to further stage the disease. And then I think the issue of pathology becomes very important. It’s a new way to look at these lesions because with the advent of newer chemoablative agents, specifically Jelmyto [mitomycin-containing reverse thermal gel], there is potential now for nephron-sparing approaches for treating these lesions.

Historically, we would only consider nephron-sparing procedures for patients with bilateral disease, solitary kidneys, or acute or chronic renal insufficiency. But now, we’re starting to see that there is an option for nephron-sparing surgery patients with low-grade disease. Low-grade disease typically represents about 30% of patients who present with upper tract masses. The tissue is very important, and the grade of the tissue is very important.

The grade of the tissue in upper tract correlates much better with invasive disease. High-grade in upper tract is considered invasive and I personally consider it to be systemic disease. That’s different from bladder, because we know we can get high-grade lesions in the bladder that are noninvasive. High-grade disease is a different disease. If you find a patient with low-grade disease and their tumor is less than 2 cm and they have low-grade selective cytology, you really should consider nephron-sparing approaches.

I think there’s a major educational deficit in urology. Not all tumors in the upper tract require a nephroureterectomy; 30% of these patients potentially qualify for nephron-sparing treatment. The critical aspects are the evaluation and the work-up. You really have to make sure that they’re truly low-grade disease.

For this particular case, access should be relatively straightforward, but oftentimes, because we’re generally using flexible ureteroscopy, there can be access problems, whether it be because of a body habitus, torturous ureter, ureteral stricture. What if this was a filling defect, say in a minor calyx, where you cannot get deflection of the scope with your biopsy forceps? Dr Handel, what is the role of percutaneous access to get tissue?

I’ve never heard of this being done specifically. But if there was a unique situation with extenuating circumstances, and no other option was available, I could conceive of a way to do this. To be clear, this would be beyond the normal scope of practice. I can think of 1 case where I actually did get access for a ureteral mass, and then I ended up doing a biopsy.

When we look at percutaneous nephrostomy access, one of the ways we assess cases is dilated versus nondilated. When we’re doing a nephrostomy access for something that has a nondilated collecting system, like a surgical injury or some type of leak or fistulous communication. It is far easier to access in obstruction, where they have a dilated calyceal system.

When we’re trying to get nephrostomy access into a decompressed system, it’s like trying to slide a needle between 2 pieces of paper deep into the belly. That can be pretty challenging. We have several ways to approach that. One is what we call tandem technique, where we intentionally stick a 21-gauge needle centrally knowing full well it won’t be our definitive access. We use it to distend the collecting system. That allows us to visualize and then stick a safe place that we can upsize to a more definitive access.

Another option is to give Lasix and contrast intravenously. There’s a sort of cocktail that is used to provide visualization of the collecting system for access, to give you transient opacification, or just [intravenous] contrast to opacify it.

Once you get access in the collecting system, you would have to maneuver toward the lesion under fluoroscopy. This is the kind of case that involves discussion with the urologist, and maybe even having both the urologist and radiologist in the room at the same time, with retrograde access, to make sure the right spot is being biopsied.

In this particular case, it’s a nice-sized calyceal system. Obtaining access wouldn’t be a problem. But if it’s not dilated, that could be tricky; just simply getting access can be a very tricky procedure.

Dr Hafron, let’s say pathology comes back with low-grade disease. What are the current therapies that are approved for the management of low-grade upper tract urothelial cancer?

Currently, Jelmyto is the only approved therapy. One of the biggest publications that came out of 2020 was the OLYMPUS trial (NCT02793128) that led to fast-tracked FDA approval of Jelmyto.

This is a chemoablative drug that is instilled as a liquid, but is heated by body temperature to a gel form, delivering about 6 hours of mitomycin in that area. The OLYMPUS trial evaluated Jelmyto in patients with tumor size of 15 mm or smaller. Impressively, 59% of patients had a complete response.

I’ve had a handful of patients that we’ve treated with Jelmyto, and I think it’s going to really improve our care and save a lot of kidneys so that we don’t always have to go to radical nephroureterectomy. We potentially can decrease our recurrence rates with this and potentially minimize progression to invasive disease.

In addition, Steba Biotech is conducting a phase 3 trial of padeliporfin (TOOKAD VTP) evaluating that agent for low-grade upper tract urothelial cancer (NCT04620239). The science behind this is fascinating. Basically, the agent is based on algae and is a systemic infusion. After infusion, once the target tissue is exposed to light, this will cause necrosis of the lesion.

What’s critical when using Jelmyto is that these patients still have to be monitored; they still have to have regular ureteroscopy and imaging. Additionally, there was a 44% urethral stenosis rate reported in the OLYMPUS trial. Dr Surena Matin, who presented long-term data from the OLYMPUS trial at the 2020 Society of Urologic Oncology annual meeting, said that he’s transitioning to placing nephrostomy tubes for instilling Jelmyto, hoping that that will decrease the ureteral stenosis rate. I think we’re probably going to transition to using nephrostomy tubes to instill it was well.

Dr Hamilton, what if the pathology comes back as high grade? What is the role of either adjuvant or neoadjuvant therapy?

I do always like to have sufficient tissue on pathology so that I can have a detailed discussion and shared decision-making with the patient as to whether cisplatin is of benefit to them. What we do know from a meta-analysis is that adjuvant cisplatin increases cancer-specific, disease-free, and overall survival.

 There is also a clinical trial evaluating neoadjuvant gemcitabine-cisplatin versus
gemcitabine-carboplatin; however, it recruited very poorly, and the data for that trial are not out yet (NCT02412670).

But when you pool all the data together, there is benefit in overall survival and cancer-specific survival. It is difficult to get patients through, but I have treated patients in the neoadjuvant setting.

is director of the Comprehensive Prostate Center and clinical associate professor of urology at Vanderbilt University School of Medicine, Nashville, Tennessee.

is a partner at the Michigan Institute of Urology, PC; an associate professor of urology at the William Beaumont School of Medicine, Oakland University; and the director of robotic surgery at Beaumont Hospital Royal Oak
in Michigan.

is an oncologist with Urology Clinics of Alabama in Homewood.

is a vascular and interventional radiologist at Beaumont Hospital Royal Oak.

1. Leow JJ, Chong YL, Change SL, et al. Neoadjuvant and adjuvant chemotherapy for upper tract urothelial carcinoma: a 2020 systematic review and meta-analysis, and future perspectives on systemic therapy. 

. 2020;S0302-2838(20)30532-7. doi: 10.1016/j.eururo.2020.07.003

Articles

Determining grade of disease is important, as nephron-sparing approaches may be feasible.

Upper tract transitional cell carcinoma: Diagnostic and therapeutic considerations

In May 2020, the FDA approved the oral poly (ADP-ribose) polymerase (PARP) inhibitors rucaparib (Rubraca) and olaparib (Lynparza) for the treatment of metastatic castration-resistant prostate cancer. These 2 novel treatments represent the first approvals in this class of medications for prostate cancer. In this interview, 

 provides an overview of these treatments, discusses the key trials that led to their approvals, and explains the urologist’s role in their use. Antonarakis is a professor of oncology and urology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland. Antonarakis has served as a paid advisor to AstraZeneca, Merck, Clovis Oncology, Janssen, and Pfizer.

Could you provide an overview of PARP inhibitors? How do they work?

PARP inhibitors work on a principle called synthetic lethality. Briefly, PARP inhibitors increase the amount of DNA damage in the cancer cell. As a general principle, a little bit of DNA damage is a good thing for a cancer cell; it helps it survive and metastasize and grow more rapidly and proliferate. But too much DNA damage can be a bad thing because it can lead to catastrophic genomic instability and subsequent cancer cell death.

PARP inhibitors work best in cancers that have mutations in homologous recombination repair (HRR) genes. The most well-known of these in prostate cancer is 

 is a gene (and a protein) that is responsible for fixing double-strand DNA breaks. There is another way that cancer cells can fix DNA breaks, which is called single-strand repair, fixing 1 DNA strand at a time. So if you have a patient with a 

 mutation, that cancer cell’s ability to fix double-strand DNA breaks is impaired. It then relies on the other pathway, the single-strand repair pathway, to fix its DNA damage. That single-strand repair pathway is done by an enzyme called PARP, primarily PARP1. If PARP1 is inhibited by a drug, such as a PARP inhibitor, in a patient who already has a mutation in the alternative mechanism of DNA repair—in other words, 

—then that cancer cell develops catastrophic DNA damage, so that the next time it replicates it’s not able to survive and it dies.

Again, this concept is synthetic lethality. It simply means that you need a one-two punch to kill the cancer cells. The first punch comes from the genetic mutation that the cancer has, and the second punch comes from the PARP inhibitor, leading to catastrophic DNA damage in the cancer cell and subsequent cell death.

Please discuss the key findings from the TRITON2 (NCT02952534) and PROfound (NCT02987543) clinical trials of rucaparib and olaparib.

In May 2020, there were 2 FDA approvals for PARP inhibitors in prostate cancer within 5 days. The first was rucaparib, a PARP inhibitor approved based on a phase 2 single-arm study without a control group, called TRITON2. The TRITON2 study, in an unprecedented way, led to FDA approval of a drug in prostate cancer without requiring randomization and without having a control group. However, it was an accelerated FDA approval, meaning that full approval by the FDA is contingent upon a positive phase 3 randomized study (TRITON3 [NCT02975934]), which is ongoing.

TRITON2 evaluated patients who had 1 or more DNA repair gene mutations. The 2 genes of greatest interest were 

 and then there were a handful of other, more rare genes included as well. Patients had to have either germline mutations within 1 of those genes, or somatic mutations in a tumor in 1 of those genes. They then received rucaparib twice daily. The primary end point of the study was not overall survival or progression-free survival like other studies that we have seen, but rather the objective response rate. A secondary end point was the prostate-specific antigen (PSA) response rate. Approximately 40% of patients with a 

 mutation who received rucaparib had an objective response, and the PSA response rate was even higher at about 50%. The efficacy in the other non-

 genes was less impressive, and Clovis Oncology, the company making rucaparib, decided not to seek FDA approval for any of the other genes. Thus, the accelerated approval for rucaparib, granted in May of 2020, was only for patients with germline or somatic 

 mutations. The other small but important point is that the TRITON2 study required patients to have metastatic castration-resistant prostate cancer, and they had to have disease progression despite previously receiving at least 1 novel hormone therapy and 1 chemotherapy. The accelerated FDA approval reflected that patient population, meaning that patients who are eligible to receive this drug (now that it has been approved) should have previously received both a novel hormone agent plus a chemotherapy agent.

The second trial, which was the PROfound (NCT02987543} study, led to the full FDA approval of olaparib. This was a phase 3 randomized study for patients with a genetic mutation in 

 or 12 other genes. The primary end point of interest was radiographic progression-free survival for patients with either 

 mutations. A key secondary end point was overall survival in this cohort. Patients with metastatic castration-resistant prostate cancer who had received at least 1 novel hormone therapy, plus up to 1 chemotherapy (although the chemotherapy was not mandated), were randomized to receive either olaparib or a physician’s choice of hormonal therapy. The trial was positive, showing a significant prolongation of radiographic progression-free survival but also overall survival in the patients who had 

As a prespecified secondary analysis, the trial was also powered to evaluate the overall patient population that included patients with mutations in any of the 15 HRR genes, not just the 3 mentioned above. In that entire study population, there was also a prolongation of radiographic progression-free survival with olaparib compared with placebo. This led the FDA to approve olaparib for not just the 

genes, but also various other HRR genes, including 

What genetic testing is needed to determine a patient’s eligibility for treatment with a PARP inhibitor?

Patients with prostate cancer who are eligible for treatment with a PARP inhibitor have to have either a germline or somatic mutation in 1 or more of the DNA repair genes. In the case of olaparib, the range of genes is more expansive and includes 14 genes, including but not limited to 

 There are a few others as well. However, in the case of rucaparib, the treatment is restricted to patients who have either germline or somatic 

 mutations only. At this time, rucaparib cannot be recommended for patients with non-

Germline genetic tests can be done using saliva or peripheral blood leukocytes. Somatic genetic testing requires a tumor sample, either a metastatic tumor biopsy or an archival primary prostatic biopsy. In addition, there are now several commercial circulating tumor DNA assays that can assess tumor DNA using a blood test.

How will urologists be involved with the administration of PARP inhibitors?

In general, the prescriptions of these agents will mostly be coming from medical oncologists. However, urologists do have an important role in identifying patients for potential eligibility for PARP inhibitors down the line; for example, patients with germline mutations in 

 will become eligible for PARP inhibitor treatment if they eventually develop metastatic castration-resistant disease. Unlike somatic genetic testing, which is currently only recommended in the National Comprehensive Cancer Network guidelines for patients with metastatic disease, germline testing is recommended for patients with nonmetastatic prostate cancer as well; for example, if they have intermediate- or high-risk localized prostate cancer, if they have any type of localized prostate cancer with a family history of prostate, breast, or ovarian cancers, or if they have an ancestral Ashkenazi Jewish background.

If patients who don’t yet have metastatic or castration-resistant prostate cancer are identified by a urologist as having a germline mutation in a gene such as 

 then those patients could be prioritized prospectively for future treatment with a PARP inhibitor as soon as they become eligible, rather than trying to scramble and get a biopsy of metastatic tissue after the patient has already developed castration-resistant prostate cancer, where some time may be lost in planning for PARP inhibitor treatment.

The other interesting thing is we are now seeing studies evolving in the neoadjuvant space and adjuvant space, where PARP inhibitors are being investigated in an experimental fashion for patients who have mutations in 1 of these HRR genes. So it is likely that several urologists across the country may have access to 1 of these neoadjuvant or adjuvant or early biochemical recurrence studies that are incorporating a PARP inhibitor in an investigational fashion for patients with prostate cancer harboring germline or somatic HRR mutations.

What adverse effects should urologists be particularly mindful of when a patient receives a PARP inhibitor, and how are these effects optimally managed?

The adverse effects of PARP inhibitors are broadly similar and overlapping. They include fatigue, nausea, anorexia, and suppression of blood counts, especially platelets and white blood cells. Fatigue is usually self-limiting and does not require intervention, although sometimes a dose reduction may be needed. Anemia, in most cases, is also relatively asymptomatic, although in some patients, it can result in fatigue or dyspnea, or other clinical symptoms. In about 15% of patients, anemia can be severe enough to warrant a red blood cell transfusion. We also need to keep a close eye on the renal function of patients, especially creatinine level, because these drugs, as a class, can cause an elevation of creatinine.

There is 1 adverse effect that is specific to olaparib that does not appear to be present with rucaparib, and that is a dry cough. Olaparib is associated with a cough in about 5% of patients. The cough disappears when the drug is stopped and often reappears if the drug is introduced again, even in a lower dose. Also, there have been case reports of a rare but serious pneumonitis (inflammation of the lung), which again can rarely occur with olaparib, but has not been seen yet with rucaparib. Olaparib may also be associated with a slight predisposition to venous thromboembolic complications, such as deep vein thrombosis and pulmonary embolism.

Finally, these drugs all have a theoretical and real (but small) risk of either accelerating or inducing myelodysplastic syndromes and potentially even acute myeloid leukemia. In patients who are older and already have preexisting myelodysplasia, these drugs should probably be avoided. If there is any evidence of a myelodysplastic syndrome, these patients should see a hematologist who specializes in myelodysplasia and should discontinue PARP-inhibitor treatment.

Can you discuss the next steps for PARP inhibitors and prostate cancer, including combination therapy trials of PARP inhibitors with immunotherapies or androgen receptor (AR) pathway inhibitors?

There are at least 2 future directions for PARP inhibitor treatments. One is to combine these agents with other standard therapies for metastatic prostate cancer. We have been using drugs such as abiraterone acetate [Zytiga] and enzalutamide [Xtandi] for almost a decade now. These are natural combination partners with PARP inhibitors. There are a number of pivotal phase 3 studies that could lead to FDA approval of these combinations. For example, there is TALAPRO-2 (NCT03395197), a phase 3 randomized study of talazoparib plus enzalutamide versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer.

In addition, there is also the MAGNITUDE (NCT03748641) trial, a phase 3 randomized study evaluating niraparib plus abiraterone in patients with metastatic castration-resistant prostate cancer. The goal of those studies is to see whether the combination of a PARP inhibitor and a novel hormonal therapy might be successful in genetically-unselected patients; in other words, not just patients who might have 1 of these HRR gene mutations.

PARP inhibitors are also being studied in the metastatic hormone-sensitive setting. The recently launched AMPLITUDE trial (NCT04497844) is a phase 3 randomized study of abiraterone plus niraparib versus abiraterone alone (in combination with standard androgen deprivation) in patients with metastatic hormone-sensitive prostate cancer who have a genetic mutation in 1 of these HRR genes. So that one is a biomarker-selected design.

The second future direction is the combination of PARP inhibitors with immunotherapies, such as PD-1 inhibitors. There are a number of phase 3 studies that are either being designed or are currently enrolling patients. One example is the KEYLYNK-010 (NCT03834519) study, a phase 3 randomized trial of olaparib plus pembrolizumab versus either enzalutamide or abiraterone in patients with metastatic castration-resistant prostate cancer who have received 1 novel hormonal therapy and 1 taxane chemotherapy. That study is expected to read out in 2022.

Some experts have said that the approval of PARP inhibitors marks the dawn of the precision medicine era in prostate cancer. In your opinion, where does precision medicine go from here in the prostate cancer treatment paradigm?

The modern definition of precision medicine often involves a genetic or genomic test identifying a particular mutation that then leads to a vulnerability of cancer to a particular drug. I would argue that precision medicine in prostate cancer started 50 or more years ago because the AR is 1 of the prototypical oncogenes that we have been targeting in this disease for a long time.

In my opinion, we have at least 2 examples of precision medicine in prostate cancer thus far, but we are still way behind other cancers such as lung and breast. The first example came in 2017 when the FDA approved pembrolizumab for any patient of any cancer type with a mismatch repair gene mutation or microsatellite instability-high genotype. However, only 3% to 4% of prostate cancers have mismatch repair deficiency or microsatellite instability. A more recent example of precision medicine came in May of 2020, with the approval of rucaparib and olaparib for HRR-mutated or 

There are additional examples of precision medicine treatments in the pipeline. There are drugs that inhibit the AKT pathway or the PI3-kinase pathway that might be efficacious in prostate cancers with either deletion or mutation in 

 or with activation of PI3-kinase or AKT pathways. One example is the drug ipatasertib (an oral AKT inhibitor), which has been tested in patients with 

 loss and may lead to FDA approval in those patients based on the positive results of the IPATential150 (NCT03072238) trial.

In this interview, Emmanuel S. Antonarakis, MD, provides an overview of rucaparib (Rubraca) and olaparib (Lynparza), discusses the key trials that led to their approvals, and explains the urologist’s role in their use. 

PARP inhibitors and prostate cancer: What urologists need to know

“It depends on the situation. If it’s an obvious situation, where the urinalysis is normal, there’s no postvoid residual, and it seems like classic stress incontinence, I don’t necessarily do urodynamics.

We typically do urodynamics when something’s unclear and confusing. I don’t always do urodynamics before doing a sling.

In the majority of cases that need a sling, where they need fewer than 5 to 6 pads a day, if for some reason the history is not clear, I would do urodynamics. If the history seems clear and reasonable, and there aren’t other issues, I don’t do urodynamics because it doesn’t really help me decide. I don’t do urodynamics unless it’s going to influence my decision or help the decision process in some way.

The decision process could indicate a patient may not be a good candidate for a sling. If, for some reason, you’re concerned there’s some other issue—involuntary contractions or another type of neurogenic component in his bladder—urodynamics can help identify that a person is not a good candidate for a sling. But in a straightforward case, I don’t necessarily do it.

Obviously, if the patient had infection, high postvoid residual, or a history of neurological issues, whether it’s a previous stroke or some other neurological condition that could influence bladder function, it’s a good tool to have if used in the right place.”

“I use urodynamics in my patients for several reasons. I want an objective evaluation of the severity of their outlet incompetence, giving me an estimation of their leak-point pressure. It provides good objective proof that it’s stress incontinence. A lot of patients suffer mixed incontinence, and if there’s a significant overactive bladder component that hasn’t been adequately addressed, oftentimes I address that first, to see if we can get the patient to a point where they have satisfactory control.

It also really provides a baseline reference so if they develop recurrent incontinence after a sling or an AUS [artificial urinary sphincter], I can repeat the study and have a look before they have anything done to compare to data after.

I have no objection to the approach of not doing urodynamics if it’s demonstrated the patient has stress incontinence and empties well. It’s not a requirement, but it’s a reasonable adjunct. Moreover, for patients who are considering a male sling as opposed to an AUS, it’s important we delineate the severity of their incontinence because the literature is replete with examples that slings are for patients that fit some strict criteria regarding their degree of incompetence.

Urodynamics allows me to have more confidence that we have properly selected those patients.

Urodynamics itself is incredibly low risk. There’s a small risk of infection but it’s more objective support that we’ve made an accurate diagnosis and we’ve objectively evaluated the severity of that diagnosis to guide the decision-making of the sling versus artificial sphincter.”

“We usually do urodynamics prior to doing either a sling or a sphincter. It’s part of the work-up to assess the capacity and compliance.

My partner does the sphincters, but I’m sure there are some situations where they don’t have any preoperative lower urinary tract symptoms with a relatively normal-sized prostate [and] normal-sized bladder and everything looks fine, [and]where they had no symptoms pre-op. [In those cases,] maybe they may consider doing it without urodynamics. But if you can you do the urodynamics, there’s little downside to doing it. You might end up with someone who has a noncompliant bladder or similar issues that you could treat prior to a sling or sphincter that might improve their symptoms, and which might be a contraindication to doing a sphincter.

You don’t want to block up a bladder that has really poor compliance because then the pressure is just transmitted to the upper tract. Usually, that would be like a neurogenic bladder, somebody with a lot of symptoms pre-op, so that’s going to be unusual.

You can also give them an idea of whether they have an element that’s not going to be necessarily treated with the sphincter. Sphincters are going to treat all stress-related incontinence, but if there is an element of urge, the patients might need to be on medication after surgery, so you can counsel them about that as well.

You can use urodynamics no matter what procedure you’re considering, but the sphincter would provide more back pressure than the sling in general.”

is in group practice and is an assistant clinical professor at Texas A&M University in Dallas, Texas, 

an associate professor of urology at the University of Arizona, Tucson, and 

is assistant professor of urology at Albany Medical College and urology section lead at Albany Stratton VA.

"We typically do urodynamics when something’s unclear and confusing. I don’t always do urodynamics before doing a sling," says 1 urologist.

Do you use urodynamics when determining when to insert a sling following a prostatectomy?

Intravesical instillation of BCG remains the most frequently utilized therapy against high-grade non–muscle-invasive urothelial bladder cancer (NMIBC). Treating urologists are quite familiar with the identification and management of early urinary and systemic adverse effects of BCG instillation. However, the spread of BCG infection to other organs is less well appreciated, likely due to the low incidence of such complications. Further, the published literature mostly consists of single-case reports. To increase awareness of these complications, Cabas et al performed a systematic review of the published literature demonstrating the frequency and timing of potentially serious post-BCG infections involving genitourinary (GU) and non-GU sites.

To identify all case reports of post-BCG infections, the investigators systematically reviewed 401 publications through Medline and other searches. Of these, 271 case reports, including 307 patients, met the inclusion criteria for the review. From these reports, the authors compiled data including demographics, tumor grade/stage, number of intravesical instillations, number of organs with BCG infection, time from last BCG instillation to signs of infection, type of imaging utilized, microbiological confirmation, type and duration of surgical and nonsurgical treatment, and patient outcomes.

Of the 307 cases of post-BCG infection, only 4 (1.3%) occurred in female patients. The average number of intravesical BCG instillations prior to developing symptoms of infection was 8 plus or minus 5.3 instillations. A single organ/site was infected in 72.0%, 2 organs were affected 20.2%, and 3 or more organs were affected 7.8% of the cases. Of all the cases identified by the authors, including those with multiple organs involved, BCG-related infection of GU organs occurred in 23.7% and non-GU organs were involved in 76.2% of cases. Most frequently involved sites included non-GU organs such as lungs, vascular system, and liver, whereas the various GU organs (testis, penis, prostate, and kidneys) were involved equally and infrequently.

The median time from last BCG instillation to clinical signs of infection varied and depended on the organs involved. The granulomatous infection of the liver and lungs (such as miliary pulmonary infection) occurred earlier, at a median time of 1 week from the last instillation. In contrast, vascular lesions (endograft graft infection or mycotic aneurysm), bone/joint involvement (prosthetics infection or spondylodiscitis), and muscular involvement (psoas abscesses) occurred late, at a median of 52, 68, and 93 weeks, respectively. Amongst the GU organs, penile lesions (erythema, ulcer, granulomatous lesions) appeared at a median of 1 week, prostatitis or abscess at 3 weeks, renal granulomatous disease at a median of 8 weeks, and epididymo-orchitis at a median of 56 weeks.

Overall, microbiological diagnosis was made in 55.6% of cases through acid-fast stain, culture, or polymerase chain reaction test. The rate of isolation and mycobacteria identification at the affected sites also appears to be related to the organs involved. Microbiological detection was noted in 28.6% of penile lesions, 35.2% of lung lesions, and nearly 60% of prostate/epididymis/testis lesions. The highest rates of microbiological detection of the mycobacteria were noted in vascular (83.6%), bone/joint (91.7%), and muscle lesions (100%). In evaluating concomitant infections at various sites, the investigators observed a strong association (

 < .001) between lungs and liver complications, bone marrow and liver complications, bones/joints and muscles, and lungs and bone marrow complications. No significant associations between concomitant infections and various GU organ sites were identified.

The reported duration of antimycobacterial therapy ranged from a median of 6 weeks for penile or testicular lesions, 8 weeks for lungs or liver lesions, and 12 weeks for bone/joint infections. Surgical intervention was most frequently required for cases of infections involving vascular (83%), bone/joint (85.4%), and muscular systems (90.5%), whereas surgical intervention was relatively infrequent for lung (6.8%) and liver (8.9%) infections.

Of the GU organs involved with post-BCG infection, a majority (55%-90%) of the penile, prostate, and kidney infections manifested within 1 month of the last BCG instillation, whereas testicular cases appeared after 12 months or longer. For the non-GU organs, there appears to be a biphasic distribution of the time to post-BCG infection. A majority (50%-75%) of the lung, liver, and bone marrow infections became apparent within 1 month. More than 50% of the infections involving vascular, muscular, and bone/joint systems appeared 12-24 months after the last BCG instillation.

An interesting observation from this compilation of 307 case reports is that only 1.3% of post-BCG systemic infections occurred in female patients. One may speculate that the male anatomy (bulbar urethra, prostate) is more prone to catheter-related trauma during instillation, followed by increased exposure of traumatized area to the BCG when voiding. Both of these would result in potential intravasation of BCG resulting in systemic spread of BCG. Thus, strict adherence to the protocol for canceling the BCG in the presence of infection, and aborting the instillation in the setting of trauma and/or any degree of gross hematuria, is required. Although systemic infections involving non-GU organs are uncommon, these infections are associated with significant morbidity, and mortality. Of the 65 cases of vascular involvement, 10 (15.4%) died of BCG-related complications. The mortality rate for the post-BCG infections involving lungs, liver, and muscles was reported to be 4.1%, 3.6%, and 4.8%, respectively.

This study provides clinically useful data on the frequency and timing of BCG-related infection of various organ systems. Urologists play a pivotal, long-term role in the diagnosis and treatment of NMIBC, and essentially serve as the primary oncologists for patients with NMIBC. It is essential for us to be vigilant about all the complications, whether local or systemic, associated with intravesical BCG. A high index of suspicion is required for early identification of these infrequent, but potentially lethal, post-BCG systemic infections.

1. Cabas P, Rizzo M, Giuffrè M, et al. BCG infection (BCGitis) following intravesical instillation for bladder cancer and time interval between treatment and presentation: a systematic review. 

2021;39(2):85-92. doi:10.1016/j.urolonc.2020.11.037

"It is essential for us to be vigilant about all the complications, whether local or systemic, associated with intravesical BCG," writes Badar M. Mian, MD.

Urologists must remain vigilant regarding post-BCG infection

In your article “What to know about COVID-19 CPT code 99072 for your urology practice”

, you stated, “You do not need to link the code to a particular diagnosis code such as ICD-10-CM U07.” Would you expound on that?

CPT code 99072’s description reads, “Additional supplies, materials, and clinical staff time over and above those usually included in an office visit or other nonfacility service(s), when performed during a public health emergency, as defined by law, due to respiratory-transmitted infectious disease.” As of the writing of this article, the current coronavirus disease 2019 (COVID-19) public health emergency is set to expire on April 21, 2021. CPT code 99072 can be linked to any international classification of diseases (ICD)-10 code used for the office or other outpatient evaluation and management service or other urology CPT code; it does not have to 

be linked to an ICD-10 code specific for a virus. The code was developed to help physicians offset the costs of supplies, time, and overhead required for all patients coming to the office during the pandemic.

Unfortunately, we have found that most if not all insurers do not pay for this code and additionally often have policies against charging patients for extra supplies, and balance billing would be a violation of their contract. You may attempt to report the code if your office is taking extra steps and purchasing extra supplies to maintain COVID-19-safe protocols; however, you may find that payers not only will not pay but may not process claims with this code reported. If you have already attempted to report the code and have not been reimbursed or seen rejections of claims outright, the problem is not diagnosis code-related but related to the status of the code for the payer, usually bundled.

1. Rubenstein J, Painter M. What to know about COVID-19 CPT code 99072 for your urology practice. 

®. October 14, 2020. Accessed January 12, 2021. 

Send coding and reimbursement questions to Rubenstein and Painter c/o

Questions of general interest will be chosen for publication. The information in this column is designed to be authoritative, and every effort has been made to ensure its accuracy at the time it was written. However, readers are encouraged to check with their individual carrier or private payers for updates and to confirm that this information conforms to their specific rules.

"Unfortunately, we have found that most if not all insurers do not pay for this code and additionally often have policies against charging patients for extra supplies, and balance billing would be a violation of their contract," write Jonathan Rubenstein, MD, and Mark Painter.

Urology coding Q&A: Is CPT code 99072 being paid?

® Clinical Practice Board, is a urologist in community practice in Colorado Springs, Colorado.

I’m not trying to hide anything; I’m really not. I have no problem with patients seeing everything in their chart. It is their medical record, after all. But I do think there should be some limitations on this access.

A surgeon I know was recently working near a major blood vessel and damaged it; things happen in the operating room despite our best efforts. The surgeon did the right thing, controlled the bleeding and in the process asked a vascular surgeon for help. After the vascular surgeon completed her work, the first surgeon finished the case, brought the patient to recovery, entered some orders in the computer, and then went to talk to the family. And the family was angry. Really angry. What happened? It turns out, the family was monitoring the chart during the case and saw the vascular surgeon’s draft operative note before either surgeon had a chance to talk to the family.

A vegan patient of mine on testosterone replacement had a slowly rising hemoglobin. Eventually, he started giving blood to the American Red Cross quarterly. We continued to monitor his labs and I started monitoring his ferritin level. Every medical student knows that chronic blood loss can lead to anemia secondary to iron deficiency. The patient called, angry that I was ordering unnecessary labs as we had never monitored ferritin level in the past.

In December 2016, the government signed the 21st Century Cures Act into law. As part of that law, the federal government mandated that health care providers offer patients free access to the medical records to include consult notes, discharge summaries, H&P’s, labs, pathology reports, imaging reports, clinic/progress notes, and all operating/procedure notes. There are a few exceptions, including psychotherapy notes and notes that might reasonably be assumed to be used in a civil or criminal case. And importantly, most systems are interpreting this law to mean near–real-time access to these records, including all notes in their draft form.

I tend to speak quickly and quietly. You might say I mumble. (You’d be right.) The number of errors I find in my draft operative notes is high and has only gone up since I’ve starting wearing an N95 when I dictate. I approached some of the hospital administrators about this potential issue and their response was that I should use pre-made templates for my procedures (dot phrases in the lingo of the hospital EMR). Further, they suggested that I stop dictating completely (a very expensive habit, I was told) and instead simply type. I believe that every case is different and hence my notes should reflect those differences and much to the administrators’ chagrin, I informed them that I am not a typist. Sorry.

Or we could not provide access to patients to notes in their draft form; they are, after all, in their draft form? Chuckle. Laugh. Get back to work, little cog.

The philosophy of “Open Notes” has been around for decades. Leaders in the field believe that providing real-time access to notes improves patient safety and patient engagement.

 I don’t disagree with those statements, but I do believe that the information patients are provided should be vetted and finalized before being published.

1. Blease C, Walker J, DesRoches Cm, Delbanco T. New U.S. law mandates access to clinical notes: implications for patients and clinicians. 

2021;174(1):101-102. doi:10.7326/M20-5370

"I have no problem with patients seeing everything in their chart. It is their medical record, after all. But I do think there should be some limitations on this access," writes Henry Rosevear, MD.

Real-time patient access to charts opens up real potential for misinterpretations

A 71-year-old man was seen by his primary care provider for a prostate-specific antigen (PSA) screen on December 5, 2011. The result was a level of 5.33. The patient’s primary care physician referred him to a urologist.

On April 5, 2012, the patient presented to the urologist for the elevated PSA. The urologist performed a history and physical exam. The urologist believed that the patient’s modestly elevated PSA was secondary to an enlarged prostate, otherwise described as benign prostatic hyperplasia (BPH). The patient was given some medication and told to return in 90 days for a repeat PSA study.

The patient did not return to the urologist until December 5, 2013. By that time, the patient’s primary care provider had repeated PSA studies in August 2013 and again in October 2013, which returned at levels of 6.67 and 5.8, respectively. At the second visit, the urologist discussed a microwave procedure to shrink the prostate. The urologist relied on the patient’s description that the values were initially high and then fell back slightly, but no repeat PSA study was performed. The urologist placed the patient back on finasteride and told him to return in 90 days.

The patient returned to the urologist a third time on April 16, 2014, and reported that his underlying urological problems had worsened. The urologist did not get a repeat PSA but concluded that the patient’s symptoms were caused by BPH. The urologist’s office subsequently carried out a microwave procedure on May 21, 2014 and told the patient to return for a follow-up. The patient never saw that urologist again.

In September 2014, the primary care provider obtained a PSA that reported out at level 8.8. The primary care provider advised the patient to see a urologist again.

In February 2015, the patient saw a second urologist who performed a PSA test, which returned at level 37. A biopsy proved prostate cancer, with a Gleason score of 7. Further evaluation and imaging studies in March 2015 revealed widespread metastatic disease to the ribs, sacrum, and spine. He was ultimately diagnosed with stage IV terminal prostate cancer.

The patient sued his first urologist, claiming medical malpractice. He claimed that the urologist was negligent for not doing a repeat PSA test and not offering a biopsy at any time. The urologist denied negligence and further denied that anything he did or failed to do caused the patient’s metastatic cancer.

At trial, the patient-plaintiff contended that he would have been completely curable with timely diagnosis and treatment. However, the jury heard testimony that the patient’s life expectancy was approximately 18 to 24 months.

The defendant-urologist argued that by not returning 90 days after the initial visit in April of 2012, he was deprived of finding out how the patient’s PSA did while the patient was on finasteride.

Experts for the defense testified that when a PSA is elevated secondary to BPH as opposed to prostate cancer, finasteride typically cuts the PSA in half and that when the PSA does not fall, despite a patient taking finasteride, urologists strongly consider prostate cancer as an alternative explanation for the abnormal PSA. The defendant-urologist thus contended that if the patient had returned within a reasonable amount of time, it was likely that the PSA would have been unchanged because it was still in the 5 to 6 range in August 2013 and October 2013. All experts at trial agreed that as of April 2012, the patient likely had cancer for years. But because the patient did not timely return after the initial urology visit, the urologist did not have an opportunity to conduct a PSA, offer a biopsy, or otherwise evaluate the patient.

Following an 8-day trial, the jury deliberated for 1.5 days, and returned a defense verdict for the urologist, finding no negligence.

Many states recognize the defense of contributory negligence in medical malpractice cases. Disregarding a doctor’s orders can be patient negligence. Failing to provide an accurate patient history may also constitute patient negligence. In this case, the defendant-urologist could argue that the plaintiff-patient was negligent for failing to timely return for a follow-up. The jury weighed and considered this evidence in deliberations, which likely affected their defense verdict.

The provider said the patient failed to timely return for follow-up.

Urologist claims patient negligence in defense of malpractice lawsuit

Treating men with metastatic hormone-sensitive prostate cancer with enzalutamide (Xtandi) plus androgen deprivation therapy (ADT) can improve progression-free survival (PFS) if patients have bone and/or lymph node metastases. The combination, however, appears to be less effective among men who have visceral patterns of spread, according to a study published in the 

The pattern of metastatic spread in prostate cancer has clear prognostic implications. What has not been understood is how a pattern of spread impacts potential benefits of adding more potent androgen receptor inhibition to ADT, according to study author Andrew Armstrong, MD, professor of medicine, associate professor in pharmacology and cancer biology, and professor in surgery at Duke University School of Medicine, in Durham, North Carolina.

“Here we show that there are clear benefits in delaying radiographic progression or death, prostate-specific antigen (PSA) progression, and other outcomes in the largest groups of men with metastatic hormone-sensitive prostate cancer and lymph node and bone metastases,” Armstrong said. “Men with organ (visceral, such as lung and liver sites) metastases were found to have a poor prognosis, and this small subgroup did not clearly have a delay in radiographic progression with the addition of enzalutamide. Much of this was driven by the poor outcomes of men with liver metastases, whereas men with lung metastases only had a more favorable prognosis and had improved outcomes with enzalutamide/ADT.”

The international group of investigators conducted a post hoc analysis of men with metastatic hormone-sensitive prostate cancer from the phase 3 ARCHES trial (NCT02677896). Investigators randomized 1146 men with metastatic hormone-sensitive prostate cancer to 160 mg/day of enzalutamide plus ADT or placebo and ADT, with the primary end point being radiographic PFS. There were 513 patients with bone metastases only, making up the largest study subgroup. Among the other subgroups, 351 men had bone and lymph node metastases, 154 had lymph node metastases only, and 128 had visceral plus or minus bone or lymph node metastases.

The study results found benefits of enzalutamide and ADT in men with node only and bone plus or minus lymph node metastases and lung metastases, regardless of disease volume.

According to Armstrong, the limited benefits in men with liver metastases suggests that it may be less androgen receptor-dependent, which calls for new strategies to understand this pattern of spread at the molecular level to reduce death and negative experiences from prostate cancer.

“Liver metastases were already known to be associated with a poor prognosis in metastatic castrate-resistant prostate cancer, but our data add to this importance in earlier disease settings,” he said.

For now, urologists and oncologists should consider a liver biopsy to evaluate for neuroendocrine or small cell prostate cancer as per National Comprehensive Cancer Network and American Urological Association guidelines, according to Armstrong.

“Such men are more likely to benefit from docetaxel and ADT in this setting, given the results of the CHAARTED [NCT00309985] and STAMPEDE trials [NCT00268476],” he said.

Radiographic PFS is a clinically relevant end point that urologists and other physicians use to make treatment decisions that impact patients’ lives in practice, Armstrong said.

There are major treatment implications when a patient with metastatic hormone-sensitive prostate cancer progresses to metastatic castration-resistant prostate cancer, requiring changes to strategies, given the abundance of approved agents in the metastatic castration-resistant prostate cancer setting. According to Armstrong, with the profound improvements in radiographic PFS observed in ARCHES, the FDA approved enzalutamide in the metastatic hormone-sensitive prostate cancer setting.

“Patients were offered cross-over and open-label access to enzalutamide,” he said. “Enzalutamide is known to improve survival in castrate-resistant prostate cancer patients already, and continuing this study to a survival primary end point was not reasonable given the results of the ENZAMET trial [NCT02446405], which demonstrated improved survival with enzalutamide in this setting.”

According to Armstrong, There are downsides to adding the androgen receptor inhibitor to treatment. Enzalutamide adds adverse effects to ADT alone, including fatigue, high blood pressure, loss of bone density, fracture risks, muscle loss, fall risk, and hot flushes. Some men experience cognitive issues with fatigue. Providers can help patients reduce these adverse effects through attention to exercise, bone health, cardiovascular risk factors, and blood pressure monitoring.

The work to find optimal treatments for these patients is far from over.

“Although enzalutamide, abiraterone, and apalutamide each extends life in men with metastatic hormone-sensitive prostate cancer, these patients still progress after several years of treatment, and new therapies are needed,” Armstrong said. “Men with liver metastases progress the fastest, and this group represents the largest unmet medical need where research is needed to understand how prostate cancers favor the liver microenvironment and how we can improve survival in this setting and prevent liver metastases.”

Future studies, he said, will examine whether enzalutamide and ADT after completion of docetaxel and ADT in these patients with poor-prognosis, visceral metastatic hormone-sensitive prostate cancer can extend survival.

For now, men with metastatic hormone-sensitive prostate cancer should be educated about their prognosis based on their disease risk and pattern of spread, Armstrong said.

: Astellas Pharma and Pfizer funded the study. Andrew Armstrong, MD,

is a consultant with Astellas, Pfizer, Bayer, and Janssen.

1. Armstrong AJ, Shore ND, Szmulewitz RZ, et al. Efficacy of enzalutamide plus androgen deprivation therapy in metastatic hormone-sensitive prostate cancer by pattern of metastatic spread: ARCHES post hoc analyses. 

 Published online December 28, 2020. doi:10.1097/JU.0000000000001568

"Here we show that there are clear benefits in delaying radiographic progression or death, [PSA] progression, and other outcomes in the largest groups of men with metastatic hormone-sensitive prostate cancer and lymph node and bone metastases,” says Andrew Armstrong, MD.

Vol 49 No 02