The discussions in this video took place prior to the COVID-19 related mandatory safety measures.
Dr. Mossanen: Good morning everyone, my name is Matt Mossanen. I'm a urologic oncologist that works at Brigham and Women's Hospital and also Dana-Farber Cancer Institute. Thank you for joining us on PracticeUpdate, another session of Genitourinary Tumor Board. Today the case will be a focus on non-muscle invasive high-risk bladder cancer. I'm joined by an excellent panel of experts in the field so with no further ado, let's just jump into the case.
The first patient we're going to discuss is a 49-year-old male, he's healthy, has normal renal function, he's a non-smoker. He was diagnosed with high-risk non-muscle invasive bladder cancer about two years ago. His original pathology was high grade Ta, and he was treated with induction BCG, and he successfully completed six out of six doses. About six months later, he developed recurrent CIS and was treated with BCG, and interferon. Then again, after that second round, developed a high-grade disease in the prostatic urethra.
He was also found to have CIS in the bladder at that time. He underwent a robotic cystoprostatectomy with pelvic lymph node dissection, and ileal conduit. Final pathology was pT0 in the bladder, so no evidence of residual carcinoma there. However, he had high-grade disease involving the prostatic stroma, and one out of 12 nodes positive for metastatic urothelial cell. He received adjuvant gem/cis x4 total cycles, and then, four months later, underwent urethrectomy with no evidence of disease in the urethra.
To start off the discussion, I'll ask Dr. Preston his approach to patients that have high-risk non-muscle invasive bladder cancer that are unresponsive to an initial induction round of BCG.
Dr. Preston: This is a very common referral for us, for a patient for us to see would be these patients who don't, do not respond to BCG, and typically, repeated BCG courses. This is an important question for patients and clinicians, and in addition to that, there's a lot of activity from the FDA and researchers to try and find new options for this space. We start by taking very good history. It's important to know all the prior treatments that they may have received from intravesical perspective, have a good idea of what procedures they've had, have a pathology review to determine the grade and stage, and also importantly, if there's any variant histology present because that could, could certainly change what our recommendations may be.
I also look for recent updated imaging of the upper tracks, and of the bladder as well, because it could, even at this stage, be metastatic disease. It is not common knowledge but bladder cancer can certainly go from non-muscle invasive, and spread elsewhere to lymph nodes, or beyond, so it is important to assess that at these initial consultations. From a treatment option perspective, if they have not responded to BCG, we have to have a lengthy conversation about early radical cystectomy, or radical cystoprostatectomy, or urinary diversion, as this is high-risk disease.
If they cannot receive a cystectomy, or do not wish one at the time, other options that we discuss include some newer trials. There's one we have currently using pembrolizumab, which is an immunotherapy, it's been shown to be effective in metastatic bladder cancer, now we've moved that forward into the non-muscle invasive space. This is an intravenous infusion given once every three weeks, and some preliminary data is promising with it's about a 39% response rate to this. We have to monitor closely for immune side effects, and we still are unsure what the long term, what the durable response is going to be with this treatment.
In addition to that there's a regime we commonly use, is called gemcitabine and docetaxel, which is intravesical chemotherapy that's given once a week for six weeks and there's also a maintenance regime that we use as well. This has shown some good promise as well in some early studies in terms of reducing the recurrence and progression of non-metastatic bladder cancer.
Dr. Mossanen: Kent, one of the questions patients often ask is if there's a role for radiation, even though it's not necessarily muscle-invasive disease where we know there's certainly an established option to use radiotherapy. Can you talk a little bit about some of the data that might be available or will be available to try to answer that question?
Dr. Mouw: Yeah, sure. Currently there's no standard role for radiation in the management of recurrent non-muscle invasive bladder cancer. That said, there's an exciting trial that is finished accrual and should report in the next year or so. This is RTOG-0926, used a bladder sparing radiation based paradigm similar to what we use in the muscle-invasive space, so patients have a maximal transurethral resection and then have concurrent chemotherapy and radiation, again using doses of both chemotherapy and radiation similar to what are used in the muscle invasive space. That trial, again finished accrual on we're awaiting, you know, some primary reporting of the data.
Biologically, I don't think that there's any reason to believe that the control would be, it would be less likely to work than we know that it does in the muscle invasive space. But agree that this is a tough clinical scenario, many of these patients have sort of run out of good options, and for those particularly who aren't eligible for cystectomy, or who wish to avoid cystectomy, I think radiation has a role and hopefully this prospective data that should be available, you know, in the next couple of months to a year will help inform our decision making further.
Dr. Mossanen: Yeah, that's exciting because it might, it might offer a whole new option for these patients that are already seeing an emergence of new intravesical therapies. I think it underscores why bladder cancer is so multidisciplinary, because it's always changing and it involves all three branches.
Dr. Hirsch, one of the questions that I have for you is, as a urologist or medical oncologist or radiation oncologist, it's sometimes hard to interpret what pathologic involvement of the urethra means. I was wondering if you could comment a little bit on how you evaluate the prostatic urethra and some of the specific considerations to stroma involvement versus just high-grade disease that's not invasive into the stroma.
Dr. Hirsch: Sure. Basically in most cancers, different organs, definitely in the GU system, will do staging based on depth of invasion, so if there's no invasion, then you're a non-invasive cancer and that's low stage. As you can start to invade the tissues, you become invasive and how deeply you're invasive into that tissue becomes a higher stage. For bladder cancer, if you're non-invasive, you are either a Ta or a Tis non-invasive cancer and as you start to invade the bladder wall, then you go to higher stage T1, T2. Some cases the tumor will actually not invade in a depth direction but will crawl along epithelial surfaces, so in this particular situation, we're starting with a primary bladder or urothelial cancer in this situation as it's crawling because there's a direct connection of course with the prostate and the bladder, and the cancer is on the urothelial surface and that is in direct continuity with the urethra, the prostatic urethra. The tumor in this situation is growing from the bladder down into the prostatic urethra. If it does not invade in the sight of the prostatic urethra that is still considered a Ta if it's a papillary tumor, or Tis if it's urothelial carcinoma in situ.
From there, similar to bladder wall, as you invade into the prostatic urethra, you increase your stage. There is a lamina propria, it's an anatomical portion of the urethra directly below the epithelial lining and if it invades into that lamina propria, that connective tissue below the epithelium, then that is a T1 cancer. If you invade through that lamina propria directly into prostatic stroma, that is considered T2 disease. But the other way that you can invade into the prostate from the prostatic urethra is that you actually, it's sometimes hard to conceptualize, but we're looking at three dimensional structures in a two dimensional plane when we look down the microscope, but there is actual direct continuity of the prostatic glands and ducts to the urethra, the secretions that the prostate make, are secreted into the urethra, and so the tumor that's crawling down the urothelium from above can creep right into the prostatic duct.
It's like, if you can conceptualize in your mind a diverticulum, that's the continuity of a prostatic duct to the overlying urothelium. If it has not invaded, the tumor can actually crawl into the prostatic ducts and continue into the prostatic glands and lobules that are even, you can invade those structures all the way to the periphery of the prostate with never invading the prostatic stroma you maintain your Ta or Tis status, your non-invasive status. But anywhere along that once you're inside the prostatic ducts or glands, you could then invade sideways, if you will, into the prostatic stroma and that makes you T2 disease again, once you're in the prostatic stroma.
The distinction from all of this is when you have, not in this particular case, if you have bladder cancer that's invaded in the bladder through the entire wall into the perivesical soft tissue and then out to the outside of the prostate and in from the soft tissues to the end, that would be considered T4 disease, because it's extension into another organ through soft tissues. But once you come down the urethra and invade, lamina propria is T1, so underneath the urothelium inside the ducts and glands, the prostate maintain non-invasive cancer, once they're in the stroma your T2 disease.
Dr. Mossanen: It certainly sounds like the architecture is complex in it. Highlights why it's so important to have a good working relationship with your pathologist so you can go over this with them, especially if you're trying to make decisions about adjuvant treatment for these patients.
Dr. Hirsch: Sure.
Dr. Mossanen: One of the other decision points that we have often at the time of surgery, is the decision to do a concurrent urethrectomy. Dr. Chang, I was wondering if you could talk a little bit about perhaps your intraoperative decision making, if you are doing cystoprostatectomy, when you might decide to add urethrectomy to the case versus to get the final pathologic result which as we know, can be quite complex if you're concerned about prostatic urethra involvement, get that sort of final pathology result and then make the decision.
Dr. Chang: Yeah, performing an urethrectomy at the time of a radical cystoprostatectomy is not terribly common. We don't routinely see disease involving the urethra and the prostatic stroma, but at the time of these procedures, it's very common to get, to assess the margin with our colleagues in pathology, and if there is a positive margin often, you know, in that case, it is very concerning that there is more disease and in that scenario, I would very much consider a concurrent urethrectomy.
The most ideal situation is that you go into the surgery knowing that there is a risk there and then you can perform sometimes a two team approach, where you're doing the cystoprostatectomy while a second team is doing the urethrectomy, thus avoiding prolonging the surgery and minimizing some of the morbidity of this combined procedure. But if at the time of the procedure, you have a concern for prostatic stromal invasion but there's a negative margin, I often monitor patients afterwards, do urethral washings, assess for disease in the urethra. I'll be honest, my practice is not to routinely do a urethrectomy for these patients, but if there is hematuria that develops at some point, or I should say blood per urethra, postoperatively or these washing show positive cytology, then I think a urethrectomy following surgery at some point in time is totally appropriate.
Dr. Mossanen: That was a great discussion. I want to thank all the members of the panel for joining us today and I want to thank all of you for joining us on PracticeUpdate.