Expert Discusses Impact of Muscle-Invasive Bladder Cancer Guidelines

Jonathan E. Rosenberg, MD

There are now interdisciplinary guidelines for the treatment of patients with muscle-invasive bladder cancer, following a collaboration with the American Urological Association (AUA) and other prominent groups, such as the American Society of Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO), and the Society of Urologic Oncology (SUO).

“These guidelines now incorporate cisplatin-based chemotherapy for patients who have adequate kidney function, no significant neuropathy, no significant hearing loss, and who are otherwise healthy enough to undergo this type of treatment,” explains Jonathan E. Rosenberg, MD.

The guidelines provide evidence-based recommendations on staging, neoadjuvant and adjuvant chemotherapy, radical cystectomy, urinary diversion, perioperative surgical management, and pelvic lymphadenectomy. For example, the organizations gave a strong grade B recommendation to clinicans offering cisplatin-based neoadjuvant chemotherapy to eligible radical cystectomy patients prior to cystectomy, when utilizing a multidisciplinary approach.

There are also a number of recommendations on bladder preserving approaches, which are an addition to the updated set of guidelines.

OncLive: Can you discuss these guidelines for bladder cancer and their significance?

In an interview with OncLive, Rosenberg, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed the guidelines and their significance for the treatment of patients with muscle-invasive bladder cancer.Rosenberg: Traditionally, muscle-invasive bladder cancer has been managed purely by urologists in the United States with radical cystectomy being the only treatment often offered. However, there have been several large, randomized trials that show a benefit with cisplatin-based neoadjuvant chemotherapy prior to cystectomy.

There’s been a large educational effort over the years and this is an outgrowth of that effort to implement appropriate therapy for patients who are candidates for cisplatin-based neoadjuvant chemotherapy. We know that it reduces the risk of death from bladder cancer by one-third and improves the survival by 5% to 10%, depending on the clinical trial.

Is immunotherapy mentioned in these guidelines?

We have worked on these guidelines to establish this as a standard of care in conjunction with other organizations, such as ASCO. These guidelines now incorporate cisplatin-based chemotherapy for patients who have adequate kidney function, no significant neuropathy, no significant hearing loss, and who are otherwise healthy enough to undergo this type of treatment. Not yet. Immunotherapy for these patients remains experimental, and there are multiple clinical trials that are testing this. There is a focus on adjuvant immunotherapy in large randomized phase III trials that are currently accruing patients. These trials are testing whether PD-1/PD-L1 inhibition versus observation or placebo—depending on the study—will improve survival for high-risk patients after cystectomy.

Postoperative treatment is generally adjuvant cisplatin-based chemotherapy for patients with high-risk disease who have not received neoadjuvant chemotherapy. In my opinion, if they have received neoadjuvant therapy, these patients should consider enrolling on one of these trials if their cancer was still high-risk after cystectomy.

Have any recent advancements in the field impacted these guidelines?

There are many patients who can't receive cisplatin-based chemotherapy for a variety of medical reasons, in which case they are not receiving neoadjuvant chemotherapy and could consider enrolling in one of the adjuvant therapy trials. To date, there are no results from these studies and we are looking for evidence that these patients would benefit from this approach. One of the questions that always arises is whether there are any molecular or clinical predictors about who would benefit from neoadjuvant chemotherapy. There are multiple intriguing technologies that are investigating this. My own opinion is that none of them are ready for primetime.

One methodology is looking at DNA damage-repair mutations that is essentially the mechanism of action for cisplatin-based chemotherapy. It damages the DNA; the cells that have defective DNA repair are unable to recover, and we see better outcomes in those patients. However, the data thus far have been retrospective—none of it has been prospective—and it requires prospective validation.

There is also evidence for RNA-expression profiling. There is one subtype of bladder cancer, the basal subtype, that might benefit more from chemotherapy, although it doesn’t mean that the other subtypes don’t derive benefit. Work still needs to be done to better understand if that classifier can be used to select patients for chemotherapy, but it’s not clear that they can tell someone that they don’t need chemotherapy or that they wouldn’t benefit from it.

How does having these guidelines benefit the treatment decisions for these patients?

That is all very exciting and interesting. There is a lot of intersection between that data, the outcomes of patients treated with immunotherapy, and advanced disease because many of the things that predict good responses to chemotherapy also predict good responses to immunotherapy. We are trying to integrate all of this knowledge to understand the potential novel targets that are responsible for these differences. Setting standards as to what is appropriate care is important in medicine and the care of patients with bladder cancer. We have a long history of failure to accrue to clinical trials , as well as a failure to follow guidelines for the treatment of these patients. Therefore, setting standards and guidelines will help to ensure that the recommendations are out there about how these matters should be handled.

What should the main takeaways be from these guidelines?

An important area is bladder preservation, which is something that is involved in these guidelines with chemoradiation. There are 2 types of bladder preservation. The first is selective bladder preservation for people who could be cystectomy candidates but might do well with chemotherapy, radiation therapy, and radical transurethral resection. Or, there are patients who also aren’t candidates for cystectomy and need treatment for their muscle-invasive bladder cancer. Those patients are also well-served by chemoradiation as opposed to no treatment, which unfortunately often happens for many patients. From a medical oncologist’s perspective, the strong recommendation for perioperative systemic therapy is important because we know it cures patients. The problem is that we don’t have a way to figure out who those patients are in advance. We need to select them so that we aren't treating everybody. We would rather only treat the patients who will benefit. At the moment, the data do support the use of these treatments. It is a major step forward to say that this is what is suggested as optimal therapy for these patients.

Is there anything else that you would like to add?

It also puts bladder preservation into the guidelines for the right patients—whether they be people who are candidates for cystectomy or not. Those are the most relevant outputs with these guidelines.It is important to accrue patients to ongoing adjuvant clinical trials. We have a long history of failed clinical trials in bladder cancer in the adjuvant setting. We have never completed a large, modern, adjuvant clinical trial. There is a series of trials in Europe that all shut down for poor accrual.

I’m hoping that we don’t see that happen with the adjuvant immunotherapy trials. The early indications are that they are being more successful at accruing patients. However, we really need to take the ball over the finish line to finally get answers to these questions.

Chang SS, Bochner BH, Chou R, et al. Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO guideline. J Urol. 2017;198(3):552-559.