The Impact of the New Muscle-Invasive Bladder Cancer Guidelines

Jonathan E. Rosenberg, MD

In an interview withTargeted Therapies in Oncology™, Jonathan E. Rosenberg, MD, discussed the guidelines and their significance for the treatment of patients with muscle-invasive bladder cancer (MIBC).

Rosenberg, a medical oncologist at Memorial Sloan Kettering Cancer Center, emphasized that one of the effects of these new guidelines is that cisplatin-based neoadjuvant chemotherapy prior to cystectomy is now being established among urologists as a standard of care for eligible patients. This treatment approach received a strong grade B recommendation in the guidelines and will improve survival for these patients.

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

Rosenberg:Traditionally, MIBC 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.

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.

Is immunotherapy mentioned in these guidelines?

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 in one of these trials if their cancer is still high risk after cystectomy.

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.

TTO: Have any recent advancements in the field affected these guidelines?

Rosenberg: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, which 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 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.

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.

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

Rosenberg: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.

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 MIBC. Those patients are also well served by chemoradiation as opposed to no treatment, which unfortunately often happens for many patients.

TTO: What should the main takeaways be from these guidelines?

Rosenberg: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.