Expert Highlights Shifting Management of Localized Bladder Cancer

John P. Sfakianos, MD

Treatment options for patients with localized bladder cancer, beyond Bacillus Calmette-Guérin (BCG), are evolving as immunotherapies and novel agents are gaining traction in the management of this population, according to John P. Sfakianos, MD.

While components of care, such as risk-stratification, restaging, and adjuvant treatment, continue to be critical, other agents have moved through the pipeline and are expected to impact patient outcomes. For example, in January 2020, the FDA approved pembrolizumab (Keytruda) for the treatment of patients with BCG-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Additionally, in a phase III trial, the investigational gene therapy nadofaragene firadenovec (rAd-IFN/Syn3) demonstrated a 3-month complete response rate of 53% in patients with high-grade, BCG—unresponsive, NMIBC with carcinoma in-situ with or without concomitant high-grade Ta or T1 papillary disease.

In an interview during the 2020 OncLive^® State of the Science Summit™ on Genitourinary Cancers, Sfakianos, an assistant professor of urology and urologic oncology at the Icahn School of Medicine at Mount Sinai Health System, discussed some of the optimal and evolving management strategies in localized bladder cancer.

OncLive^®: Could you discuss the importance of restaging transurethral resection of bladder tumors (TURBTs)?

Sfakianos: You always want to make sure that patients are properly staged. It is very important to differentiate a non-muscle invasive tumor versus a muscle-invasive tumor. The reason for that is because the treatments are drastically different. With muscle-invasive tumors, physicians have to consider multimodal therapies and more radical treatments versus a non-muscle invasive tumor that is considered intravesical, or has treatments [that are inserted] into the patient's bladder.

We feel that if a patient has a non-muscle invasive tumor and a minimal amount of disease in the bladder at the time of treatment, they are going to have the best response rate. These patients have a better response than a patient who has a single TURBT with adjuvant therapy. The reason for that is because you probably are getting a better effect and the disease is being minimized.

We can see that 30% to 50% of patients will still have tumors at restaging, and up to 20% of patients will actually have a higher stage than we initially thought, which changes the therapy [that is being used].

How is adjuvant therapy being used in the management of localized bladder cancer?

One of the concerns that we always have with [removing] tumors is that we do this through the urethra. We scrape away the actual tumor so there is concern that as we are scraping in this confined space, we may be spreading tumor cells to different areas. We also know that the disease itself is multifocal, because whatever caused the first tumor was likely a carcinogen in the urine, which is in contact throughout the remainder of the bladder and likely can cause the same damage in another part of the bladder.

When we go in to remove the tumors, we immediately use adjuvant therapy, which is usually chemotherapy—either mitomycin or gemcitabine—and is recommended to be used up to 24 hours after resection. The sooner [it is used] the better, and we think that minimizes the ability for these cancer cells to spread to other areas of the bladder. Also, if there is damage and the tumor initiates somewhere else, [adjuvant therapy] can minimize the recurrence of these non-muscle invasive tumors.

What are some circumstances in which adjuvant treatment would not be used?

It is very important that you do not use adjuvant treatment if you think the muscle of the wall of the bladder was penetrated, because it will perforate the bladder layers—there is a hole that may expose the outside of the bladder. The reason for that is because these treatments are cytotoxic and would have an effect on wound healing, so you may end up not being able to properly heal that area. You do not want chemotherapy to be exposed to the outside of the bladder and to other abdominal or pelvic organs.

How do you use risk-stratification to inform treatment decisions?

This is something that has come around over the last few years. Our ability to risk-stratify patients allows us to better use guidelines to treat those patients. The American Urological Association’s guidelines break patients into 3 risk categorizations: low-risk, intermediate-risk, and high-risk. Patients who fall into the low-risk category do not have much of an option in terms of therapy. Those tumors have not historically responded to intravesical therapy and they do have a risk of recurrence, but a very low risk of progression.

Intermediate-risk patients are those who can receive intravesical BCG and/or intravesical chemotherapy. It is usually based on the amount of risk factors that [are found with] the tumors and patient. We do have a BCG shortage right now, so we are treating the intermediate-risk group with more intravesical chemotherapy.

High-risk patients are the ones who we want to receive BCG, because they have a risk of progression and more aggressive tumors. Those may be patients who have failed BCG, as well and you want to consider chemotherapy, clinical trials, or more radical surgery.

How does variant histology factor into this space?

Variant histology is also very important. This is part of restaging TURBTs where having a very good pathologist with genitourinary experience [is essential]. The variant histology can vary from micropapillary to sarcomatoid to neuroendocrine. It is also very important to know some of the variant histological risks, such as lymphovascular intervention, and whether they are present or not, because that helps physicians with the risk-stratification of the patient. The variant histologies can be more aggressive and their treatments differ.

How do you approach treatment following BCG? What are the different options being explored?

There have been many agents tried in a variety of clinical trials in different ways. We have cytotoxic agents and intravesical chemotherapies. We also have gemcitabine and docetaxel. The combination of those 2 drugs is being further explored, and there are data that shows very high response rates when you combine them. We hope that future larger, prospective clinical trials can maintain that because it would be a great treatment option for patients.

What has been approved recently this year was systemic therapy with pembrolizumab for patients who are specifically carcinoma in situ and unresponsive to BCG. That is FDA approved as standard-of-care and it is the first approval in many years that has allowed options for our patients.

The other category that is under review by the FDA and will hopefully be approved shortly is nadofaragene firadenovec, which is an adenovirus that produces interferon. This allows for pro-inflammatory response and an immune regulator of the local area to fight off cancer. There are now a variety of clinical trials that vary from novel approaches to delivering chemotherapy to the tumors and technology-based therapies, such as photodynamic therapy. There are a lot of options being explored, but many have been tried—and few have succeeded, unfortunately—but the future is looking brighter.