Successful Bladder Cancer Programs Rely on Old Pillars, New Innovations

Daniel Saltzstein, MD

Building a successful bladder cancer program requires clinicians to employ a multifaceted approach that prioritizes good surgical practices, embraces immunotherapies with an understanding of the adverse effects (AEs) that can accompany them, and being up to date in terms of options for patients withBCG-unresponsive disease as well as those with transitional cell carcinoma (TCC) of the upper urinary tract, according to a presentation during the 2023 LUGPA Annual Meeting.

“Bladder cancer is the most dangerous disease us urologists treat,” Tom Jayram, MD, a neurologic oncologist and the codirector of the Advanced Therapeutics Center at Urology Associates, and a clinical associate professor of urology at Vanderbilt University in Nashville, Tennessee, said during his moderation of the presentation. “It’s very exciting to see the progress that has been made in the past few years [with] big groups consolidating their resources, trying to improve the structure of our programs, and improve some of the gaps that we had previously encountered in bladder cancer care. Now we’re in a position where all groups know the importance of all the new therapies and modalities that are coming into the space.”

Jayram began the panel discussion by noting that much of the progress that has been observed in certain areas of prostate cancer care in the past 10 years could mirror what is on the horizon in the next 10 years in the bladder cancer space. He highlighted how multiple new FDA approved therapies, a changing understanding of disease biology, and the uptick in enrollment of patients treated in the community setting into clinical trials, among other factors, have already affected prostate cancer care and that these same factors are already affecting bladder cancer care.

“In prostate cancer, there [have been] a lot of new drugs and diagnostic tests that are very effective,” Daniel Saltzstein, MD, the medical director of research at Urology San Antonio in Texas, said during the presentation. “We’re starting to see the same things in bladder cancer, [such as] better imaging modalities, better biomarkers, and clinical trial opportunities, [allowing us to] move drugs into earlier stages of disease.”

Emphasis on Surgery Remains

Although there is much excitement surrounding the development of new therapeutic agents, the panelists emphasized that good surgical practices are still mandatory in an effective bladder cancer treatment program. Particularly, transurethral resection of bladder tumor (TURBT) and radical cystectomy were championed by the panel as surgeries that still have a major impact on patient outcomes.

TURBT is especially important to achieve the best outcomes for patients with papillary disease. A complete, deep TURBT allows for accurate staging and risk stratification and restaging for patients with non-muscle invasive bladder cancer. In terms of radical cystectomy, the panelists emphasized that it is imperative to centralize these surgeries to high-volume, experienced providers and to develop standardized postoperative pathways to facilitate more effective recovery and, ultimately, patient functioning after surgery.

“Bladder cancer is fundamentally still a surgical disease. The most impactful thing we can do for patients is a good transurethral resection,” Jayram said.

The panelists noted that a deeper understanding of biomarkers such as circulating tumor DNA, FGFR, and PD-L1 can potentially be useful to clinicians in terms of informing better surgical practice. Similarly, the continued advancement of imaging techniques such as PET and MRI will help guide surgery, making it as safe and effective as possible.

“Clinical trials are definitely using biomarkers––usually cytology,” Saltzstein said. “I don’t know if there’s a biomarker out there at this point in time that can [allow a patient to avoid cystoscopy]. In more of the advanced bladder cancer trials, FGFR and PD-L1 status are important but they’re not ready for primetime yet as far as how we manage a patient going forward.”

Understanding the Safety Profile of Immunotherapies

Although immunotherapies offer the potential of durable responses for patients with bladder cancer, these agents also have unique toxicity profiles that need to be understood to be properly employed, the panelists said. For CTLA-4–directed agents, the most common grade 1 or 2 immune-related AEs (irAEs) include skin conditions, gastrointestinal (GI) toxicities, and pulmonary toxicities. Skin and GI toxicities are also common in PD-1/L1-directed agents, but at lower rates than those targeted towards CTLA-4. All 3 agent classes have relatively low rates of grade 3 to 5 irAEs, although CTLA-4–directed immunotherapies can lead to GI events in this severity range.

“This is a new set of toxicities,” Jayram said. “It’s not [the same as] chemotherapy-related treatments. They’re usually milder than chemotherapy and basically stimulate your body to generate an inflammatory response and that inflammatory response can affect any and every organ system.”

To combat irAEs, corticosteroids reman the primary method of treatment. Topical steroids can help combat mild skin reactions, although higher grade toxicities may necessitate systemic steroids. For patients with moderate (grade 2) irAEs, the panelists recommended holding treatment with the given immunotherapy, redosing if toxicity improves, and considering a low-dose steroid like prednisone if necessary. For severe, grade 3 to 4 irAEs, they recommended starting high-dose steroids with a slow taper, such as prednisone 1 to 2 mg/kg daily or infliximab 5 mg/kg once every 2 weeks.

Considerations in BCG-Unresponsive Bladder Cancer and Upper Tract TCC

Patients with BCG-unresponsive bladder cancer still present a challenge for many clinicians, however newer treatment options have emerged for these patients in recent years. Treatment with pembrolizumab (Keytruda) has displayed some efficacy, although this approach can lead to systemic toxicities, giving some urologists hesitancy to fully employ it. The combination of gemcitabine and docetaxel has conferred high response rates, both in patients with papillary disease and carcinoma in situ, but these agents can still be difficult for community providers to obtain and administer. Nadofaragene firadenovec-vncg (Adstiladrin) can be given via convenient dosing schedule, but the best practices for administering this treatment are still unclear.

“[In terms of] clinical trials, there are [multiple avenues] being studied,” Jayram said. “There’s the pretzel, which is a small device that’s placed in the bladder that dilutes chemotherapy or targeted therapy. There’s photodynamic therapy, which is basically light energy or some form of radiation therapy that’s being put into the bladder. Then, there are combinations with BCG and immunotherapy, and BCG alternatives which are gene therapy drugs. This is a busy time for bladder cancer [because] there are a lot of active trials coming out.”

For patients with upper tract TCC, the panelists emphasized the need for proper patient identification and counseling, as well as disease surveillance after treatment. Retrograde and antegrade approaches are possible and nephron sparing treatment is an option for patients with low-grade upper tract TCC. They noted that the real-world experience with these approaches has been favorable and that these practices should be easily adoptable for all urologists.

Reference

Jayram T, Krishnan J, Henderson J, Saltzstein D. Successful bladder cancer programs: what should you be offering your patients today and tomorrow. Presented at: 2023 LUGPA Annual Meeting; November 2-4, 2023; Lake Buena Vista, FL. Accessed November 2, 2023.