Understanding Optimal Therapy for Locally Advanced Bladder Cancer

Definitive management for locally advanced, nonmetastatic muscle-invasive bladder cancer can be complicated in the face of comorbidities and disease that extends beyond the bladder, according to Neil Desai, MD, MHS, who explained that the choice of bladder preservation or radical cystectomy requires detailed discussion with the patient around the importance of quality of life and risks for morbidity and mortality.

“The biggest highlight here is the ongoing [investigation] of how to [pursue] good management for suboptimal medical [scenarios] that respect the patient’s ability to tolerate treatment and not hurt them as a primary principal. Beyond this, we must think into the adjuvant space,” Desai said following an OncLive® State of the Science Summit™ on bladder cancer and renal cell carcinoma (RCC).

In an interview with OncLive following the event, Desai expanded on a patient case that was highlighted during the event, and expanded on the need for further research regarding potential treatment strategies for patients who may not benefit from standard approaches. Desai is an associate professor and director of Clinical Research in the Department of Radiation Oncology, as well as the Dedman Family Scholar in Clinical Care, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center in Dallas, Texas.

OncLive: Could you introduce the case that was discussed on the panel?

Desai: I presented a case of locally advanced bladder cancer invading into the cervix in a woman with comorbidities, including renal dysfunction. [This patient] was offered neoadjuvant chemotherapy and the question afterwards was what to pursue regarding definitive management of the muscle-invasive, nonmetastatic bladder cancer.

What were some of the options that were discussed for this patient?

The patient underwent a radical cystectomy with ileal conduit diversion following neoadjuvant chemotherapy. The most important question was what could be done differently because [she experienced] a poor outcome from a post-operative mortality event.

This is a difficult case, and that’s why it was highlighted [as more of] a real-world case where the patient was not the best cisplatin candidate, did not tolerate neoadjuvant chemotherapy well, and underwent cystectomy [because she] was not an ideal candidate for chemoradiation because of the locally advanced disease status. [It came down to] picking a lesser of two evils and how to interpret that in our own practices. That was the debate at hand.

What are some of the pros and cons for each approach that was discussed?

I’ll take the pros and cons of chemoradiation or triple modality therapy for bladder preservation upfront first. As I mentioned during the presentation of the case, this wasn’t a classic bladder preservation case. It [had to do with] how to definitively manage locally advanced bladder cancer for which the competing risk of distant relapse was very high, and the competing risks of comorbidity-related morbidity [and] mortality were also high. There’s a bit of a guessing game here; we don’t want to be nihilistic. We want to offer definitive therapy for a disease that can cause lots of local morbidity, as well as overall mortality risk. However, we have to be realistic and pay attention to how the patients tolerating therapy.

In a patient who tolerated a gemcitabine/carboplatin–based neoadjuvant chemotherapy regimen, which we don’t normally consider because of their comorbidities, this is the first clue that the usual management may not be the best for this patient in terms of getting through a cisplatin-based course [of treatment before going] onto cystectomy. While I did note that this was a locally advanced bladder cancer case, there was still cervical cancer and cervical invasion. This was not an ideal bladder preservation case in that it was hard to monitor outcome afterwards when there’s disease beyond the bladder. In this case, I would have still offered chemoradiation for local regional control, which would offer less invasive initial therapy locally.

The con of that would be that the failure rates are higher and ensuing morbidity from a chemoradiation approach in a locally advanced case than a CT2 case for instance. Moreover, when there’s disease involvement of areas beyond the bladder the surveillance relegated to imaging and cystoscopy will not be sufficient. [However], chemoradiation would have been a reasonable option in this case, even if not ideal.

As a second option, a patient may elect radical cystectomy. That was what was selected here because of the locally advanced disease, and that was what was chosen by the patient. That [approach] removes the bladder as we know, as well as an anterior exenteration, essentially trying to clear the margin, which they did, as well as sample the lymph nodes. Especially in a locally advanced case, where there may be a higher propensity towards lymph node invasion, that lymph node sampling may be of value. However, not an extended lymph node sampling where there’s no data for that being beneficial.

There is the pathologic benefit of knowing what’s going on, as well as the definitive management of an aggressive local disease. The downsides are a much more invasive intervention with high morbidity and mortality risks in the acute setting and the quality of life concerns that come with it. There’s no right answer [here]. [We were faced with selecting] what the patient could adapt to best in terms of their risk profile.

Is there any ongoing or planned research that could potentially help clarify the optimal approach here?

In muscle-invasive bladder cancer ideal therapies are not accessible to nearly half of patients regarding cisplatin chemotherapy eligibility, either due to comorbidities or renal dysfunction. When up to half of patients may not be eligible for cisplatin-based neoadjuvant chemotherapy, we must have alternatives, and this was highlighted [in our discussion]. There’s a lot of ongoing research looking at optimal regimens for perioperative or neoadjuvant chemotherapy or perioperative systemic therapies that involve immuno-oncology [IO] agents, or even novel antibody-drug conjugates. There are some promising early results [there], but we’re still waiting on data to show they can be an alternative that is not more harmful than beneficial.

There are certainly many avenues of ongoing research in the neoadjuvant setting before cystectomy. Soon thereafter, we would expect to follow, if there’s success in these areas, with novel combinations of these agents with radiation. With that said, in the chemoradiation setting for patients who are not cisplatin eligible, this has long been a major issue. There are effective regimens for concurrent chemotherapy with radiation, namely 5-fluorouracil and mitomycin c or low-dose gemcitabine bi-weekly, which has been vetted in large scale trials.

Even if you get through a successful local therapy, and the patient does well in tolerating these [therapies], how do we reduce the chance of micrometastatic disease progression? Most avenues of investigation are focused on the use of adjuvant IO agents. We all know the existing approvals for adjuvant, single-agent immunotherapy. [Might we be able to focus on] biomarker selection based on positive circulating tumor DNA in the serum blood as a predictor of who may benefit from that?

Most avenues of research [there] are looking not only at the front end of non–cisplatin eligible patients, but also in the patients who get through local therapy for locally advanced disease, whether you might select them for adjuvant IO agents to decrease that metastatic progression risk.

Was there anything from the kidney cancer portion of the event that stood out to you from a radiation oncology perspective?

A lot has been said about the use of higher dose per day precision radiation techniques, such as stereotactic body radiotherapy [SBRT], to address oligometastatic RCC to defer systemic therapies, [which may provide] a quality of life benefit. [Also], the use of SBRT to address oligoprogressive disease sites when on systemic therapy, otherwise having good control of micrometastatic disease, to extend the efficacy of that same agent without switching, or at least to extend the effect of it.

These are two very important areas that have transitioned into the setting of large-scale trials. We’re leading large scale randomized trials looking at [treating] the oligometastatic population with SBRT, [hoping] this may defer the need for systemic therapy without compromising outcomes [or] quality of life.

Lastly, SBRT is now being used as a treatment for primary site RCC, especially when not amenable to partial nephrectomy. There’s quite a lot of international efforts on this. We are part of the IROCK Consortium, as well as the ongoing trials in both the upfront disease space as well as in the metastatic space where consolidation to the primary is being used and explored in the ongoing phase 2 NRG-GU012/SAMURAI trial [NCT05327686]. There are lots [of agents] that can be used with radiation nowadays in RCC across the spectrum.

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