Mian Makes Sense of Multidisciplinary Bladder Preservation Approaches

Omar Mian, MD, PhD

Selective bladder preservation is an option for several patients with muscle-invasive bladder cancer in order to spare the native bladder, according to Omar Mian, MD, PhD, and multidisciplinary management in terms of patient selection, treatment, and follow-up is a critical component of care for this population.

This approach has been proven to have equivalent survival benefit in well-selected patients vs radical cystectomy and neoadjuvant chemotherapy. Additionally, several technological advancements in recent years have improved the ability to target the bladder with focused radiotherapy, added Mian; this has limited dosing to normal tissues, and thus, have reduced toxicities associated with the treatment.

“Bladder preservation is a good option for many patients with muscle-invasive bladder cancer,” said Mian. “Have your patients seen in a multidisciplinary setting and involve medical and radiation oncologists early. Many of these patients will eventually need surgery, but some may not. It's important to engage with your colleagues.”

In an interview with OncLive^® during the Institutional Perspectives in Cancer webinar on Bladder Cancer, Mian, a radiation oncologist, physician/scientist, and associate staff at Cleveland Clinic, further discussed selective bladder preservation in patients with muscle-invasive bladder cancer, biomarkers of response, and the utilization of hypofractionated radiation vs traditional approaches in this population.

OncLive^®: What is the current state of bladder preservation in MIBC

Mian: Selective bladder preservation with tri-modality therapy using transurethral resection of bladder tumor [TURBT] to achieve maximal debulking followed by chemotherapy and radiation delivered together is a good option for many patients with muscle-invasive bladder cancer. Most oncologists know this, but it's still a treatment that is underutilized, primarily due to practice patterns rather than any evidence suggesting that it should not be used in those who are eligible.

Selective bladder preservation is an option for many patients with this disease; it's an option that allows sparing of the native bladder and it is a curative-in-intent treatment. [This approach is] equivalent with regard to survival in well-selected patients vs radical cystectomy and neoadjuvant chemotherapy. However, it’s better when you deliver it with chemotherapy, so radiation alone is not a sufficient substitute for chemoradiation and maximal TURBT.

Additionally, several technological advancements have improved our ability to target the bladder with focused radiotherapy. The influence has had a real effect in reducing normal tissue toxicity, primarily bowel toxicity. Quite a few series have compared intensity-modulated radiotherapy and volumetric modulated arc radiotherapy. We have quite a bit of data emerging to suggest that this allows for improved dose symmetry with respect to bowel doses, [with less] grade 2/3 toxicities. This is taking a treatment that maximizes quality of life and makes it even better by reducing acute toxicities.

Multidisciplinary involvement and multidisciplinary patient selection process are also [an important component of this]. There is a need to identify patients who are eligible [for this] and refer them to both a medical oncologist and a radiation oncologist. Those patients need coordinated care during treatment, [especially with regard to] timing of TURBT followed by chemotherapy and radiation, and timing of chemotherapy dose during radiation. They need follow-up care, so these they can retain their bladder.

Patients who have had a prior malignancy are at increased risk of developing another malignancy; this is particularly true in diseases like bladder cancer, where there is a field cancerization effect. That bladder is at risk for having a second tumor and that bladder is also at risk for having a primary tumor come back. Close surveillance with regular cystoscopy imaging is the rule in muscle-invasive bladder cancer, which is a disease with a tendency to metastasize. Those patients need multidisciplinary follow-up care, as well. This is worth it in the trade of saving the native bladder and still curing their cancer.

[There are] a number of biomarker studies for better patient selection based on molecular features of their tumor. Some of the work we have done here at the Cleveland Clinic, as well as in my lab is looking at variants of bladder cancer and how we can use their molecular characteristics to define groups of patients with bladder cancer who we can then more rationally assign to treatment paradigms, at least that’s the goal.

You mentioned that tri-modality treatment is appropriate for the majority of patients with this disease. What is the hesitation in applying this to practice?

One issue is that it's a function of practice patterns and, I hesitate to say it, but maybe some bias. Patients see the surgeon up front, and many times, the surgeon, with the best intentions, is concerned that the patient has a more aggressive tumor. That patient may not see the multidisciplinary team or may not see more then the medical oncologist for neoadjuvant chemotherapy. It's one of these things where we've moved away from that approach in many cancers. The standard now, in diseases like breast cancer and prostate cancer, is for patients to see the entire team for a multidisciplinary evaluation.

In bladder cancer, oftentimes, patients will go very quickly to surgery or receive chemotherapy with the goal of receiving surgery. Many patients tell me, ‘I didn't know that radiation and chemotherapy together were an option,’ or ‘I didn't know bladder preservation was an option.’ This is where we need to do a better job. We need to inform patients all of their options are.

Some of the working groups for bladder preservation and tri-modality therapy for the Bladder Cancer Advocacy Network have tried to think about this question. Another thing that comes up repeatedly is that perhaps due to the criteria that we've used to select patients for bladder preservation, we have kind of boxed things in a bit. The ideas that no patient with hydronephrosis, or tumors can’t be greater than a certain size, multifocal vs unifocal tumors, location within the bladder, molecular features, and variant histology are all soft criteria that are sometimes used to say, ‘Bladder preservation is not a good option for you. You should go straight to surgery.’ We don’t have good evidence to support that. Many of those features I mentioned are prognostic features, not necessarily predictive features. These features aren't necessarily predictive of response to 1 treatment vs another. If they have surgery or chemoradiation, factors like hydronephrosis tend to portend a worse prognosis with respect to local recurrence and spread.

We have to be careful with how we apply this selective term and how we talk about who the right patients for bladder preservation are. Patient selection is important, but we can't be overly strict, or no one will be eligible. We have to follow the evidence that we have.

With regard to the biomarkers of response that you alluded to, are those moreso for systemic agents or can they be applicable to surgical approaches, as well?

I think they can be [applied to] any approach. There's now this classification scheme of bladder cancer subtypes that has gained some traction; it emerged initially from The Cancer Genome Atlas Program. Several of my colleagues and physicians from institutions around the country are looking at factors such as mutation profile and gene expression profile to characterize bladder cancer into subtypes. This is really helpful for us in terms of deciding which patients might do better with multimodality therapy, as opposed to going straight to a single modality or neoadjuvant chemotherapy and a surgery approach. Those are coming down the line. There are a number of folks who are trying to commercialize this molecular subtyping to give genomics and gene expression profiling–based scores, so we can assign patients into more rationale treatment groups. 

Specifically, for radiation, several biomarkers have emerged, including MRE11 expression, DNA damage response alterations, and in some cases, according to the modeling, protein and gene alterations that seem to predict for response or lack of a response to radiotherapy or DNA-damaging agents like chemotherapies. We now have several trials attempting to stratify based on DNA damage response mutations, such as the ALLIANCE study in localized bladder cancer. This is done with the goal of deintensifying treatment for those patients who are going to respond really well to neoadjuvant chemotherapy. These patients may not need aggressive resections or radical radiotherapy because they respond so well to systemic [therapy] because of specific vulnerabilities in the tumor with respect to DNA repair capacity. It increases the selectivity of the therapies we have. These DNA damage response mutations fall into the category of BRCA and others for which there is now molecular testing and functional testing available to stratify patients into sensitive and less sensitive groups for the purposes of deintensifying, or in some cases, intensifying treatment.

In terms of delivery techniques when it comes to radiation, you mentioned hypofractionated radiotherapy and how it’s noninferior, if not superior, to traditional approaches. What are the data to support that and have toxicity mitigation strategies been suggested to supplement that approach?

There was a meta-analysis that was just presented at the European Society of Radiation Oncology that looked at all the patients who enrolled in the BC2001 and the BCON studies. In these 2 controlled trials, patients were randomized to systemic therapy plus radiation or radiation alone, both of which show the benefit to combination therapy. These studies, although there wasn't a randomization criteria, allowed fractionation to be either 55 Gy in 20 fractions or 64 Gy in 32 fractions, so hypofractionation and conventional fractionation, respectively.

Approaching about 1000 patients total, about half of whom were treated with each fractionation scheme, the meta-analysis shows that the shorter fractionation is noninferior with respect to overall survival. In some patients, it appears that local control may be better with a shorter fractionation. We know a higher dose per day is more effective for certain disease types and urothelial carcinoma of the bladder may turn out to be 1 such cancer.

These data reinforce something that many genitourinary oncologists are already doing, which is using shorter fractionation schemes, because they're effective and easier for patients. For quality of life–maximizing treatment, it's important to think about the burden of treatment. Four weeks as opposed to 6 or 6.5 weeks is quite a big difference.

Where is future research headed?

In terms of emerging therapies and where the research is taking us, a big area of excitement is around the combination of radiotherapy and immunotherapy in bladder cancer, particularly up front in the neoadjuvant setting, as well as concurrently with chemoradiation and bladder preservation. Several Cooperative Group studies and institutional studies are looking at that question now. Does that combination lead to any additive synergistic effects? [Will the] radiation chemotherapy drive increased immune recognition or clearance of the tumor? That's an area of very active investigation.