Dr. Ralph de Vere White¹,²; Primo N. Lara, Jr.¹,³; Peter C. Black⁴; Christopher P. Evans¹,²; Marc Dall’Era¹,²
(¹: UC Davis Comprehensive Cancer Center, ²: UC Davis Department of Urology; ³: UC Davis Department Hematology/Oncology; ⁴: Vancouver Prostate Center University of British Columbia and Division of Urology Vancouver, BC.)

In 2018, the estimated number of new cases of urothelial bladder cancer (UC) in the United States was 81,000, with 17,240 estimated deaths.[1] Comparable numbers from 2004 were approximately 64,000 and 12,000, respectively.[2] The 5-year survival rate in 2018 for patients with regional UC was 35% (ref 1). Why has mortality from UC — of which 80% is accounted for by patients presenting with muscle invasive urothelial cancer (MIUC) — remained unchanged for over 30 years?

In contrast, recent representative publications, be they from single or multiple institutions, cooperative groups or metanalysis, that focus conceivably on the same patients with local-regional UC, report a far better survival rate for patients treated with intent to cure. For example, in a 2018 paper, patients with T2 MIUC had a 10-year disease-specific survival (DSS) following a radical cystectomy (RC) of 79%, while patients in the same stage group, treated with tri-modal therapy, had a 10-year DSS of 69%.[3] If patients undergoing RC received standard-of-care neoadjuvant chemotherapy (NAC), 5-year survival rates for a subset of patients of up to 85% have been reported.[4] For patients whose initial therapy was definitive chemotherapy, 5-year survival rates of 72% are expected.[5]

These outcomes are a far cry from the national 35% survival rate reported by the American Cancer Society for 2018. Why the disparity? Guidelines all support RC as a component of optimal care for patients with MIUC. Guidelines mostly favor also using NAC.[6,7,8] That said, RC has been the treatment of choice for the past 30 years, and yet survival has not improved. The answer, we believe, is because far too many patients are not undergoing RC and are not receiving any treatment with curative intent. This belief is bolstered by the only two retrospective database studies, which directly address this subject. Gray et al reported on the treatment of 28,691 patients with MIUC, utilizing the NCDB.[9] Overall, only 41.3% of the cohort underwent RC, while 3.7% underwent partial cystectomy and 7.6% had definitive radiotherapy.  For patients 50 years or younger, 64% underwent RC, while 15% were treated with surveillance. In the 61-70 year-old age group, the comparable figures were 60% and 19%, respectively. Gore et al employing the SEER database reported on the treatment of 3,205 Medicare patients with Stage II UC. Only 21% (678 patients) underwent RC, having a 42% five-year survival rate, while 51% (1459 patients) were treated with surveillance, resulting in a 14.5% 5-year survival rate.[10] The apparent difference in the two results from different data sets can be explained by the fact that in the NCDB, 80% of cases come from teaching/research hospitals affiliated with a medical school and/or an NCI designated cancer center while SEER is more reflective of the general population.[10]

Why, in Gore’s paper, did so few patients receive standard of care RC? The data showed that the main reasons for patients not receiving RC were age, comorbidity, and distance traveled to a center offering RC. As the 66-69 age cohort was the youngest one analyzed, age, here, is not a factor. Furthermore, it is impossible to believe that 125 patients in this age group were judged to be too ill to join the 132 patients who did undergo RC, or received another therapy with curative intent. This leaves distance travelled to a center that performed RC as the only potential limiting factor to curative therapy. The chances of patients receiving RC were reduced when they had to travel 5 or more miles for treatment and by 50 miles, their chances of receiving RC diminished by 40%.

Significantly increasing the number of patients that undergo RC may be difficult. Hospitals and urologists may, for many reasons, shy away from offering RC, starting with the high complication rate associated with this operation. Overall 90-day mortality has been reported to be 7.2%. Centers of Excellence report major complication rates within 90 days of 24%, ER visits 38%, readmissions 30% and death 4%.[12,13]

The low reimbursement for RC may be another reason hospital systems and many urologists feel that RC, in terms of time and resources, is of too high cost to them. Even if patients have their surgery at a major center, often the local hospital and urologists are left to deal with complications and recovery. Subsequently, patients so treated, experience worse outcomes than those whose complications are managed at major centers.[14]

How can we best address this problem? First, we can increase efforts to facilitate more patients undergoing RC. However, that alone is unlikely to fix the problem. In order to increase access to treatments with curative intent, urologists will have to champion patients who, for whatever reason, are not undergoing RC, to receive tri-modal therapy with appropriately dose radiation and intent to cure. The choice of treatment will have to be dependent upon patient’s choice, supported by physicians who treat this deadly cancer.  It will also depend upon the expertise available to the patient in their community. This will require a true team approach: the team consisting of urological oncologists, radiation oncologists, medical oncologists, nurses, social workers, and experts in participatory research. There will also be a need for Centers of Excellence to partner with smaller centers, community practices, and individual providers to help ensure that their patients with UC receive the best therapy possible. Many of these Centers of Excellence already have cancer care networks established that could form the basis for implementing the above approach. The effort needs to be led by an interdisciplinary leadership team. In the US, this may consist of key delegates from The American Urological Association (AUA) and The Society of Urological Oncology (SUO), joined by The American Society of Clinical Oncologists (ASCO) and The American Society of Radiation Oncology (ASTRO), and the Bladder Cancer Advocacy Network (BCAN). These groups have come together to issue clinical guidelines with joint presentations to publicize them. The next step has to focus on increasing uptake and adherence to these guidelines by providers.

The first response may be that this is a matter of education and should be addressed by the AUA educational office. However, the AUA has done an incredible amount in educating urologists about the treatment of this disease. They have run instructional courses, plenary sessions, state-of-the-art talks, feature articles, made it a part of recertification and put out many practice guidelines.

Going back to 2013, the NCCN Guidelines for patients with cT2 Disease recommended radical cystectomy (RC) with a strong consideration for neoadjuvant chemotherapy, or bladder preservation following maximum TURBT with concurrent chemo and radiation therapy. For patients with extensive co-morbid disease or poor performance status, TURBT alone or radiation therapy plus chemotherapy, or chemotherapy alone, was recommended.[6]

In 2017, the AUA, together with ASCO/ASTRO and the SUO, published updated guidelines. There were 35 recommendations for patients with newly diagnosed muscle invasive bladder cancer. They recommended curative treatment options should be discussed before determining a plan of therapy based on both patient’s co-morbidity and tumor characteristics. Patient’s evaluation should be completed with a multi-disciplinary approach. Again, recommendation was for RC and neoadjuvant chemotherapy. Patients with MIUC who elect multi-modal bladder preservation therapy, should have maximum TURBT, chemotherapy, combined with external beam radiation therapy.[7]

The latest guidelines to be published were the NCCN guidelines of 2019. These differ from the 2013 guidelines, not with regard to RC or neoadjuvant chemotherapy, but include a third option offered to patients with cT2 Disease, which is concurrent chemo-radiation therapy, supported by category 1 evidence. For patients who were not cystectomy candidates, the recommendation was for concurrent chemo-radiation therapy, radiation therapy, or TURBT and also consider intravesical BCG. These patients should have reassessment of tumor status 2-3 months after treatment. If the tumor was still persistent, they should then receive chemotherapy or concurrent chemo-radiation therapy or palliative TURBT and best supportive care.[8]

These guidelines are extensive, yet it is not possible to believe that if they are followed, 53% of Medicare patients will be treated by surveillance alone.

Last October, Dr. Nitti reported for the AUA educational office, the results of a survey of urologists that treat UC. In that survey, 91% said that they followed guidelines when treating Non-Muscle Invasive UC, yet somehow, as reported at the SUO last year, only 15% of people with T1 UC in the United States actually undergo treatment that follows AUA/SUO guidelines. The survey further reported that 89% of Urologists were following the guidelines when treating MIUC, yet, 51% of Medicare patients with MIUC are reportedly treated by surveillance only.

Clearly, in following these guidelines, there is a huge dichotomy between what practicing urologists believe they are doing, and what is actually happening. So, the next stage, we believe, would have to be some form of root cause analysis and implementation, as opposed to just an educational approach.

Urologists and their leadership were faced with a similar, but different problem a decade ago. PSA-driven prostate cancer detection led to too many patients undergoing prostate biopsies, resulting in over-detection and treatment of insignificant cancers. This led to development of new guidelines and drove novel methods and technologies for prostate cancer detection and determination of who should be appropriately treated. Six new molecular tests were commercialized that help determine which patients should be biopsied, re-biopsied and then once prostate cancer is detected, help determine which patients should undergo immediate treatment versus active surveillance.[15]  This approach has led to a decrease in biopsies and many more patients with low risk diseaseplaced on active surveillance.[16, 17]  Now, the same leadership must embrace an equally disturbing problem—namely, patients with MIUC who are being grossly undertreated. We believe adopting this policy will lead to the first decrease in mortality from this disease in 30 years.