Bladder Cancer in 1990

Thirty years ago, bladder cancer research in many academic centers was focused on two main areas: the incorporation of adjuvant treatments with cystectomy to improve oncologic outcome and the development of continent urinary diversion techniques to replace ileal conduit. We understood the basic biology of the disease on a histological basis, and the tumor suppressor p53 was identified as a driver mutation for invasive cancers early in that decade. There was very little interest by Pharma in developing alternatives to bacillus Calmette-Guérin (BCG) treatment for non-muscle invasive disease, and new chemotherapies and targeted therapies for metastatic disease mostly failed to show improvement over cisplatin combinations, with few survivors past 2 years.

Because clinical staging was so inaccurate, the focus was on using chemotherapy after surgery when we had accurate pathological staging available. In that decade, studies were completed in the U.S. and Europe showing the benefit of giving chemotherapy prior to cystectomy instead. Also, continent urinary diversion was routinely being offered in a few centers as an alternative to ileal conduit, with many published insights from those surgeons to help with patient selection and functional outcomes.

Bladder Cancer in 2021

There have been three critical advances in the past decade that hold the promise of completely changing how we treat our patients. The first was the application of next generation sequencing and “omics” analysis of bladder tumors. The Cancer Genome Atlas (TCGA) project set the stage for this, with many groups making additional contributions toward our understanding of the complex biology of these tumors.^1,2 These have shown that invasive bladder cancers can be divided into 6 different subtypes with different prognoses and different responses to systemic therapies. So far, these have mostly been tested in a retrospective fashion, and most experts agree that prospective trials will be needed before we can reliably use them to determine treatment.³ However, just recently a clinical trial has used the presence of DNA repair gene mutations that seem to confer high sensitivity to cisplatin in a prospective trial testing whether chemotherapy could be used as monotherapy for those patients.⁴

The second advance was the development of the class of PD1 and PDL1 checkpoint inhibitors–the first real advance in the systemic treatment of bladder cancer in 50 years. There are now 5 drugs approved for metastatic bladder cancer in this class with more in development, and exploration is underway to move these treatments into earlier stage disease. A recent count showed more than 20 clinical trials of checkpoint inhibitors with or without other treatments before or after cystectomy, including over 8,000 patients internationally.⁵

Finally, there has been a renewed interest by the pharmaceutical industry in the treatment of non-muscle invasive cancer, with many innovative approaches to both intravesical and systemic therapy already being tested. Many of these are in phase III trials and we can expect U.S. Food and Drug Administration (FDA) approvals in the near future. These may give our patients many more options beyond what is currently available.

What the Future Holds

I often think about what would really change the lives of our patients. As surgeons, we focus on the ultimate goal of cure, but there are many other aspects that are equally and sometimes more important to patients. These include all the physical, psychological and financial burdens of surveillance and treatment. These affect the patients with low grade, low-risk cancers just as they do those who have life-threatening disease.

Non-muscle invasive cancers

How can we minimize the burden of surveillance and treatment for patient with low and intermediate-risk disease? Can we replace cystoscopy with a highly accurate urine or imaging test? Many urine tests have been developed but so far have fallen short of eliminating the need for cystoscopy, but this may be within reach using molecular testing in the urine.⁶ Can we reverse pre-cancerous changes in the urothelium or develop a pill to prevent recurrence?

For patients with the most dangerous non-muscle invasive cancers, can we more accurately predict which tumors are destined to progress and which ones will respond to our various intravesical or systemic therapies? We will soon have many more of these available with widely varied mechanisms of action, likely at increasingly high cost. We will need to figure out how to sequence these new treatments and how to avoid subjecting our patients to the risks and financial burden of treatments that are not likely to be effective.

Muscle invasive and locally advanced tumors

Can we more accurately clinically stage patients with muscle invasive cancers? New multiparametric magnetic resonance imaging (MRI) technology and development of the Vesical Imaging–Reporting and Data System (VI-RADS) interpretation tool are already showing promise in this arena.⁷ As we have observed with prostate MRI, dissemination of the technology and skills required to interpret the studies is going to take time, but improvements in these technologies can be expected to continue at a rapid pace, likely assisted by machine learning algorithms. Similarly, current fluorodeoxyglucose-positron emission tomography (FDG-PET) scans have not shown significant improvement over standard computerized tomography (CT) for staging muscle invasive bladder cancer, but the field of molecular imaging is exploding as well.⁸ New PET molecules will likely allow us to better identify occult metastatic disease in the future, much as we have seen with prostate cancer. Finally, the role of “liquid biopsy” with plasma cell-free DNA testing may become increasingly useful for identifying patients most likely to benefit from systemic therapies, and those who can safely avoid them.⁹

Chemoradiation is increasingly being adopted in the U.S. as an alternative to cystectomy. But much of the improvement in outcomes to date has come through patient selection, limiting treatment to the lowest risk patients. Perhaps molecular testing will allow us to identify patients who are most likely to achieve long-term local control with radiation, even in those without “ideal” features.

Can we predict response to specific systemic therapies in the individual patient? There are strong hints that the 6 molecular subtypes of bladder cancer may respond differently to chemotherapy versus immunotherapy. The addition of these correlative studies to the many ongoing prospective clinical trials should soon help us get the evidence we need. When we only have one option, we may not be willing to withhold treatment even if it only has a small chance of benefit, but we already have four different classes of treatments, including chemotherapy, checkpoint inhibitors, antibody-drug conjugates like enfortumab vedotin and targeted agents like erdafitinib. Perhaps in the near future, molecular classification will allow us to get closer to truly personalized medicine for patients with muscle invasive localized cancer.

Finally, as long as cystectomy is part of our treatment, we need to continue to work to improve the experience for our patients undergoing cystectomy and urinary diversion. Robotic cystectomy has been rapidly adopted and will undoubtedly continue to increase as our trainees become more and more comfortable with this technology and less with open surgery. However, most studies have shown that the use of the robot has had little impact on some of the key outcomes that matter the most to patients, including major complication rates, readmissions, prolonged recovery and quality of life. We need to work with our colleagues in geriatrics toward a better understanding of frailty and “prehabilitation” as applied to patients undergoing this surgery. And lastly, as less than 15% of cystectomy patients nationally undergo continent urinary diversion today, we need to ensure that these options remain available and to develop better tools to facilitate real shared decision making around the choice of urinary diversion.

Conclusion

This is a very exciting time to be involved in managing patients with bladder cancer. I expect that by the end of this decade, our treatment paradigms will have changed quite radically and for the better. We need to continue to support clinical trials so that we can reach these important goals.