Don't Remove Bladder for Localized Muscle-Invasive Cancer

M. Alexander Otto, PA, MMS

May 26, 2023

The usual treatment for localized muscle-invasive bladder cancer (MIBC) is to remove the bladder. More conservative organ-preserving options have been held in reserve for patients who cannot undergo surgery.

But investigators are now challenging that orthodoxy.

Conservative treatment should be offered to all such patients whether they are candidates for surgery or not, says a team led by Alexandre Zlotta, MD, PhD, a urologic oncologist at the University of Toronto, Canada.

The startling conclusion comes from a study that was published online on May 12 in The Lancet Oncology. The investigators say their study provides the best evidence to date in which bladder removal was compared with conservative treatment.

They analyzed data for patients who underwent radical cystectomy for localized MIBC and data from patients who underwent trimodality therapy, or maximal transurethral resection of bladder tumor followed by concurrent chemoradiation therapy.

The team found no difference in oncologic outcomes at 5 years and better overall survival with trimodality therapy, in part because of the 2.5% perioperative mortality rate with cystectomy.

The study is the largest multi-institutional investigation to date to compare oncologic outcomes between the two approaches. With randomized trials unlikely, it "provides the best evidence possible to guide management," Zlotta and colleagues conclude.

"This article has gained a lot of traction in bladder cancer circles, and I think for good reason. What makes this study unique is that it attempts to perform an apples-to-apples comparison of the two study groups," said Vidit Sharma, MD, a urologic oncologist at the Mayo Clinic in Rochester, Minnesota.

These are "indeed...important finding[s]. I anticipate more providers and patients will be willing to choose trimodality therapy as a result of this work," Sharma told Medscape Medical News when asked for comment.

Previous Trials Closed Early

Zlotta and colleagues note that several randomized trials tried to pit the two options against each other but failed to meet recruitment goals and closed early.

Part of the problem is that there wasn't enough evidence to support conservative management, so patients were hesitant to enroll, but without trials, good evidence could not be produced. It was a catch-22.

As a result, radical cystectomy remains the most widely used curative-intent treatment for MIBC despite frequent and sometimes life-altering complications and the risk of perioperative death.

In their study, the investigators sought a way out of the conundrum by running the next best thing to a randomized trial ― a propensity score–matched study in which 282 patients who underwent trimodality therapy were matched in a 1:3 ratio with 437 patients who underwent radical cystectomy. All participants were eligible for either approach.

The team concludes that "trimodality therapy, in the setting of multidisciplinary shared decision making, should be offered to all suitable candidates with muscle-invasive bladder cancer and not only to patients with significant comorbidities for whom surgery is not an an oncologically equivalent alternative to radical cystectomy in select patients."

Time to Revisit Treatment Guidelines?

Commenting on the study, Sharma said that careful "patient selection for trimodality therapy [is] key."

He noted that patients in the study were ideal candidates for trimodality therapy. They had T2–T4 N0M0 muscle-invasive urothelial carcinoma with solitary tumors less than 7 cm across, and they did not have bilateral hydronephrosis or extensive carcinoma in situ.

Patients who opt for organ preservation must be committed to ongoing follow-up ― including surveillance cystoscopies, biopsies, and potential intravesical therapies ― and they must understand that there is a risk of recurrence that they wouldn't have had their bladders been removed.

In the study, the recurrence rate with trimodality therapy was 31%, and 13% of patients underwent salvage cystectomies over a median follow-up of about 5 years. The delay in surgery did not compromise oncologic outcomes, the investigators note.

Sharma's team is researching the pros and cons of trimodality therapy in comparison with radical cystectomy in various scenarios. Sharma said that In the meantime, "bladder cancer providers should continue to offer trimodality therapy to appropriately selected patients with MIBC who are motivated to preserve their bladder."

Also approached for comment, Zachery Reichert, MD, PhD, a urologic oncologist at the University of Michigan, Ann Arbor, was impressed by the findings.

"Excit[ingly], this study shows oncologic equivalence (at this follow-up duration at least) which is excellent," he told Medscape Medical News, although he noted that even with propensity score matching, unknown confounding "factors may [still] exist."

He said another issue to consider is that patients with high symptom burden may not find as much relief with trimodality therapy as they would with cystectomy.

Even so, "this study highlights the need for better provider and community education on chemoradiation as a viable/equivalent option" to surgery, "and quality improvement projects should target that."

Reichert added that he hopes that urology guidelines will revisit trimodality therapy "in light of this new data."

Study Details

With 1:3 matching in the study by Zlotta and colleagues, 282 trimodality patients were matched to 837 radical cystectomy patients.

After matching, men made up three quarters of both groups, and the mean age for both was just over 71 years. Across both groups, 90% of patients had cT2 stage disease, about 11% had unilateral hydronephrosis, and almost 60% underwent neoadjuvant or adjuvant chemotherapy.

Patients were treated from 2005–2017 at Massachusetts General Hospital, Boston; Princess Margaret Cancer Centre, Toronto; and the University of Southern California, Los Angeles.

Results from the propensity score–matched analysis show that the rate of 5-year metastasis-free survival was 74%, and the rate of 5-year disease-free survival was 76% in both arms; the rate of 5-year cancer-specific survival was 83% with cystectomy, vs 85% with trimodality therapy.

Overall survival favored trimodality therapy, at 77% vs 72% (P = .0078).

The postoperative mortality rate was 2.5% with radical cystectomy; no deaths occurred within 90 days of trimodality therapy.

Sensitivity analyses that were restricted to patients who underwent radical cystectomy and who received neoadjuvant or adjuvant chemotherapy showed no difference in metastasis-free survival, cancer-specific survival, and disease-free survival compared with trimodality therapy.

Results were virtually identical in a second analysis that was based on inverse probability treatment weighting.

Outcomes for radical cystectomy and trimodality therapy were not statistically different among centers, which speaks "to the potential generalizability of the findings, at least in high-volume centers," the study team says.

Radical cystectomy in the study consisted of cystoprostatectomy for men and anterior exenteration with bilateral pelvic lymph node dissection and urinary diversion for women.

The study was funded by the Sinai Health Foundation, the Princess Margaret Cancer Foundation, and Massachusetts General Hospital. The investigators had numerous ties to industry. Zlotta has received consulting fees from Janssen, Verity Pharmaceuticals, Ferring, mIR Scientific, Tolmar, and Theralase. Sharma and Reichert have disclsoed no relevant financial relationships.

Lancet Oncol. Published online May 12, 2023. Abstract

M. Alexander Otto is a physician assistant with a master's degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email:

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