Surveillance After Complete Clinical Response From Neoadjuvant Chemotherapy for Bladder Cancer?

During the first day of the Society of Urologic Oncology Annual Meeting, James M. McKiernan, MD, of Columbia College of Physicians and Surgeons, provided the argument for surveillance in the event of complete clinical response (cCR) after neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC).

He began by addressing what the guidelines say for systemic therapy for MIBC: “Utilizing a multidisciplinary approach, clinicians should offer cisplatin-based NAC to eligible patients prior to radical cystectomy (RC).” However, the exact regimen and duration for cisplatin-based NAC is not agreed upon.

Approximately 82,000 new bladder cancer diagnoses are expected this year, 20,000 of which will be MIBC. Forty-two percent of those are expected to achieve pT0 after NAC, which means about 8,400 patients will undergo RC without evidence of cancer in their bladder. “That operation, in the best of hands, has a 2.7% mortality rate, a 25% readmission to hospital rate, and a 64% complication rate,” Dr. McKiernan said. Additionally, the therapeutic benefit of RC in “truly pT0” is unknown, he argued, and up to 10% of these patients will relapse systemically despite an operation to remove their bladder.

What do they guidelines say about the morbidity of RC? He read, “Clinicians should counsel patients regarding complications and implications of treatment on QOL (eg, impact on continence, sexual function, fertility, bowel dysfunction, and metabolic problems).” High-grade complications are observed in approximately 20% of patients, mortality rates are less than 3% in most cases but can be as high as 6%, and readmission rates are up to 30% with ICU admissions of 26%.

Dr. McKiernan then posed a multitude of fundamental questions pertaining to pT0, including whether we can accurately determine if cT0 is equivalent to pT0 after NAC (“We cannot with a great deal of confidence”).

A study by Columbia in conjunction with MSKCC of 148 “very highly selected patients” who underwent surveillance after cCR was highlighted. The 5-year disease-specific survival, overall survival, and cancer-free survival was 90%, 86%, and 76%, respectively. Among these patients, 48% had disease recurrence in the bladder, including 37% as non-muscle invasive bladder cancer (NMIBC) and 11% as MIBC. For those with MIBC, most of the 11% “occurred early because of errors in diagnosis, meaning misclassification of complete responders when they were not, in fact, complete responders.” Importantly, he added that 2.7% of patients experienced an intra-bladder relapse that could not be salvaged by RC, leading to an “unnecessary mortality event.”

When further elaborating on the impact of misclassification of cCR, Dr. McKiernan provided the data to suggest that there is a 1.9% risk of mortality due to surveillance for misclassified cCR, which is a lower risk of mortality of RC to begin with (again citing that 2.7% statistic).

NMIBC recurrence does not seem to be a predictor of MIBC or metastases in this setting, he continued, and the guidelines state that patients who experience NMIBC recurrence should receive local measures such as TURBT with intravesical therapy or RC with bilateral pelvic lymphadenectomy.

How do you identify, with confidence, the patients with high-risk cT0 versus those with low-risk cT0? He showcased a study that showed that “in an unselected population, omitting cystectomy is a bad idea.” And how do you identify those that are not going to recur? Among the listed factors were absence of secondary MIBC, Cis, variant histology, and hydronephrosis; mpMRI findings, and Re-TUR findings before NAC.

Again, Dr. McKiernan went back to the guidelines, this time in relation to complete clinical response. The AUA says to perform RC as soon as possible following NAC (ideally within 12 weeks), and for patients with newly diagnosed MIBC who desire to retain their bladder, as well as for those with significant comorbidities, bladder preserving therapy should be offered when clinically appropriate. However, the EAU acknowledges that overtreatment is a possible negative consequence of RC, and NAC alone will rarely produce a durable complete response despite the fact that around 56% of patients will have a cCR. Furthermore, the EAU noted that bladder-conserving strategy with TUR and systemic chemotherapy could lead to long-term survival with an intact bladder in selected patients.

To round-out his presentation, Dr. McKiernan highlighted the latest data and evidence to suggest that maximal TUR, mpMRI, and ctDNA will help improve patient selection for surveillance after cCR, as well as pending improvements in systemic therapy.