By Mary Ellen Schneider
Active surveillance after neoadjuvant chemotherapy may someday be an option for some patients with muscle invasive bladder cancer and certain predictive genomic factors, according to interim findings reported at the American Society of Clinical Oncology’s 2021 Genitourinary Cancers Symposium.
In the interim analysis of the RETAIN BLADDER trial, which evaluated risk-enabled therapy following cisplatin-based neoadjuvant chemotherapy, 81% of patients in the active surveillance group were able to retain their bladder (Abstract 397). Follow up is underway for the primary endpoint of two-year metastasis-free survival.
“Sparing a cystectomy would be highly desirable if long-term oncologic outcomes are not compromised,” said Daniel M. Geynisman, MD, of Fox Chase Cancer Center, who presented the study findings.
But Dr. Geynisman stressed that risk-adapted bladder preservation is not a standard of care at this time. The current standard of care for muscle invasive urothelial carcinoma is neoadjuvant cisplatin-based chemotherapy followed by cystectomy or chemoradiation. Candidate prognostic and predictive biomarkers in urothelial carcinoma include alterations in DNA damage response genes. Previous studies have shown that alterations to ATM, ERCC2, FANCC, and RB1 are associated with response and long-term survival.
RETAIN BLADDER is a phase 2, prospective trial designed to evaluate a risk-adapted approach to patients with clinically localized muscle invasive bladder cancer. “This is not a randomized trial, but rather a trial of allocation,” Dr. Geynisman explained.
Patients were eligible for the trial if they had clinical T2-T3 urothelial carcinoma without metastasis or spread to the lymph nodes, ECOG performance status of 0-1, and urothelial predominant histology. All patients underwent transurethral resection of the bladder tumor (TURBT) and were sequenced for mutations, specifically alterations in ATM, ERCC2, FANCC, or RB1. This was followed by three cycles of neoadjuvant chemotherapy with accelerated methotrexate, vinblastine, doxorubicin, and cisplatin, and a second TURBT.
Patients with at least one mutation of interest and no residual tumor activity at the time of restaging were put on active surveillance. The active surveillance regimen included a pre-determined set of cystoscopic, radiographic, and clinical evaluations. The remaining patients received intravesical therapy, chemoradiation, cystectomy, or some combination of those treatments.
A total of 71 patients were enrolled in the trial across four academic centers, with data cutoff on Jan. 1, 2021. In this intention-to-treat population, 34 patients had cystectomy, 5 patients had chemoradiation, and 13 patients had intravesical therapy using Bacillus Calmette-Guerin (BCG).
Less than half of patients (33 patients) had a mutation. Twenty-six patients with mutations were put in the active surveillance group and two patients without mutations were put on active surveillance.
Of the 38 patients who were mutation negative, 10 patients had a recurrence. Of those patients, nine developed metastatic disease and seven died.
Among the 26 patients who were mutation positive and placed on active surveillance, 17 patients experienced a recurrence and two patients died from metastatic disease.
At a median follow up of 18.8 months, the median overall survival had not been reached in the intention-to-treat population. Of those 71 patients, 86% of patients are alive and 81.7% are metastasis free.
Among the 26 patients who were mutation positive and on active surveillance, 92.3% are alive and 88.5% are metastasis free at a median follow up of 20.6 months.
The most common mutation seen in the study was RB1, with half of patients displaying this alteration. ATM alterations were seen in 42% of surveillance patients, followed by 31% with ERCC2, and 4% with FANCC. Multiple mutations were seen in 27% of patients. Dr. Geynisman noted that ERCC2 mutations were present in 56% of patients who did not have recurrence and in 18% of patients who did recur.
Two other trials of bladder preservation therapy are ongoing. Additionally, the RETAIN-2 trial, which will examine risk-enabled therapy after neoadjuvant immune-chemotherapy for bladder cancer, is now open at Fox Chase Cancer Center, Dr. Geynisman said.