Data from a recent Phase II study (NCT03451331) suggests that a combination of chemotherapy and immunotherapy could help preserve the quality of life for patients with muscle-invasive bladder cancer. This research, which was recently published in Nature Medicine, showed that gemcitabine and cisplatin plus nivolumab had promising efficacy in this patient population without the need for bladder removal (2023; https://doi.org/10.1038/s41591-023-02568-1).
"Surgery to remove the bladder can be curative for some patients with muscle-invasive bladder cancer, but the surgery is life-altering," noted study author Matthew Galsky, MD, Co-Director of the Center of Excellence for Bladder Cancer at The Tisch Cancer Institute, a part of the Tisch Cancer Center at Mount Sinai. "We know that in patients who received neoadjuvant chemotherapy prior to surgery, a subset will have a pathological complete response.
"Unfortunately, we only know if a pathological response has been achieved after the bladder is removed," he continued. "We reasoned that a subset of patients with muscle-invasive bladder cancer could experience long-term bladder intact survival with transurethral resection of bladder tumor (TURBT) plus systemic therapy alone."
Background & Methods
Whether or not cystectomy is needed for all muscle-invasive bladder cancer patients has been an ongoing point of discussion, and Galsky and colleagues designed a Phase II study to shed further light on this issue.
"Our primary objectives," the study authors explained, "were to estimate the clinical complete response rate and assess the positive predictive value of clinical complete response for a composite outcome measure (2-year metastasis-free survival in patients forgoing immediate cystectomy or
Patients with muscle-invasive bladder cancer were given 4 cycles of gemcitabine and cisplatin coupled with nivolumab. This was followed by clinical restaging, and patients who achieved a clinical complete response were not required to undergo a cystectomy. For patients who did not achieve a clinical complete response, bladder removal was the recommended course of action.
Clinical restaging involved MRI of the abdomen and pelvis (unless contraindicated, in which case CT scans were substituted), CT of the chest, cystoscopy with biopsies according to a recommended template, and urine cytology, noted Galsky and colleagues.
In this study, clinical complete response was defined as "no evidence of high-grade malignancy on biopsy; no malignant cells on urine cytology; and no definitive evidence of local or metastatic disease on cross-sectional imaging."
Findings & Conclusions
Between August 2018 and November 2020, the study authors enrolled 76 patients with a median age of 69 years. The majority of patients were male (79%) and the most common clinical stage was cT2N0M0 (57%). Seventy-two of the enrolled patients underwent restaging. Of those who did not, one developed metastatic disease. The other three developed adverse events-cerebrovascular accident, deep venous thrombosis, and increase in creatinine-and had a cystectomy.
Galsky and his team reported that 33 of 76 patients (43%) achieved the co-primary endpoint of clinical complete response. "Lower baseline clinical T stage was associated with a higher likelihood of a clinical complete response, although clinical complete responses were observed in patients with cT2-T4 disease," they noted.
Thirty-two of the patients who reached a clinical complete response chose not to proceed with immediate cystectomy. One patient opted to undergo the procedure, which revealed a low-grade ypTaN0 urothelial cancer, according to the researchers, who noted that the positive predictive value of clinical complete response was 0.97 (95% CI: 0.91, 1), which met the co-primary objective.
At the time of the data lock, the median metastasis-free and overall survival for the entire study cohort was not reached, Galsky and colleagues reported. "To further contextualize the prognostic impact of achieving a clinical complete response as related to metastasis-free survival and overall survival, a post hoc landmark analysis was performed using the time of clinical restaging as 'time 0,'" they noted in their paper.
This analysis showed that patients who achieved a clinical complete response had significantly longer metastasis-free survival and overall survival when compared with those who did not achieve a clinical complete response.
The median follow-up for patients who had a clinical complete response was 30 months. The 32 patients who opted out of immediate cystectomy underwent a median of 8 cycles of maintenance nivolumab. Eight of these patients were later treated with cystectomy for local recurrence. This included one patient for an abnormal MRI scan with no cancer detected on TURBT or cystectomy, according to the investigators.
"Seven of eight patients had <=ypT2N0 disease on cystectomy," the research team reported. "Two additional patients developed non-invasive local recurrence during follow-up (low-grade cTa and cTis) and were managed with TURBT and intravesical BCG, respectively, without evidence of subsequent recurrence."
Among the 39 patients who did not reach a clinical complete response, 34 opted to undergo cystectomy. Of the five who did not, four received off-protocol radiation and one declined any local therapy.
In terms of safety, the most common all-grade treatment-emergent adverse events included fatigue, anemia, neutropenia, and nausea. Seventy-five percent of patients experienced Grade >=3 treatment-emergent-adverse events with the most common being anemia, neutropenia, and urinary tract infections. One patient died due to sepsis after a bowel perforation that occurred at the time of cystectomy, reported the study authors, while noting this was not attributed to systemic therapy.
"In an effort to refine future selection of patients for this risk-adapted treatment approach, a secondary objective of the study was to assess whether the presence of a set of genomic alterations in baseline TURBT tissue would enhance the positive predictive value of clinical complete response," wrote Galsky and colleagues.
Of the 76 enrolled patients, tumor-only targeted DNA sequencing of pretreatment TURBT tissue was available from 73. "Somatic alterations in prespecified genes or increased mutational burdens did not improve the positive predictive value of clinical complete response," according to the Mount Sinai-led research team.
"The possible exception was the presence of a pathogenic mutation in FANCC, ATM, and/or RB1 in patients with a clinical complete response, which was limited to five patients, all of whom had pathogenic RB1 mutations," stated Galsky and colleagues, who noted the relevance of this finding is unclear.
"An exploratory analysis was also performed to assess the association between the prespecified genomic alterations and achieving a clinical complete response," they reported. "Clinical complete response rates were higher in patients with tumors harboring ERCC2 mutations or TMB >=10 mut/Mb versus patients having tumors without such alterations, but these associations did not achieve statistical significance after correction for false discovery."
Galsky and his team acknowledged that this study does come with potential limitations. As mentioned, the median follow-up of patients who achieved clinical complete response was 30 months.
"The vast majority of local and distant recurrences occur within 2 years of treatment in previous bladder-sparing studies of MIBC, although whether the same pattern and timing holds true for patients not undergoing cystectomy or receiving radiation is not well established," the study authors explained. "Therefore, longer-term follow-up data are needed to fully understand the impact of this treatment regimen on disease control."
Given the need for later cystectomy in some patients who develop local recurrence after a clinical complete response, there is a question of whether all patients achieving this response should undergo (chemo)radiation to further optimize the likelihood of bladder preservation, Galsky and colleagues suggest.
"The complex interplay of issues related to organ preservation, cancer control, and potential overtreatment with such an approach warrants further consideration and investigation," they elaborated. "Patient-reported outcome data would provide important additional context, but such information was not collected in our study."
Implications & Next Steps
This is one of the few studies to prospectively test the concept of whether TURBT plus systemic therapy can be used as a bladder-sparing treatment for muscle-invasive bladder cancer and the first to incorporate immune checkpoint blockade, Galsky told Oncology Times.
"We set out to determine how often the combination of chemotherapy and immunotherapy could eliminate any detectable evidence of bladder cancer," Galsky noted. "We then set out to determine in individuals in whom no evidence of cancer could be detected after this treatment [if they] would be cancer free 2 years after finishing treatment.
"We showed that in just over 40 percent of individuals, we couldn't detect any cancer using a series of tests after completing the treatment," he continued. "In those 40 percent of individuals, a subset had no evidence of cancer 2 years later despite not having their bladder removed. "
This clinical trial helps establish a consistent approach to assessing "clinical response" to treatment and a uniform and rigorous definition of clinical complete response, according to Galsky, who noted it also provides information about the relationship between achieving a clinical complete response and long-term outcomes. This research effort helps lay the foundation for further approaches testing this paradigm, he emphasized, highlighting that two follow-up studies have been designed with one already activated.
"Treatment for muscle-invasive bladder cancer is in need of major improvements from both a quality-of-life and an effectiveness standpoint," Galsky concluded. "If additional research confirms our findings, this may lead to a new paradigm in the treatment of muscle-invasive bladder cancer."
Catlin Nalley is a contributing writer.
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