Treating Muscle-Invasive Bladder Cancer without Removing the Entire Bladder

A new study suggests that a large proportion of patients with muscle-invasive bladder cancer may avoid cystectomy, the operation that removes the entire bladder, and have long-term disease-free survival with a functioning bladder.

About half of the patients undergoing bladder-preserving tumor removal plus systemic chemo-immunotherapy had clinical complete responses (cCRs) in the 1-year interim analysis of 64 patients.

These new results, presented at the American Society of Clinical Oncology (ASCO) 2021 virtual annual meeting, come from the phase-2 HCRN GU 16-257 clinical trial and were reported by Dr. Matt D. Galsky.

The stages of bladder cancer are shown below:

Where did the idea of treating bladder cancer without surgery come from?

In fact, this treatment approach, involving transurethral resection of the bladder tumor (TURBT) followed by systemic therapy, has long been known to be effective in achieving durable bladder survival in up to 40% of patients with muscle-invasive bladder cancer. This response is also highly associated with long-term disease-free survival.

However, previous data were insufficient to establish this treatment approach; Dr. Galsky highlighted 3 distinct barriers:

1. The scarcity of prospective studies evaluating the approach;
2. Inconsistency in defining and measuring clinical complete response across approaches; and
3. Limited understanding of the role of delayed cystectomy in patients who experience recurrence.

The importance of the study

Radical cystectomy is a major operation and requires diversion of urinary flow, with life-changing effects. Clearly, if we can identify which patients have their muscle-invasive bladder cancer completely treated with transurethral resection and systemic therapy alone, a group of patients may avoid cystectomy, and long-term disease-free survival with an intact bladder may be possible.

To this end, Dr. Galsky and colleagues designed the HCRN GU 16-257 trial. They were armed with new data suggesting that mutations in DNA damage response genes (DDR alterations) are sensitive to cisplatin-based chemotherapy and associated with increased tumor mutation burden (TMB) and thus potentially sensitive to immunotherapy. They aimed to test their hypothesis, using DDR and TMB status as immunotherapy biomarkers to predict response to systemic therapy. 

For the study, 76 patients were enrolled at seven centers between August 2018 and November 2020. Of these, 64 underwent TURBT and systemic treatment with 4 cycles of gemcitabine and cisplatin plus the checkpoint inhibitor nivolumab.

Of the patients, 31 (48%) achieved a clinical complete response (cCR) during a median follow-up of 13.7 months.

One patient who achieved cCR chose immediate cystectomy; pathology showed that the patient had a low-grade papillary tumor. Of 8 patients with regional recurrence, 6 underwent cystectomy.

Study participants were mostly male (79%), with a median age of 69. To enroll, they had to be cisplatin-eligible with stage cT2-T4a urothelial bladder cancer; 56% had stage cT2 disease, 32% cT3 disease and 12% cT4 disease.

Treatment included 4 cycles of gemcitabine, cisplatin and nivolumab followed by clinical restaging with urine cytology, bladder imaging, cystoscopy and the relevant biopsy.

How is clinical complete response (cCR) defined?

The authors defined cCR strictly using findings after cycle 4. Oncologic imaging and urine cytology had to show no abnormalities after cycle 4. Bladder biopsy had to show no evidence of disease greater than low-grade papillary tumors after cycle 4. Patients meeting this definition could continue without cystectomy and receive weekly maintenance nivolumab for eight cycles.

Patients who did not achieve cCR underwent cystectomy.

Treatment was generally safe, and none of the criteria for stopping the trial early were met. These criteria included a high rate of grade 3. or higher immune-related side effects and a high rate of muscle-invasive and/or metastatic recurrence among those achieving cCR.

Genetic biomarkers

Genetic testing showed that a tumor mutation burden of 10 mut/MB or greater, or alterations in ERCC2, was significantly associated with achieving cCR.

Conclusion

These findings suggest that recurrence-free survival with an intact bladder is possible after TURBT and systemic therapy in muscle-invasive bladder cancer. Additional studies are needed to evaluate the durability of the observed responses and the role of genomic biomarkers in management algorithms.