SAN FRANCISCO – Two concurrent chemoradiation induction regimens had similar safety and efficacy when used as part of a bladder-sparing strategy in patients with muscle-invasive bladder cancer, suggest primary results of the NRG/RTOG 0712 trial. But one offers better patient convenience.
The selective bladder-preservation paradigm entails maximal transurethral resection of the bladder tumor (TURBT) followed by induction radiation and concomitant chemotherapy, lead author John J. Coen, MD, a radiation oncologist with 21st Century Oncology, Providence, Rhode Island, noted at the 2018 Genitourinary Cancers Symposium. Patients then undergo cystoscopy to assess their response.
“A key component of this therapy is close urologic surveillance,” he noted. “This is trimodality therapy with close urologic surveillance, and cystectomy is prompted at the earliest time it’s indicated.”
Dr. John J. Coen
The 70 patients enrolled in the multicenter randomized phase 2 trial had undergone TURBT and were randomized evenly to twice-daily radiation plus 5-flourouracil-cisplatin (the RTOG standard at the time of trial planning) or to daily radiation plus gemcitabine (a modification of a successful regimen developed at the University of Michigan). All were offered adjuvant chemotherapy regardless of whether they responded and whether they underwent consolidation therapy or cystectomy.
At a median follow-up of 5.1 years among the 52 evaluable patients, the 3-year rate of freedom from distant metastasis, the trial’s primary endpoint, was 78% with twice-daily radiation plus 5-flourouracil-cisplatin and 84% with daily radiation plus gemcitabine, according to results reported at the symposium, which was sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Both values were higher than the trial’s predefined benchmark of 75% for defining the regimen as promising. “This trial wasn’t necessarily powered to compare arms, so the conclusion would be that both arms exceeded the benchmark and it would be appropriate to evaluate both arms further in subsequent trials,” Dr. Coen commented.
In each trial arm, more than three-fourths of patients had a complete response, and about two-thirds of patients were alive and free of distant metastasis with their bladder intact at 3 years.
Toxicity, which was supposed to be the tie-breaker if efficacy was similar, was also essentially the same for the two regimens. Both were fairly well tolerated in the acute period; the primary grade 3 and 4 toxicities were hematologic ones.
“So where do we go from here? I think this trial does demonstrate concurrent gemcitabine is a reasonable alternative to cisplatin for patients undergoing selective bladder preservation,” Dr. Coen summarized. “This is especially important in patients with poor renal function or hearing loss. And bladder cancer is often a disease in the elderly, so tolerance of various regimens is a very important aspect to planning further trials.”
“This trial also demonstrates that daily radiation is a reasonable alternative to twice-a-day radiation, which had become the standard through the RTOG on more contemporary trials,” he added. “Daily radiation would allow wider adoption of selective bladder preservation by trimodality therapy.”
Clinical implications
“I would have to see more details about the toxicity data for the chemotherapy, the radiosensitizers,” session co-chair Yair Lotan, MD, a professor of urology at the UT Southwestern Medical Center, Dallas, Texas, commented in an interview. “But in general, if you have two equivalent protocols in terms of effectiveness, and one is less toxic or more convenient, that’s always preferable. From the standpoint of coming once a day rather than twice a day to get radiation, if I were a patient, I would prefer that regimen”
Current practice in this patient population likely hinges on where a patient is treated, he said. “Based on the new nonmetastatic muscle-invasive guidelines, many of them would be recommended surgery or possibly chemoradiation protocols, and then there are a lot of factors such as patient preference and outcomes that would probably impact the decision making.”
“Certainly, this study won’t prove standard of care because standard of care in the global picture for a patient with muscle-invasive disease really will depend on a randomized trial of surgery versus radiation or chemoradiation, multimodal therapies,” Dr. Lotan maintained. “Not every patient is even eligible; some patients with hydronephrosis or unresectable disease may not be the best candidates for multimodal therapy. But more information from these types of trials may help clinicians decide which multimodal therapy approach to use.”
Study details
Patients enrolled in NRG/RTOG 0712, a multicenter randomized phase 2 trial supported by the National Cancer Institute, had clinical T2 or T3-4a bladder cancer. Hydronephrosis and obvious lymph node involvement were exclusion criteria.
Like the rate of freedom from metastasis, the rate of complete response after induction therapy was similar for the two arms: 87.9% with twice-daily radiation plus 5-flourouracil-cisplatin and 75.8% with daily radiation plus gemcitabine.
“These rates exceed historical complete response rates, and this is likely a result of improved selection over time and more thorough TURBTs performed over time,” Dr. Coen proposed. “Over the course of multiple successive RTOG trials, our selection criteria have been refined. One excellent example would be that hydronephrosis has been excluded on more contemporary trials, but if you look at older trials, those patients were included.”
The 3-year rate of bladder-intact distant metastasis–free survival was 66.7% and 69%, respectively. “This is a very important endpoint. These results are excellent,” he commented. “And there is really no appreciable difference between the two arms on the actuarial analysis.”
As far as specific treatment failure events in the trial overall, three patients died, eight underwent cystectomy, and eight developed distant metastases. Although numbers were small, these events appeared fairly evenly distributed across arms.
The rate of grade 3 or 4 acute toxicity was 57.6% with twice-daily radiation plus 5-flourouracil-cisplatin and 54.6% with daily radiation plus gemcitabine. The large majority of events were blood and bone marrow toxicity. “It’s quite notable that the rates of GU and GI toxicity were very low,” commented Dr. Coen, who disclosed that he had no relevant conflicts of interest.