The results of a large, matched cohort study from three major institutions have led investigators to call for broader use of trimodal therapy for muscle-invasive bladder cancer.
Radical cystectomy (RC), or the surgical removal of the whole bladder, prostate glands and seminal vesicles in men, or the bladder, uterus and fallopian tubes in women, is the traditional gold standard. But with trimodal therapy (TMT), patients can keep their bladders and avoid a long surgery. The procedure, which is called transurethral tumor resection, requires removing cancerous tumors from the bladder followed by chemoradiation.
After matching hundreds of patients requiring RC or TMT, “the oncologic outcomes seem to be equivalent. ...We do believe that TMT should be offered as an effective alternative for these patients,” said lead investigator Alexandre Zlotta, MD, PhD, director of uro-oncology at Mount Sinai Hospital, Toronto, after he presented the findings at the American Society of Clinical Oncology’s Genitourinary Cancers Symposium
“The findings that patients with clinical T2 disease have similar outcomes with either approach is encouraging,” said Matthew Zibelman, MD,, an assistant hematology/oncology professor at Fox Chase Cancer Center, Philadelphia, when asked for comment.
Trimodal therapy is already an alternative to cystectomy in guidelines for patients with clinical T2-T3 disease who have no, or minor, unilateral hydronephrosis, and unifocal tumors of 7 cm or less, among other criteria.
However, oncologists shy away from it preferring to reserve trimodal therapy mostly for patients who are not candidates for surgery, Dr. Zlotta explained.
The problem is a lack of head-to-head randomized data comparing the two approaches. Attempts at trials in the past closed early because of lack of accrual, and it seems unlikely there’ll be another attempt in the future.
A ‘very valuable’ option
Dr. Zlotta and associates wanted to address the evidence gap with the next best thing, a large, matched cohort study. In lieu of a level 1 data, he said their work provides “the best possible evidence” comparing the two approaches and supports TMT as a “very valuable” option so long as centers can provide the necessary follow-up, including salvage cystectomy if needed.
Dr. Zibelman said the retrospective study “cannot completely account for unmeasured variables that may have predisposed patients to get trimodal therapy over surgery, which may have influenced the final data.”
Sill, “trimodal therapy likely provides oncologic outcomes similar to surgery in carefully selected patients ... and should be discussed ... as a bladder-preserving option,” he said.
The study matched 1 to 3, 282 patients undergoing trimodal therapy with 421 patients undergoing radical cystectomy. The patients were treated during 2005-2017 at Massachusetts General Hospital, Boston; the University of California, Los Angeles; or the Princess Margaret Cancer Centre, Toronto.
Patients had cT2-T3/4a disease without positive nodes or metastases. The entire cohort would have been eligible for either TMT or RC under current guidelines.
Propensity score matching produced well-balanced study arms, with a median age of about 71 years; cT2 disease in about 90%; hydronephrosis in about 11%, and adjuvant or neoadjuvant chemotherapy in about 60% of both arms.
At 5 years, both cancer-specific survival (78% with RC and 85% with TMT; P = .02) and overall survival favored TMT (66% RC vs. 78% TMT; P < .001), although Dr. Zlotta said the stark OS difference could have resulted from chance.
Trends also favored TMT in the primary outcome – 5-year metastasis free survival (73% RC vs. 78% TMT; P = .07) – as well as in distant failure-free survival (78% RC vs. 82% TMT; P = .14). The 5-year pelvic node failure-free survival was 96% in the RC group versus 94% with TMT (P = .33).
There were slight differences in surgical protocols between the study centers, and while adjuvant therapy was used at Massachusetts General, neoadjuvant chemotherapy was used in Toronto.
The differences might have introduced confounders, but “I have to say we were pretty reassured to see that we observed exactly the same results” regardless of where subjects were treated. It was “incredibly surprising, but comforting,” Dr. Zlotta said.
Another potential confounder – poor surgical technique – also wasn’t an issue. A median of 40 lymph nodes were removed during cystectomy, which “speaks to the quality of the surgical series,” he said.
The tumor recurrence rate was 20.5% in the TMT arm; 13% of patients had subsequent salvage cystectomies. Perioperative mortality was 2.1% in the RC arm.
There was no outside funding for the work. Dr. Zlotta had ties to numerous companies and honoraria/research funding from or being a consultant to AstraZeneca, Merck, Verity Pharmaceuticals, and others. Dr. Zibelman didn’t have any disclosures.
This article was updated on 3/10/22.