Contrary to outdated perceptions, quality of life after radical cystectomy has dramatically improved. Patients can return to highly active lifestyles, including professional sports and marathons, debunking the myth that the procedure ends an active life. This is a crucial patient counseling point.
Though trials adding immunotherapy to BCG were largely negative, they had an unexpected positive outcome. The rigorous protocol adherence required in the trials educated the broader urology community on the correct, and more effective, way to administer BCG with proper induction and maintenance, raising the standard of care.
The success of neoadjuvant immunotherapy trials like Niagara and those with EV-Pembro means most patients will receive immune therapy before surgery. This fundamentally shifts the clinical landscape, making the question of starting adjuvant immunotherapy less relevant as perioperative treatment becomes the standard.
The InVigor011 trial showed that about half of post-cystectomy patients are ctDNA-negative and have an excellent prognosis with a minimal relapse rate. This provides a clear biomarker to spare a significant portion of patients from the toxicity of unnecessary adjuvant immunotherapy, as the benefit is confined to ctDNA-positive individuals.
Surgeons may find cystectomies challenging after neoadjuvant EV-Pembro. This difficulty is not a drug side effect but a consequence of high efficacy. The therapy makes previously unresectable tumors operable, forcing surgeons to operate on fibrotic, remnant tissue, which is an inherently more difficult procedure.
The RETAIN bladder-sparing trial revealed a key limitation of circulating tumor DNA (ctDNA): it does not reliably detect non-muscle invasive bladder cancer. This means ctDNA surveillance is insufficient for monitoring local recurrence in bladder preservation protocols and cannot replace regular cystoscopies.
A positive ctDNA test in a patient with non-muscle invasive bladder cancer (NMIBC) is a red flag that may indicate more advanced disease than initially suspected. However, it should not be misinterpreted as definitive evidence of metastatic disease. It warrants further workup, as resecting the primary tumor can clear the ctDNA.
A critical warning for clinicians: data showing that ctDNA-negative patients can skip *adjuvant* therapy (InVigor011) should not be extrapolated to the *neoadjuvant* setting. Stopping the post-operative portion of a perioperative EV-Pembro regimen based on a negative ctDNA result is unsupported by data and risks under-treating patients.
The success of EV-Pembro in perioperative trials has established it as a foundational treatment. The emerging clinical philosophy is to initiate EV-Pembro for a wide spectrum of muscle-invasive disease and then decide on subsequent steps, like surgery, based on the patient's response, marking a major strategic shift.
While adjuvant immunotherapy benefits ctDNA-positive patients, it may not be the optimal strategy. Given their near-certainty of relapse (95%), using a single-agent immunotherapy when a more potent combination like EV-Pembro exists for metastatic disease raises the critical question of whether these high-risk patients are being undertreated.