Clinical Complete Response (cCR), assessed by imaging and biopsy, is the primary endpoint for avoiding surgery in new trials. However, these tools are known to be unreliable, potentially missing up to 25% of residual post-mucosal tumors and leading to undertreatment.
While bladder preservation is a key goal, there is an unavoidable risk. Forgoing definitive local treatment like surgery means a subset of patients will not be cured by systemic therapy alone and will miss their opportunity for a potentially curative operation, a crucial ethical consideration.
A major diagnostic challenge in bladder-sparing therapy for T4 tumors is the "fibrotic scar." When a large tumor responds to therapy, it leaves behind fibrotic tissue that is indistinguishable from residual cancer on an MRI, making it nearly impossible to confirm a true complete response.
Using radiation as a consolidation therapy after chemo has a significant downside. It damages local tissue, limiting future surgical options and often precluding a neobladder reconstruction—a major quality-of-life factor for patients who may relapse later and require surgery.
The excitement around new systemic therapies has already created a "Wild West" environment where patient and surgeon motivation for cystectomy has plummeted. This cultural shift is outpacing prospective data, raising concerns that patients are making major decisions outside of rigorous clinical trials.
While promising, circulating tumor DNA (ctDNA) from plasma is not yet ready for guiding local treatment decisions in bladder cancer. Data from studies like RETAIN show it is insufficient for identifying patients with residual disease confined to the bladder, limiting its utility in bladder-sparing protocols.
New bladder-sparing trials mandate nine cycles of EV-Pembro to replicate the conditions of successful surgical trials. This conservative approach ignores that patient response is front-loaded while toxicity is back-loaded, likely overtreating many patients to ensure comparable efficacy.
Designing a randomized trial to compare surgery versus systemic therapy alone is nearly impossible. A previous attempt, the SPARE study, failed to recruit because clinicians and patients already had strong pre-existing opinions on the best course of action, a bias that persists today.