The bladder cancer conundrum is how to accurately determine the type of tumour, treatment and timing that is ideal for each patient? This is epitomised by the use of neoadjuvant chemotherapy (NAC) for muscle‐invasive bladder cancer (MIBC). MIBC is a deadly disease; if untreated, the 2‐year mortality rate is 85%  and even if treated the overall survival (OS) rate at 5 years is 50%. In this context, NAC is appealing because it may improve outcomes. In 2003, a landmark study by Grossman et al.  examined NAC prior to radical cystectomy (RC) for MIBC. The median survival (44 vs 77 months, P = 0.06) and pT0 rates, which equate to the best survival rates (30% vs 15%, P < 0.001), were improved with NAC. A meta‐analysis of 11 randomised control trials in >3000 patients reported an OS benefit of 5% at 5 years with platinum‐based NAC . Whilst NAC improves outcomes, especially for those patients who achieve pT0, it is also important to examine outcomes for patients with persistent MIBC and to determine if NAC is helpful in those patients.
In this issue of the BJUI, Lane et al.  attempt to answer this question by examining outcomes for patients with persistent MIBC after RC alone or NAC followed by RC. Using Surveillance, Epidemiology, and End Results (SEER)‐Medicare data, the authors examined 1505 patients that underwent RC alone and 381 patients that received NAC and RC from 2004 to 2011. The authors report that after propensity weighted Kaplan–Meier analysis, the 5‐year OS rate was improved amongst patients that received NAC and RC as compared to patients that had RC alone if there was pT2–T4N0M0 disease on final pathology (43.5% vs 37.2%, P = 0.001). However, there was no difference in cancer‐specific survival (CSS) for NAC with RC compared to only RC (53.7% vs 58.4%, P = 0.76). After adjusting for confounders, the authors found similar results. The use of NAC and RC was found to have an OS benefit (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.67–0.94; P = 0.006) for pT2–4N0M0 patients but not a CSS benefit (HR 0.88, 95% CI 0.72–1.08; P = 0.23).
Since previous studies have established the value of NAC in patients that are down‐staged to pT0 disease, the authors also focused their subset analysis on patients not down‐staged and instead had persistent MIBC. On subset analysis, NAC and RC patients with pT2N0M0 disease had an OS but no CSS benefit. For pT3–T4N0M0 patients, there was no OS or CSS benefit. This may suggest that a subset of non‐responders, such as those with pT2 disease, may experience some benefit from NAC despite persistent disease. Lastly, it is worth noting that whilst NAC improves outcomes, is better tolerated before surgery than adjuvant therapy, and is supported by high‐quality evidence, utilisation remains suboptimal. In this study , 381 of 1886 patients (or only 20%) had NAC and only 55% of these received cisplatin‐based therapy. Utilisation patterns vary and updated studies may show different results though. Overall, the authors should be congratulated for a study that is relevant, thoughtful and directed at an important clinical topic.
In this study , one issue that is raised is the challenges of accurate preoperative staging. The authors in this paper analysed patients according to pathological stage to limit confounding, as determining the exact stage of patients prior to NAC and RC cannot be done exactly. In this study, pT2 patients had on OS benefit after NAC but pT3–4 patients did not benefit. Clinical staging relies on transurethral resection, imaging and examination under anaesthesia to establish the diagnosis. Without final staging, it is difficult to precisely parse out which patients are clinical T2 vs T3 disease before RC. Predicting which patients are non‐responders is particularly important because these patients may be exposed unnecessarily to the risks of chemotherapy and may have delays in surgery that can negatively impact their outcomes. Therefore, even if the optimal treatment is known, identifying which patients will benefit can be challenging.
Fortunately, there is an exciting future for MIBC on the horizon. First, traditionally bladder cancer staging relies on determining the depth of invasion. In the future, more refined categorisation may help better characterise tumour subtypes. Through innovative multiplatform analyses, an improved understanding of distinct subtypes in bladder cancer has emerged . Consequently, better subtype recognition may herald more targeted, and effective, therapy. Next, it is essential to determine the right type of treatment. Now, NAC is the standard of care for MIBC. However, there are several exciting trials examining other effective options to be used alternatively or synergistically. For example, the use of immunotherapy in the preoperative space is being studied and may shift how we manage MIBC. Lastly, the question of timing is key. Now, the order of surgery and systemic therapy may be a new frontier and perhaps the most significant question we are trying to solve. The possibility of understanding new subtypes of tumours and having new treatment options may require new timing for specific therapies in certain patients. It is conceivable that certain subtypes would be best managed with systemic therapy immediately whilst others with upfront surgery.
Certainly, more work needs to be done. So, what can we do now? We can promote the overall well‐being of our patients. Urologists can be conduits to help patients live healthy lifestyles and engage in behaviours that will promote psychological stability and physical strength. Encouraging daily activity, increasing fruit and vegetable consumption and, if needed, weight loss are options. Smoking cessation represents an imperative opportunity where urologists can make a positive impact . Prehabilitation programmes focused on preparation for surgery can be done during NAC or while waiting for surgery and incorporate these elements. In this way, waiting time is leveraged to make small but cumulative improvements – ‘a little bit at a time’ is possible.
For now, we will continue to study the bladder cancer conundrum: subtypes of tumours, various treatments, and the best timing for therapy. Regardless of these results, it is likely patients with bladder cancer will still need some combination of surgery, systematic therapy and supportive care while they heal. In the interim, promoting well‐being is one way to help patients live healthier lives whilst making them more resilient to undergo whatever treatments may emerge next.
by Matthew Mossanen and Adam S. Kibel
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