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  • The cumulative interpretation of our observational results


    The cumulative interpretation of our observational results suggests that neoadjuvant CHT unlikely improves CSM and OM outcomes in pT2N0 MIBC patients. Although our analysis is observational in nature, it is in very close agreement with prospective studies that allowed subgroup analyses of neoadjuvant CHT in pT2N0 patients [4,5]. In those studies, pT2N0 patients derived no survival benefit from neoadjuvant CHT, as was the case in the current observational study. It should be of note that two of other prospective randomized trials of neoadjuvant CHT do not allow Mocetinostat (MGCD0103, MG0103) of the results according to pT2N0 vs pT3 or higher stage. In consequence, a residual uncertainty persists regarding the efficacy of neoadjuvant CHT in pT2 patients. To address this uncertainty, unpublished data from previous clinical trials that specifically focus on pT2 patients without contamination with higher stages would be necessary to eliminate this uncertainty. Today, two or more decades after publication of the results or completion of these studies, it is unlikely that previously unreported data will be released into public domain. It is also quite unlikely that novel neoadjuvant CHT trials will be designed or completed. However, given the advent of immunotherapy and its promising role in MIBC, data examining neoadjuvant CHT relative to combination of neoadjuvant CHT, as well as neoadjuvant CHT relative to immunotherapy alone, may provide us with novel insight. Since such studies are already ongoing [17,18], contemporary neoadjuvant CHT efficacy results will become available within the upcoming years. Our study is not devoid of limitations. First and foremost, our database lacks detailed information regarding CHT. Specifically, data on the exact timing of CHT administration are missing. However, both North American and European guidelines do not recommend adjuvant CHT in patients with pT2N0 at final pathology, if neoadjuvant CHT was previously administered. In consequence, no patients should have received adjuvant CHT in our analysis based on this premise. Moreover, the exact composition of CHT regimens was also not available in the current database. However, neoadjuvant CHT should only be used in patients platinum eligible, since non-platinum neoadjuvant CHT has no proven survival benefit [1]. In consequence, no patients should have received non-platinum based regimens according to these considerations. Second, the nature of the SEER database that relies on Consensus Stage assignment does not allow to discriminate between clinical and pathological UCB stage. In the setting of neoadjuvant CHT, its administration may result in partial or even complete responses. Patients with complete responses (pT0) are known to exhibit substantially better survival than those with no response (pT2). However, the proportion of pT0 patients after neoadjuvant CHT is marginal (between 7 and 10%) [19,20]. In consequence, the effect of complete response on cancer control will be equally marginal since fovea will only affect 7 to 10% of RC patients. Based on this consideration, we postulated that lack of ability to adjust for the effect of down-staging unlikely affected a considerable proportion of patients, i.e. no more than 10%. Additionally, lack of ability to discriminate between down-staged patients and those who have not been down-staged does not change the overall effect of CHT on the cohort of patients whose consensus stage was pT2, since down-staged and non-down-staged patients are included in this population. Therefore, the effect recorded in our analysis fully accounts for the beneficial effect of downstaging that may have occurred in some patients. In consequence, the only real limitation that is operational within the current analysis consists of our inability to quantify CSM in the small fraction of patients that received neoadjuvant CHT and have shown a complete response. Third, it should also be emphasized that the SEER database does not provide performance status or renal function. In consequence, we could not exclude patients with poor performance status and/or poor renal function, who would usually not be offered cisplatinum-based perioperative CHT. Moreover, the SEER database does not allow adjustment for baseline comorbidities. This said, our analyses target OM, as well as CSM, and the results targeting both endpoints were virtually identical. In consequence, it is unlikely that comorbidities resulted in other-cause mortality that was differentially distributed between CHT and no CHT patients. Fourth, data regarding secondary cancer control endpoints, such as recurrence rates and progression-free survival, are unavailable in the SEER database and these represent additional weaknesses. Additionally, the SEER registry does not provide specific information on urinary diversion type and surgical approach (open vs. minimally invasive). Last but not least, the historical nature of our database does not allow the ascertainment of patients treated with immunotherapy.