Quality of transurethral resection of bladder tumor procedure influenced a phase III trial comparing the effect of KLH and mitomycin C

Abstract

BackgroundRetrospective analysis of Center effect of the multi-center trial conducted to compare Immucothel (KLH Immunotherapy drug product) with Mytomycin-C (MM) concluded that efficacy evaluation of the drug product may be impacted by physician’s subjective performance of Transurethral resection of bladder tumor (TURBT).MethodsA randomized trial was performed in 18 hospitals (clinical centers) and a total of 553 recruited, 283 patients under KLH arm and 270 patients under MM. An initial statistical analysis of efficacy comparisons between KLH and MM based on log-rank test performed for each center (hospital) showed 6 hospitals out of 18 hospitals a p-value of <0.05 and remaining 12 hospitals showed a p-values of >0.05. No association was observed between number of patients analysed and the associated p-values across hospitals. Final statistical analyses were carried out under each drug product using Kaplan-Meier survival analysis along with log-rank test after combining all eligible patients data for 6 hospital group and 12 hospital group.ResultsMedian recurrence free survival (RFS) times (in weeks) showed statistical significance (p-value = 0.03) between two groups of hospitals under KLH arm, while similar median values showed no statistical significance (p-value = 0.05).ConclusionCenter effect with respect to median RFS values under KLH was more pronounced than under MM. Under the presence of such center effect, for reasons other than product related effects, concluding superiority of one drug product over another may create confounding bias conclusions in multi-center clinical trials. In the above cited clinical trial study, physician’s prior experience on TURBT might have contributed to center effect in examining efficacies of KLH and MM. Similar observation was also noted in the literature on studies dealing with TURBT and in other clinical studies.Trial registrationData set used in this study is based on previously documented clinical trial in the literature: See (Lammers et al., J Clin Oncol 30:2273–9, 2012) and Acknowledgments.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-017-1843-5) contains supplementary material, which is available to authorized users.

Consensus Definition and Prediction of Complexity in Transurethral Resection or Bladder Endoscopic Dissection of Bladder Tumours

“…A PubMed search of “transurethral resection” (of) “bladder” and “morbidity” or “complication”, or “mortality” or “death” yielded 585, 664, 9 and 95 articles, respectively. Of these, 89 articles relevant to the process of defining complexity were analysed, obtaining 36 articles ( Table S1 ) which were instrumental in highlighting adequacy, operative time and morbidity as the three drivers that characterize a complex surgery, as opposed to an uneventful procedure [ 4 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ].…”

“…A PubMed search highlighted three dimensions that characterize a complex surgery, as opposed to a satisfactory and uneventful procedure. Adequacy was recently introduced in the European Association of Urology (EAU) guidelines to insist on the importance of complete resection of all visible tumours with the detrusor muscle in the specimen, a surrogate marker of resection quality that controls the risk of early recurrence [ 9 ] and may impact adjuvant treatment [ 11 ]. Surgery longer than one hour was included following a large population-based report from the American College of Surgeons National Surgical Quality Improvement Program (NSQIP), where it related to postoperative complications independently from age, comorbidities, tumour size and ASA classification [ 31 ].…”

“…Second, quantitating the difficulties entailed by a “good-quality” TURBT [ 7 ] would offer a solid ground to confront the morbidity and oncological outcome of a potentially complex procedure. Documenting variability is also important when analysing the benefits of different systems of resection or evaluating adjuvant treatments in research protocols [ 11 ]. Although all controlled trials to date overlooked the bias of complexity, we believe that crucial information such as the complexity score or, at the very least, a minimal dataset including size, number and position of the tumours should be documented and balanced in clinical research.…”

Elucidation of Novel Molecular Targets for Therapeutic Strategies in Urothelial Carcinoma: A Literature Review

“…The majority of the AEs in both arms were mild, with fever, fatigue, and flu-like symptoms occurring more frequently in the KLH group ( 72 ). However, a 2017 retrospective analysis of this trial argues that outcomes from each drug regimen may have been skewed by operator dependence of the surgeons performing the patient population’s TURBT; thus, further trials must be conducted to elucidate the efficacy of KLH ( 73 ).…”