Table 1.

Design rules for neoadjuvant bladder cancer trials

	Specifics	Impact of failure to observe rules
Rule 1	Incorporate complex biology	Failure of single agent chemotherapy in randomized neoadjuvant trials
Rule 2	Avoid variable constants	Impact of suboptimal surgery: worse survival curves for control groups possible impact in adjuvant trials – e.g. No disease
Rule 3	Repetition doesn’t make it right	Serial reports and overviews of RTOG studies: dilutes impact of long-term follow-up in survival curves large numbers still do not prove superiority
Rule 4	Randomization trumps historical controls	Phase II single agent neoadjuvant trials suggested possible survival benefit **
Rule 5	If it doesn’t make sense, it’s probably wrong	Use of disease-free interval as primary parameter for adjuvant trials Misinterpretation of meta-analyses of adjuvant therapy – inclusion of inappropriate sets of data Failure to implement level 1 clinical trials data in treatment of invasive disease

 ^**By comparison, phase III trials proved clinical and statistical benefit of neoadjuvant MULTI-AGENT chemotherapy.