The point at which a lot of campaigns have derailed is, where named characters start to appear, and players deliberately start to interfere with the flow of both the adventure, and the continuity of the setting. I am very fortunate to have had players who didn't do so, but ample horror stories of players with the mindset "If it has stats, we can kill it!"
I know of Game Masters who actually need to stay away from established eras just as not to give their players a chance of rolling high enough and impregnate princess Leia, or blow up the Milennium Falcon, or kill Darth Vader before Luke confronts him on the Death Star II.