Well, I never read the Thomas Wolfe book but I know the Greek philosopher Heraclitus said "You can never step in the same river twice". Because when you step in it the second time, it is not exactly the same river. I guess you can't go home again because your home is no longer the same place it was. Like your parents turned your bedroom into an office. Or maybe your bedroom is exactly the same but this in itself seems unfitting because you have changed so much, and the bedroom that used to be real now seems like a museum exhibit that doesn't fit your life.
That's what I think the title means. Maybe I should read the book and find out more though. It's about #231 on my next to read list.