I have gone with a modular grid structure according to Thinking With Type (Ellen Lupton). I am dealing with the 7 x 7 square format, and I figured that this type of layout was appropriate. I am able to place columns anywhere, and it provides a lot of freedom within this sort of structure. Basically, as long as something lines up with a line in this grid it will work...for the most part.
In my first two trys at these spreads I decided that I want to go in a more formal approach. I want something that is clean and fresh with not too much going on. I enjoy white space, because it provides a place to rest for the reader, and functionally it provides a place to write notes or it is where your fingers can reside while holding the book.