For using many projects in intranet or hosting scenarios, it is recommended to split up data used globally (especially caches) and data used for specific projects. E.g. use one mxd (e.g. named global_content.mxd) with a data frame each for orthofotos, hillshades, topographic maps and cadastral data. Use other project specific mxds including project specific contents (e.g. line data etc.).
The different data frames can be combined in WebOffice author in the map collection. Switching between the mxds queries can be created on all related layers.
The result of using this structure is a centralizing of resources and a massive saving of effort revising different mxds. The only speciality is the configuration of each data frame in the map collection.