When I used a CNC router/cutter at work (20 years ago) offsets were calculated automaticallly. In essence, you drew your cutline, and told the machine which side of the line was the finished side, and it calculated the toolpath from that.
The two problems with a router type cutter are:
Inside corners will be rounded, the radius equalling the tool diameter. Not a big deal, a little filing to square the corners back up, and much easier than cutting and filing with knives and saws.
Keeping the sheet firmly attached to bed. Our Roland X-Y-Z used a vacuum table to hold the sheet down, but cutting out small pieces caused a small shift when finishing the cut. This was overcome by gluing the sheet down to some MDF. If you cut through your sheet, but not all of the way through the MDF, you should be fine. We used to spray our Acrylic\Lexan or whatever with contact adhesive. The Contact adhesive was fine, It was sprayed on the protective cling, leaving our plastic untouched. Double sided tape would probably work great. If your lucky, in the last 20 years maybe they've solved the problem of keeping things anchored.
It should be noted these are both minor issues, I am not trying to scare you off, just letting you know my experiences from 20 years ago.