All the interstellar Science Fiction roleplaying systems and settings I can think of rely on faster-than-light travel (generic systems like GURPs or Hero System discuss the option of forgoing it, but I don't think either devote much space to it) and fairly rapid FTL, at that. It isn't surprising; most starfaring sci-fi literature does so as well.
There are hard(er) sci-fi writers that generally adhere to a more realistic, slower than light universe, like Alistair Reynolds, Greg Egan or Charles Stross. Reynolds' star travelers enter cyrogenic "reefer sleep" to handle the years long voyages in "lighthuggers." Stross and Egan in some of their stories have digital minds broadcast across the distance as light to be reconstituted at the receiving end.
There are also works with sort of slow FTL, so that voyages still require years. Ruocchio's Sun Eater series has characters entering cryogenic fugue to pass the years. Simmons' Hyperion Cantos has FTL that still results in time dilation so ship time is less than the years than pass for observers.
It strikes me that whatever the method, space travel that takes long periods of time, and where the traveler is somehow able to personally elide the effects of so much time passing (either through cryogenics, weird time effects, or even just posthuman immortality) would make for an interesting aspect to a setting and campaign.
The PCs might set out as smugglers or free traders with valuable cargo for a 20-year voyage (from the perspective of the destination) and arrive to find the market had changed or a natural disaster had ruined their chances for making the sale. Mercenary PCs hired for a job, could find the government they were sent to defend toppled by the time they arrive or the person they were to report to succeeded by someone less friendly.
Both of these changes are bad for the PCs, but they could have just as easily been advantageous. The point is with years or decades passing, the setting should hardly stay static. I think this would have the effect of modifying PC behavior a bit. It would make them take space travel less for granted, for one thing. Trips between worlds are no longer trivial. Two, even with cryogenesis or the like, long travel times would make PC aging meaningful.
Using a series of random tables to accomplish these changes would of course include the GM in the fun of discovery. A dynamic setting is often, I think, a more alive feeling one than a static one.
