Sure you can—I've run several campaigns in Greyhawk. However, after a year or so I'd want to play in a different setting or even a different game system to do something different and so I don't get burned out.
My point here is that you do not need to move settings or game systems to run something entirely different.
Here are three campaigns that ran from level 1 to 17+ - back to back - in my same setting.
1.) As low levels PCs, the group found the entire nation they were in overrun by an invading force and were amongst refugees that traveled to a mostly ruined land to resettle. From levels 5 to 11 it was essentially a hexploration game, followed by a political intrigue game that took them to the Hells, my Sigil, and the city of Brass. Following that, they had to lay siege to a great portal in the center of the Hells and defend it for a prolonged period while rituals were performed. Then, retirement.
2.) The low level PCs found a magic manor that could travel the planes. The owner of the house hired them to help him locate and recover the pieces of the Rod of 7 Parts (aka the Rod of Law), and then use it to repel an incursion from the Far Realm. This series of adventures took the PCs to many different places on my primary world, the moon, the Ethereal the Feywild, the Shadowfell, my Elemental Plane, etc... In the end, the Pcs had to fight, negotiate, explore and trick their way into collecting information and pieces of the Rod - before they had to use it as part of a very Cthulian storyline.
3.) The PCs started the campaign by doing a service for an ancient ship captain. As a reward, they received his pinnace. They took to the high seas and became pirates, then pirate bunters, then smugglers. Interspersed were water based adventures, exploring islands and ruins, etc...
Then they discovered a Spelljammer Helm, and took the ship thrugh a portal to the Astral Seas where their adventuring took on a 3rd dimension. Eventually they ran afoul of the Githyanki and ran a storyline that I stole from the Firefly movie (with a few tweaks). The campaign ended with a high level TPK as the grup decided to make a stand to buy time to stop an enemy army from reaching innocents before they could be evacuated.
Outside of basic D&D rules being used, these were all very different. Even though we used the same core rules, the change of PCs in each game resulted in very different feels to the game for the players, and different things to which I had to respond as a DM.
I've run the same setting for 40 years (with evolution to it), and it is never tiring or 'same old same old' to me.
That being said, I
also enjoy running a Gurps Wild West Game, or a short super hero campaign in a low mechanic system. However, I do not want to do these things because I am tired of my D&D setting - I want to do them because I think they're also fun, like board games and video games are also fun.