The plot of this episode revolves around Francine trying to break George Clooney's heart. In "Deacon Stan, Jesus Man" it was revealed that Clooney was her one free kill, part of a deal between her and Stan. Stan chose Susan Sarandon.
This episode takes place over a full year's time.
When the doctor calls from Costco, Roger tells Hayley that it is Dr. Kirkland. This is a reference to Kirkland being Costco's store brand.
George Clooney does not provide the voice for his character in the episode - that's courtesy of André Sogliuzzo. On the other hand, the other celebrity cameo voices by Bruce Boxleitner and Kate Jackson as Scarecrow and Mrs. King (1983) are provided by the actors themselves.
This is the first episode in which Hayley Smith gets sick, and the only episode where someone gets cancer.