Batiuk, 60, himself a cancer survivor, said the miracle some readers are hoping for won't happen.
"I honestly don't think readers know what they want," he said. "They think they know what they want. But what they really want is for me to give them a surprise every now and then."
The King Features strip, which is published in about 400 newspapers, will chronicle Lisa's experience through October. It is written and drawn by Batiuk in his workshop above his home's garage in this Cleveland suburb.
"Funky Winkerbean" started in 1972 and at first focused on gags about teenagers at the imaginary Westview High School.
Over the years, Batiuk has used it to explore sensitive topics such as dyslexia and teen suicide. Lisa was first introduced in the early 1980s as a high school student who became pregnant without being married.
The strip has chronicled her often determined and whimsical approach to life's challenges. She was first diagnosed with breast cancer in 1999 and underwent a mastectomy and chemotherapy. The story line resulted in a book, "Lisa's Story."
Batiuk returned to the story line in April 2006 after he had undergone successful treatment for prostate cancer three years earlier. He said it gave him new insight into the disease. He said he knew what was going through Lisa's mind, because all those dark thoughts crossed his.
Last year, Batiuk completed the Lisa saga now running in the papers. He has moved on to a different story arc, one that shows what happens to the "Funky Winkerbean" characters a decade after Lisa's death.
He laughed at what he knows is coming in the lives of his characters.
"I have a real leg up on people, because I know how cool the work is going to be and how much fun it is to see these characters as parents," he said. "I'm having a ball with it."
First, though, Lisa must die, leaving behind her husband, Les, and a daughter.
"To me, there is a miracle in Lisa's story," Batiuk said. "It's not that much of a downer. It's a hopeful story, because it shows how a loving couple treats each other under all circumstances."