Three months before physicians at Medical University Hospital discharged Madelyn Graf to hospice – some of them convinced that her cancer was incurable and her death was imminent – she came home from the gym perfectly healthy except for a stomach ache.
But the pain became progressively intense that afternoon, wrapping around her torso. It was hard to explain, different than a bug or a pulled muscle, she said. Worse. Graf shed her workout clothes, took a pain pill, then took another one a couple hours later when the pain wouldn’t die down. Finally, she called her husband.
“Are you going to be coming home soon?,” she asked Jim Graf. “I think I need to go to the hospital.”
Madelyn Graf, a 67-year-old retired nurse, spent most of that night in the emergency room at MUSC, waiting for an available bed. She was sent home two days later, diagnosed with a tumor in her left lung that measured almost 9 centimeters. A biopsy in early June confirmed she had advanced, metastatic cancer. It was Stage 4. It had already spread to her adrenal glands and buttocks.
“Being a nurse, I looked at this and thought this doesn’t look good at all," she said. "It was so big and so close to my heart."
But this was Graf’s “third trip down the cancer road,” as she called it, and she had no reason to suspect that the chemotherapy her doctors ordered to kill the tumor wouldn’t work. She had already survived two bouts of non-Hodgkin’s lymphoma many years earlier. Besides, Graf didn't have any symptoms associated with lung cancer. No cough, no chest pain, no weight loss, no shortness of breath. She said she felt OK. She exercised every day and rowed with her beloved Dragonboat team on the Ashley River three times a week.
But after two rounds of chemotherapy, Graf learned in July that the powerful drugs weren’t working. Scans showed all the tumors had grown larger.
Seven rounds of radiation treatment failed, too. At the gym in mid-August, her vision became blurry. The next day, she felt the side of her face go numb. She caught herself drooling. On a Sunday morning, she woke up and couldn’t talk to Jim, couldn’t find the words she wanted to use. These were all classic symptoms of stroke. Chunks of her lung tumor had been breaking off and restricting blood flow to her brain.
Graf was admitted to the hospital again, where doctors told her the cancer had spread to her brain and that the lung tumor had grown so large it was pressing against her heart. They said she would probably have a major stroke and die. That, or the tumor would rupture her heart. Either way, the prognosis was catastrophic.
“She was actually sent to hospice," oncologist John Wrangle said. It was an appropriate decision, given the circumstances. "You can’t imagine a more desperate scenario.”
Wrangle recommended that Graf go home to James Island. He didn't want her making decisions in such a dark place. Surgery wasn't an option, but he asked Graf to return the following week to discuss what they might try next.
"I just kind of smiled and looked at him, thinking, ‘Is he being unrealistic?’ I mean, they’ve told me I’m going to die," Graf said. "I went home and basically slept a lot and we planned my funeral.”
She didn't realize that earlier last year, the FDA had approved a new, incredibly expensive immunotherapy drug called Opdivo to treat metastatic, squamous non-small cell lung cancer. Graf's cancer didn't quite fit the criteria for coverage, but Wrangle wanted to convince Medicare to green-light her treatment.
"Let's keep going," he told her.
Immunotherapy is the newest way to treat cancer – and it’s working miracles right here in Charleston.
Take Marvin Manuel, for example. He travels from Beaufort to the Charleston VA Medical Center once every three weeks for an immunotherapy infusion. Two years ago, he had dozens of tumors in his brain and stomach. Now, there's only one left.
“It went away, just kind of cured it,” he said.
He's not alone. Sybil Russell and her husband split their time between Union and Charleston so that she can get an immunotherapy infusion at Charleston Hematology-Oncology Associates once every 10 days. A few years ago, Russell was taking four different chemotherapy drugs. Now, all she takes is Opdivo and her liver cancer is under control. She feels a little tired after her infusions. Otherwise, no side effects.
“This is just unbelievable,” she said. “It really is.”
Then, of course, there’s Jimmy Carter. Last year, the former president announced that melanoma had metastasized to his liver and brain. By March, it was gone. He credits an immunotherapy drug called Keytruda for his recovery.
"It has dramatically changed the way we treat patients," said Dr. Gene Saylor, a Charleston oncologist.
Chemotherapy drugs, introduced more than a century ago, destroy cancer cells with chemicals. These drugs are trained to target fast-growing cells in the body because cancer cells typically divide much more quickly than healthy tissue. Of course, chemotherapy can affect healthy tissue, and the side effects can be debilitating.
Immunotherapy, by comparison, works much differently. Doctors like to say that these drugs "take the brakes off" the body's immune system. Cancer often evades detection inside the body by disguising itself with pathways called "immune checkpoints." When immunotherapy drugs send the immune system into hyper-drive, cancer cells can't hide. The body's natural immune response destroys the dangerous tissue.
But they don't always work.
Keytruda, for example, was five times more likely in a clinical of patients with advanced melanoma to reduce the size of their tumors. Still, only 21 percent of patients taking the drug in this trial saw their tumors shrink and only 2 percent of patients saw all of their visible tumors disappear from any scan. That makes Jimmy Carter's case quite unique.
Some patients can't tolerate immunotherapy drugs. Occasionally, the drugs provoke a severe auto-immune response, resulting in potential toxicities including inflammatory lung, liver and thyroid disorders. Depending on the severity of these symptoms, patients may need to delay treatment and begin a course of steroids and or discontinue the drug immediately.
Then, of course, there's the cost. One infusion of Keytruda alone costs thousands of dollars. A physician at Memorial Sloan Kettering Cancer Center pointed out last year that another immunotherapy drug costs approximately 4,000 times the price of gold.
And those costs quickly add up. Cancer patients are typically prescribed immunotherapy infusions once every two or three weeks. Insurance companies, including the federal Medicare program, bear most of the costs, but patients often remain on immunotherapy drugs for years at a time, prompting serious questions about exorbitant health care costs in the United States. Treating one patient with immunotherapy easily approaches $150,000 a year.
"These drugs are phenomenally expensive," Wrangle said. "Society has to work out how it deals with the cost of these things. But when it comes down to an individual patient decision, there’s no real room for judgement about costs. At least, that’s how we practice medicine in America."
When Graf met Dr. Wrangle for the first time more than a year and a half ago, she asked him if he prayed. It wasn't an unusual question. She told him she believed in the power of prayer and in miracles.
“And I said, ‘I’m going to be your first miracle,'" she remembered. "When I think back that I said that, I can’t believe it."
She received her first Opdivo infusion at Hollings Cancer Center on Sept. 1 last year.
At first, it didn't seem to work. She couldn't eat or sleep. Chills racked her body. She became so weak that she couldn't walk from the front door to the sidewalk. She honestly thought the drug was killing her.
“I really felt my body was at war with something," she said. "And it was. It was at war with my tumors."
But then, after her second infusion, her symptoms improved. Within three weeks of her first treatment, an MRI and PET scan showed that her tumors had shrunk by 50 percent. The lung mass wasn't dangerously pressed against her heart anymore, and the cancer had completely disappeared from her brain. It was literally miraculous. She couldn't believe the news.
"In fact, I said, 'Could you please show me on the scan?'," she remembered. "It was just amazing to see. I was like, 'Praise God. This is unbelievable.' We were just rejoicing."
And she kept improving. Sixteen months after her first infusion, Graf's lung tumor has been reduced to scar tissue. She recently had her infusion port removed. Wrangle recommended earlier this month that she take a break from the drug for a while because the arthritis in her knee has been acting up. All told, she's had 32 Opdivo infusions, worth hundreds of thousands of dollars. Medicare, and her Medicare supplement plan, covered all of it.
Graf gladly tells her story – about faith, hope and a “doctor who believed in me,” she said – but from a scientific perspective, there is some danger in sharing it.
Her results aren't unique, but she is an outlier. Most cancer patients who try immunotherapy will fail to reap any benefits from it. Wrangle said they're frequently crestfallen when the possibility of a cure fails. That's why he was frank with Graf about her chances from the outset.
“There’s a weird balance that you have to take in such frightening scenarios. You have to offer tempered optimism. I was realistic with her about what her chances were turning that ship around."
But it's such a new era, he said. "If this was even three years ago, Madelyn wouldn’t be with us today. That’s guaranteed.”