He knew the cure could be more painful than the disease, but his wife’s condition was worse than he could have imagined. Her first chemotherapy treatment after colon cancer surgery had flattened her.
Kerrie Prettitore was 42. She’d come through surgery well, but her oncologist had recommended chemo after cancer cells were detected in one of her lymph nodes.
The New Jersey couple had been upbeat, hoping to maintain a comfortable routine and a positive attitude for their three kids, the youngest of whom was 2. Kerrie’s good health and vitality would carry her through chemo’s side effects, they hoped.
But now, shortly after that first chemo treatment, she lay in intensive care at The Valley Hospital, barely conscious. For days she’d been nauseous, suffering from relentless diarrhea, painful mouth sores and scratched corneas. She was running a fever. She had stopped talking, and when her husband, Glenn Prettitore, had asked her to write, she doubled letters and misspelled words. She’d lost 18 pounds.
Kerrie’s chemotherapy, a three-drug combination called FOLFOX, included the drug 5-Fluorouracil, or 5-FU. Patients who receive 5-FU face an increased risk of “serious or fatal adverse reactions,” its label cautions, if they have an unusual genetic condition called DPD deficiency.
DPD deficiency — shorthand for dihydropyrimidine dehydrogenase deficiency — is found in 3 to 5% of the population. It usually has no symptoms other than an inability to break down fluorouracil drugs. People who have DPD deficiency lack some or all of the enzyme needed to process the drug, so it stays active, destroying the body’s rapidly dividing cells.
Most people, like Kerrie, haven’t been tested for the mutation and don’t know they have DPD deficiency until after they receive their first dose of 5-FU or capecitabine, a related cancer-treatment drug. For some, that is too late.
Kerrie’s oncologist arranged for a test.
Glenn looked at his wife and knew she didn’t have much time.
Over the next hours, he learned there was an antidote for 5-FU overdoses that could offer his wife a glimmer of hope. It was available only through a study, however, and had to be given within four days of an overdose. Kerrie had received her 5-FU infusion more than three weeks earlier.
Still, Glenn couldn’t let her die. He had to get her the antidote.
Nearly 300,000 cancer patients a year in the United States receive 5-FU as part of their chemotherapy treatment for cancer. Approved almost 60 years ago, it’s a mainstay against colorectal cancer. It is also sometimes used for head-and-neck cancers and cancers of the breast, stomach, esophagus, pancreas and skin.
DPD deficiency — the condition that interferes with the body’s ability to process 5-FU — is “relatively rare,” said Dr. Robert Diasio, director of the Mayo Clinic Cancer Center in Minnesota and an authority on the deficiency. Fewer than 5% of the Caucasian population have a partial deficiency and fewer than 1% have a total deficiency, he said. (The rate in non-Caucasians is higher but has not been thoroughly studied.)
People with a complete deficiency have almost always died when they received 5-FU. Those with a partial deficiency can develop such severe reactions they spend days or weeks in intensive care.
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Like most chemotherapy drugs, 5-FU blocks cancer cells and other rapidly dividing cells from multiplying. Most people process 5-FU in their livers in less than an hour, breaking down 80% of it. Those who can’t will retain what is essentially a super-dose that ravages their bodies. At toxic levels, the drug destroys the mucus lining of the mouth and digestive tract. It can also cause corneal abrasions and cross the blood-brain barrier, leading to a lethal inflammation of the brain.
The impact on patients who have a toxic reaction is horrific.
- In Portland, Oregon, David McIntyre “died an excruciatingly painful death” last December — 19 days after his first round of 5-FU chemotherapy for bile-duct cancer. He suffered vomiting, diarrhea, mouth sores, three strokes and pneumonia and was in a coma the last days of his life, wrote his wife, Joanne, on a website about DPD deficiency.
- In Battle Creek, Michigan, Kathryn Surprenant died at 61 in 2012, three weeks after a single treatment with 5-FU for colon cancer. The mucus lining of her digestive system and respiratory system was so damaged she couldn’t recover, said her husband, Ken Surprenant, who started a website to promote awareness of 5-FU’s potentially fatal side effects.
- In England, Lynn Stevens, 66, died last March, within four weeks of her first and only 5-FU treatment for colon cancer. “Her last weeks were agony,” her husband told the Daily Mail. “Her entire digestive tract was burnt, as if by acid.”
An estimated 10% of the cancer patients in the United States who receive 5-FU — nearly 30,000 people a year — develop severe toxic reactions, according to Wellstat Therapeutics, the company that developed the antidote for 5-FU overdoses. Of those, almost 3,000 — nearly 1% of the patients who receive the drug — die.
And yet there is a test that can help to identify patients at risk. For a few hundred dollars, it detects some of the most likely genetic mutations to raise the risk of a toxic reaction to 5-FU. But in the United States, pre-screening before 5-FU treatment is not routine.
There is also an antidote to 5-FU available if a life-threatening reaction develops. It costs more than $80,000. But few know it exists.
Glenn Prettitore and other anguished survivors of those who have died would like to change that.
Getting the antidote
Kerrie was a graphic designer who developed advertising materials for drug companies when she met Glenn at a ski house she shared with his sister. Their 2003 marriage, in a snowstorm in Manchester, Vermont, was like a Currier & Ives print. Within a decade, they had three children: Liam, Fiona and Maeve.
The Long Islander loved winter and the outdoors. She snowboarded and mountain biked. The family hiked. They lived in an Arts and Crafts style house in Ridgewood with their dog, Logan. She was “a very grounded, strong, quiet person,” said Glenn, who is a physical therapist.
As Glenn sat beside Kerrie’s bed at a New Jersey hospital, learning everything he could about DPD deficiency, he had the help of four siblings and an army of friends.
Glenn quickly learned of the then-experimental antidote that reverses the effects of accidental 5-FU overdoses. Under a research protocol approved by the Food and Drug Administration, its manufacturer was compiling case studies of its use.
Erik Gamelin, an oncologist expert on DPD-deficiency and the co-founder of a French company that tests for it, received a call from Glenn while Kerrie was in the ICU. Glenn’s brother had identified Gamelin from his published studies on DPD deficiency, then tracked him from France to his new employer in California. Glenn “told me what his wife was facing,” Gamelin said. “It was really, really, really bad.”
In studies done by Gamelin’s laboratory in France, a combination of genetic testing and blood testing has been shown to cut the risk of a fatal 5-FU overdose by 95%.
Gamelin knew what a death caused by a toxic reaction to 5-FU looked like. Even though Kerrie was beyond the window of opportunity for the antidote, Gamelin thought it might be of some benefit.
“That was all I needed to hear,” Glenn said.
At Glenn’s request, Kerrie’s oncologist, Dr. Louise Ligresti, spoke with Gamelin on a Friday, 23 days after Kerrie’s 5-FU infusion. By then, testing had confirmed that Kerrie had a complete DPD deficiency.
The antidote — uridine triacetate, called Vistogard — wasn’t approved for widespread use when Ligresti reached Wellstat Therapeutics’ 24-hour hotline to ask if the company would release it for Kerrie.
The company refused. Her case didn’t fit its research protocol, which had been approved by the Food and Drug Administration and aimed to measure the effects of Vistogard within 96 hours of an overdose. The oncologist asked instead for a “compassionate use” release. The company said it was not allowed.
As Glenn received this distressing news, a friend thrust a note in front of him with two words: “IND approval” — a suggestion that they try to get “Investigational New Drug” approval from the FDA to release the antidote.
Emergency IND approval is a special FDA procedure that authorizes an experimental drug to be used in an emergency situation when there’s not enough time to go through the usual approval process, or when the patient doesn’t meet the criteria for the existing study.
Glenn could see Kerrie was getting worse by the minute. Let’s try this, he told the oncologist.
Within minutes, another friend launched a social-media campaign. Overnight, every contact Glenn and his supporters had was asked to press the FDA and Wellstat to give Kerrie access to Vistogard. A Wellstat executive said emails flooded in.
The FDA official contacted by Kerrie’s doctor knew about Wellstat’s study. She called the company and approved the drug’s emergency release.
The next morning, a Saturday, a Wellstat representative drove the antidote 250 miles from the company’s offices in Gaithersburg, Maryland, to Ridgewood, New Jersey.
Then, another hurdle emerged.
Vistogard comes in tiny granules, which are to be mixed into soft food and eaten. But by the time the antidote arrived, Kerrie could take nothing by mouth.
The medicine clogged her feeding tube. Racing against the clock, the drug rep and a hospital pharmacist devised a way to suspend the granules in a solution that flowed through the tiny tube.
Kerrie received four doses a day for five days — the entire recommended amount.
Then they waited.
No one knew whether it would have any effect.
No other patient had received the antidote so long after exposure to 5-FU. Two patients who had received it at 250 and 350 hours after their 5-FU infusions had died.
Trying to heal
For weeks after receiving the antidote, Kerrie lay in a coma, fed through a tube, breathing with a ventilator and beset by infections. Twice, she almost died.
Then her white blood cells, which fight infection, rebounded. She moved her foot, and Glenn rejoiced. A few weeks later, she opened her eyes, stared, then closed them again.
Each step forward gave Glenn hope. He knew there was no road map for Kerrie’s recovery. The chemical injury to her brain made her a case study of one.
Eventually, Kerrie moved to a rehabilitation institute, then to long-term care. Glenn fought, won and lost numerous insurance battles.
Kerrie first showed a potential path to consciousness early in her stay at the rehabilitation institute, when she startled at the sound of someone clapping near her ear. Provoked by loud stimuli, she gradually became more awake, opened her eyes, and began to track objects.
Over the months that followed, the feeding tube was removed, and she began to take food by mouth. She was weaned from the ventilator. The cancer was gone. Her hair, which had fallen out, grew back.
By the spring of 2016, Glenn likened her mental state — called minimal consciousness — to a waking dream. She could say a few words, even provide the last digit in her phone number when he recited the first nine. One day, he placed a doughnut under her nose and asked, “Do you remember this?” She answered, “Oh, God, yeah.” Then she reverted to her dreamlike state.
In May 2016, two years after Kerrie received the antidote, a reporter accompanied Glenn on a visit to his wife. Kerrie’s eyes were closed, though she appeared to be almost cocking her head to listen. She sat upright in her wheelchair. The skin on her cheekbones was smooth, unlined. She seemed utterly peaceful.
Glenn leaned in to speak in her ear, asking her to open her eyes. After a while, she did, and stared at him.
Sometimes she seemed engaged, almost struggling to speak. She opened and closed her mouth, as if chewing gum. Sometimes she smiled. For a visitor, it was impossible to tell what she perceived.
Her left hand clutched a soft stuffed cylinder that prevented her nails from cutting her palm due to the stiff contraction of her hand. The long, delicate fingers of her right hand stroked her left gently or fluttered through the air.
Glenn hugged her and told her he loved her.
He visited every day. So did Kerrie’s mother. Glenn’s mother, aunt, siblings and friends all stopped in. The kids came. Friends created a website, StrongMom.org, to raise funds and update the community on Kerrie’s progress.
By May 2016, Kerrie could follow basic commands to nod yes or no, wink, give high-fives, and blow a kiss. “When I tell her she looks beautiful,” Glenn wrote on the blog, “She often replies, ‘Aww. Thank you.’”
Many people expected her progress to plateau, he said, “but Kerrie’s still learning new things.”
The glide path was long and gradual, he believed, but it trended upward.
Until it didn’t.
Kerrie’s medical condition, despite her progress, remained extremely fragile. In her fourth year after chemotherapy, she suffered frequent seizures, some of them life-threatening. She was hospitalized with pneumonia and other complications. She developed bedsores and a perforated colon.
Four years and two months after her fateful infusion with 5-FU, Kerrie died. She was 46 years old.
Screening for DPD deficiency
Before her death, Glenn Prettitore filed suit against the hospital and doctor who treated his wife. A settlement was reached earlier this year.
To honor Kerrie’s memory, Glenn drove to Trenton recently to speak at a hearing of the state Senate Committee on Health and Senior Services.
He urged the lawmakers to pass a measure, introduced by Democratic state senators Fred H. Madden Jr. and Richard Codey, to require oncologists who plan to prescribe 5-FU or a related drug to offer their patients a genetic test for DPD deficiency.
Uncertain of the cost of testing and the recommendations of professional cancer societies, the legislators listened but did not take a vote.
Screening for DPD deficiency before chemotherapy is now routine in France, Italy and the Netherlands, Glenn told the legislators. Advocates are pressing for it in the United Kingdom. Yet in the United States, “patients like Kerrie are still not routinely informed of the deadly risks.”
Cancer patients are more likely to be informed about such side effects of 5-FU as hair loss, nausea or fatigue, “without any mention of the risk of dying an excruciating death,” he said.
“Our hope is that a test will be offered to every patient about to undergo 5-FU chemotherapy,” he told the committee.
“Had Kerrie been tested prior to the chemotherapy,” he said, “I would have her at my side speaking to you today.”
Lindy Washburn on Twitter: @lindywa