GAINESVILLE, Fla. — Three weeks earlier she’d been done. Done with the chemo and the uncertainty and the fatigue that pinned her to a bed where her husband found her sobbing after he put the boys to sleep. “When can I just pull the plug?” she asked.
And now Rachel Lefebvre, 43, and her husband, Fred, were here, at her oncologist’s office.
First the doctor would tell them if a last-line chemo drug had slowed the breakaway growth of her liver tumors. It had, he said, and Fred instantly grasped his wife’s knee. Now, he told them, is the time to take their one shot at one of the most promising kinds of experimental cancer treatments, known as immunotherapy.
One shot, and one shot only. Dozens of treatment options. Precious little time to decide.
Go.
Late-stage cancer patients confront an array of painful decisions, but in the age of immunotherapy, patients like Lefebvre face an especially torturous one: the selection of a clinical trial.
Immunotherapy, which harnesses the body’s immune system to attack tumors, brings with it the hope of significant remission, if not a cure, for some patients. But clinical trials often exclude those who have already had similar treatments, in part because researchers are seeking clear indications of a particular drug’s effectiveness.
For patients, that means the stakes on a single decision couldn’t be higher. And many have little data on the drugs to guide them.
“There are almost too many options on the table,” said Dr. Thomas George, Lefebvre’s oncologist, who specializes in gastrointestinal cancer and experimental medicine at University of Florida Health. “We have all these really great ideas and we want to try them all, and, honestly, the first try may not be the right one for them.”
“Yet we’re prohibited, because of how the studies work, from trying them all,” he added. “And we don’t want to advise wrong and miss an opportunity.”
Lefebvre’s calculus is more visceral.
“When the clock is ticking and your cancer is growing and nothing else is stopping it, you have to jump in at some point,” she said.
Immunotherapy treatments have transformed care for certain forms of cancer, and they have shown promise even for colon cancer, which Lefebvre was diagnosed with in 2013.
But the devil is in cancer’s details, and Lefebvre is especially bedeviled by hers.
In the most successful immunotherapy approach to date, drugs called checkpoint inhibitors strip the cloaking mechanism that cancers use to hide from the body’s immune system. This is how Jimmy Carter’s melanoma was forced into remission, for instance.
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Checkpoint inhibitors have been shown to work dramatically — that is, for some of the 20 percent to 40 percent of patients who actually respond to the drugs. So far, that list mostly includes patients with cancers of the bladder, kidney, lung, and skin and Hodgkin’s lymphoma, and a tiny fraction of colon cancer patients: those with so-called microsatellite-instable, or “MSI high,” tumors.
Lefebvre has microsatellite-stable, or MSS, colon cancer.
In June, however, came results from a small clinical trial involving 23 colon cancer patients. At least eight with the same condition as Lefebvre responded to a combination of two therapies that are already on the market for other cancers — one an immunotherapy and another that targets the cancer’s genetic driver.
That announcement, and early rumors of the trial’s success, set off a flurry of new immunotherapy research for MSS-type colon cancer. Roughly 40 trials are seeking to unlock other successful immunotherapy approaches. Some combine different checkpoint inhibitors, while others combine those with chemotherapy drugs or other experimental therapies.
Preparing for her appointment late last month, Lefebvre leafed through a printout of the trials. Some treatments appeared more promising than others. Some had waiting lists. Some were closer to her home in Melbourne, Fla., where she and Fred are raising their sons, Pierro, 12, and Sebastien, 10.
But most of them excluded patients who have already tried immunotherapy.
“You have to choose very wisely,” she said. “But it’s a little like eeny, meeny, miny, moe. It’s impossible to make a good decision.”
After George gave Lefebvre and her husband the good news on her scans, she set the list of trials on her lap. Within 40 minutes, they would have narrowed it to three.
Three options, none of them perfect.
Only around 3 percent of adult cancer patients enroll in clinical trials, and, traditionally, that reluctance is understandable. The newer experimental drugs were merely different forms of chemotherapy — highly toxic chemicals that might buy a patient more time, but usually with dismal side effects.
Immunotherapy and other so-called “precision oncology” treatments, which are tailored to specific characteristics of a patient’s cancer, are another matter. These drugs are designed to spare healthy cells and target only malignancies, and although some can cause serious side effects, patients avoid some of the more taxing downsides of chemo like hair loss and nerve damage. The potential for remission, though small, is real.
But many oncologists — especially generalists who aren’t affiliated with teaching hospitals — don’t encourage patients to explore trials. Some lack the time to keep abreast of the latest scientific findings. Others remain skeptical that clinical trials are worth patients’ time, or the money required to seek genetic testing, the foundation for many precision oncology treatments.
Read more: Experimental cancer therapy holds great promise — but at great cost
“My first oncologist was ‘chemo for life,’” Lefebvre said of the treatment strategy. “I asked her about some other options I’d read about. She told me I spend too much time on Google.”
Lefebvre had her tumor genetically sequenced and found another general oncologist locally who was willing to try other options. She also sought second opinions from George, traveling three hours to Gainesville each way every few months to see him. And on the advice of other survivors, she started researching trials early in her treatment, knowing she would need to be relatively healthy to qualify.
Even with occasional consultations with George, though, Lefebvre has largely navigated the maze of clinical trials on her own. For her, and for most patients, this DIY approach first means an online visit to ClinicalTrials.gov, the government’s database for roughly 52,000 clinical trials (as of last week) across an array of disease groups.
“ClinicalTrials.gov is an absolute monster from a patient usability perspective,” said Rick Bangs, a bladder cancer survivor who is cochair of the National Cancer Institute’s patient advocate steering committee. “The NIH is working to fix it, but right now it’s horribly inefficient.”
Patients with colorectal cancer who search for open trials on the site are offered more than 1,400 different options. The search terms “colorectal cancer” and “immunotherapy” yield 79 open trials. The study descriptions teem with medical language few patients would understand, and many of the study pages are out of date, Bangs and others said.
Read more: A cancer researcher races to find a cure — for his own incurable cancer
Lefebvre researched colorectal cancer advocacy groups and eventually found the blog of Tom Marsilje, a cancer researcher who is also battling stage 4 colon cancer (of the MSS subtype). Marsilje has become a go-to source for other patients in his position, posting trial news, answering questions, and circulating a list of trials for other MSS patients to consider.
“I meet people every day who have their oncologist tell them immunotherapy clinical trials don’t work for colon cancer, and there aren’t open trials. Both are completely false,” he said. “So it’s really up to the patients to figure out a strategy for clinical trials, and a vast majority of them don’t have the background to make educated judgments.”
Lefebvre has that background, and even she has struggled.
She earned a PhD in psychology and trained at Massachusetts General Hospital, specializing in trauma and anxiety counseling, which she still practices, though with shorter-term clients. (“I’m up-front with prospective clients about my health,” she said.)
On the evening before her appointment with George, she and her husband sat for a sushi meal. She drank tea instead of wine, to better ease the burden on her liver.
Outwardly she shows no signs of illness. She has an athlete’s build, thanks partly to a youth spent skiing in her native Canada, and recent years practicing yoga and paddleboarding the inlets near her home with Fred.
Of the two, Lefebvre is more the extrovert, punctuating conversations with jokes delivered with a wink. But when speaking about her likely clinical trial options, her frustration showed.
One included an immunotherapy combination that delivered promising results, but only half of the participants were to receive the treatment. The rest were to receive either a standard chemotherapy or a checkpoint inhibitor already proven ineffective for MSS-high patients.
Another trial would test the combination plus Avastin, a drug that has worked for Lefebvre in the past, but it is only open to 33 patients nationally and already has a waiting list. Another would test around 100 patients with a drug that targets cancers with specific molecular profiles and has shown results in the lab but hasn’t yet been tested on many humans. For both trials, she would have to travel to Denver.
New options arise almost monthly, but when, during her appointment with George, she asked if she had time to wait, he told her softly that she did not.
Lefebvre did not outwardly react. Instead she flipped through the spreadsheet of trials. George patiently guided her through at least six.
“If you were my sister or a family member,” he said. “I’d say make a trip to Denver.”
The trip would allow her to simultaneously apply for two good trials: the combination of immunotherapies plus Avastin, which George labeled Plan A, and the trial involving the previously untested but promising drug, which he called Plan B.
Lefebvre asked him about a wildcard option: buying the combination of drugs that proved effective in the Denver trial and administering them at home. Assuming her insurance would not cover such an off-label option, it could cost as much as $20,000 monthly.
George wasn’t enthusiastic about it, because he wouldn’t know how to adjust the doses or monitor the treatments according to the trial protocol.
Fifty minutes into the appointment, her questions dwindled. “Thank you so much,” she told him. “Every time I leave here I never leave hopeless. There’s always a light somewhere. So it’s precious.”
On the way home, Lefebvre called the researcher leading the “Plan A” trial in Colorado. He could not tell her how long the wait list might be.
“There were a lot of silences,” she said.
The trial would likely open by year’s end, the researcher told her. If enough patients drop out because of complications from their disease, or if they go on other trials first, there could be room for her.
So Lefebvre decided she would find a place to rent in Denver with Fred, while his parents watch the boys.
She would also sign up for Plan B, and she has not given up on the wildcard option. (Throughout this process, Lefebvre has been blogging about her experience.)
“It doesn’t feel real yet because everything is so up in the air,” she said. “I haven’t thought deeply about what it’ll be like to get into a trial like this, but I know it’ll be major changes.”
She said both her emotional and physical strength returned in the days after she broke down with Fred and asked him when she could be done with it all.
The resiliency, she said, may in part reflect her body’s response to her current chemo treatment, but it also stems from a sense of optimism that has always been a part of her life.
“I think I’m psychotically delusional sometimes, but I still think I can get through this,” she said. “So I put my face on and I just keep going.”
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