For cancer patients, severe side effects from powerful drugs have long been a trade-off for living longer. Today, patients and doctors wonder if all this suffering is necessary.
They have sparked a movement to radically change the way new cancer drugs are tested, with the US Food and Drug Administration urging drugmakers to do a better job of finding the lowest effective dose, even if it takes more time.
Advances in treatment mean millions of people are surviving for years with incurable cancers. Jill Feldman, 54, of Deerfield, Illinois, lived 15 years with lung cancer thanks to these advances. His parents both died of lung cancer within months of their diagnosis.
But his cancer drug causes joint pain, fatigue and mouth sores that make eating and drinking painful.
“If you drink something too hot, you really burn your mouth. That’s what my mouth feels like 24/7,” Feldman said.
She reduced the dose with her doctor’s blessing, but wants drugmakers to study lower doses early in the research process.
“No one should have to suffer avoidable harm from treatment,” she said.
Unlike other diseases, cancer drug development has focused on finding what is called the “maximum tolerated dose.”
To speed up testing of chemotherapy drugs, researchers increased the dose in a few people in early studies to determine the highest possible dose that patients can tolerate. This “more is better” philosophy works for chemotherapy, but not necessarily for new cancer drugs – like the one Feldman is taking – which are more targeted and work differently.
Chemotherapy is like a battering ram where aggressive strikes are a good strategy. But new cancer drugs are more like a front door key. For example, they target a mutation that stimulates the growth of cancer cells or stimulates the body’s immune system to join the fight.
“It only takes a small dose to stop this cancer driver,” said Dr. Lillian Siu, who leads cancer drug development at the Princess Margaret Cancer Center in Toronto. “If you can get what you pay for, why go higher? »
Through a program called Project Optimus, the FDA is pushing drugmakers to include more patients in early dose-finding trials to get better data on when lower doses may work. A key motivation for the project was “growing calls from patients and advocates for cancer drugs to be more tolerable,” Chanapa Tantibanchachai, an FDA spokesperson, said in an email.
Many of the new cancer drugs were developed using the old strategy. This leads to problems when patients skip doses or stop taking the medications due to side effects. Some recommended doses were officially lowered after the drugs were approved. Further dose reductions occur one patient at a time. Nearly half of patients in late-stage trials of 28 targeted therapeutic drugs had to reduce their doses, according to one study.
“We pushed the dose as high as we could,” said Dr. Patricia LoRusso, who directs drug discovery at the Yale Cancer Center. “You experience side effects and then you have to stop the medication to recover from the side effects and the tumor can grow.”
There is also huge variation from patient to patient. The amount of a pill that reaches the bloodstream can vary due to liver and kidney function and other differences. But that means reducing the dose for everyone risks underdosing some patients, LoRusso said.
“The challenge is: where is the sweet spot? » said LoRusso.
Dr. Julie Gralow, chief medical officer of the American Society of Clinical Oncology, plans a study of 500 patients to test lower doses of two drugs for breast cancer that has spread.
The study will compare two strategies: starting treatment at the full dose, then reducing the dose if side effects occur versus starting with a lower dose and increasing the dose if the patient is doing well.
Much of the questioning of high doses has come from patients with metastatic breast cancer, including from the Patient Centered Dosing Initiative, which has conducted influential surveys of patients and cancer doctors.
“We will be on treatment for the rest of our lives,” said Lesley Kailani Glenn, 58, of Central Point, Oregon. “We want to try to live as best as possible, knowing that the treatment will never stop. »
In the 11 years she lived with the disease, she climbed Mount Whitney in California, hiked the Cinque Terra in Italy and started a nonprofit.
When Glenn learned that cancer drug research favored high doses, she began working with her doctor. She has been taking medication at lower doses and even lower doses when she can’t live with the side effects. Diarrhea is her deal breaker: she wants to be able to walk her dog or run errands without worrying about a bathroom emergency.
“The last thing we want to do is have our quality of life robbed,” Glenn said.
Through Project Optimus, the FDA is encouraging drug developers to perform more head-to-head dosage comparisons. That could slow the process, said Dr. Alice Shaw, who leads early development of cancer drugs at Novartis.
“It will require more patients and then, as you can imagine, it will also take more time to identify, recruit and treat those patients,” Shaw said. According to Shaw, adding six months to a year to the process must be weighed against the urgent need for new cancer drugs.
But getting the right dose early will lead to more effective drugs in the long run, said Dr. Timothy Yap, a drug developer at MD Anderson Cancer Center in Houston. “If patients don’t take the medicine, it won’t work. »
Johnson writes for the Associated Press.
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