FOR DECADES, cancer drug doses were set by finding the highest amount of the drug that could be taken without unacceptable side effects, called the maximum tolerated dose. But researchers have realized that the highest tolerable dose isn’t always necessary for patients to receive a benefit, particularly for newer cancer drugs such as immunotherapy and targeted therapies.

A review published in the August 2024 issue of Lancet Oncology looked at 31 drugs approved in Europe and the U.S. from Jan. 1, 2020, to June 30, 2023. A multidisciplinary panel of experts determined that the recommended regimens for 20 of the drugs could potentially be adjusted, either by lowering the dose or by spacing out the treatment schedule, without losing efficacy.

Previous research has shown, for example, that immune checkpoint inhibitors can be effective given every six to eight weeks instead of the current standard of every three or four weeks, says William Douglas Figg Sr., director of the Clinical Pharmacology Program in the National Cancer Institute’s Center for Cancer Research. Figg was not involved with the Lancet Oncology study.

In other cases, the dose itself might be reduced. In 2005, Brian Koffman, a retired family doctor and medical educator, was diagnosed with an aggressive variant of chronic lymphocytic leukemia (CLL). After several years of different treatments, Koffman, now the chief medical officer and executive vice president of the nonprofit CLL Society, was enrolled in a clinical trial for the small-molecule inhibitor Imbruvica (ibrutinib) and prescribed the standard 420 milligrams a day.

In the time since Koffman first received Imbruvica, research has suggested that one cycle at the maximum dose followed by a reduced dose is just as effective as ongoing treatment at 420 milligrams. This is good news for patients who experience adverse effects from Imbruvica, which can include pain, severe headaches, bleeding and vomiting.

When developing traditional chemotherapies, researchers found that the maximum tolerated dose was needed. “For 40 or 50 years, we were lucky if we had a 20% response rate,” Figg says. To increase the odds that a drug would be effective, they researched the highest dosages they could provide with acceptable side effects.

As experts learned more about the molecular biology of tumor cells, standards for treatment changed, says Figg. “When we got smarter, some 25 years ago, we started designing drugs that were more specific to targets that were unique to the tumor,” he explains.

There are now many clinical trials looking for ways to optimize dosing regimens, says Figg. These adjustments, if shown to be effective, could make cancer treatment more convenient for patients while sparing them from unnecessary toxicities and costs. The FDA has two programs currently examining cancer drug doses: Project Optimus to guide the selection of doses for new treatments, and Project Renewal to look at dosing of some already approved drugs.

Many patients are on board with a new approach to dosing. In results from a patient advocate-led survey of 1,221 patients with metastatic breast cancer published in the July 2024 issue of JCO Oncology Practice, 86% of respondents reported having at least one significant side effect. One in five people who reported having side effects went to the hospital or emergency room, and 43% missed at least one treatment after developing adverse effects, which usually improved after reducing the dose. Almost all the patients surveyed said they would be interested in flexible dosing.

Research has shown some common cancer drugs can be just as effective at lower doses and decreased frequency. One study, published in The Breast in December 2021, looked at patients with advanced breast cancer treated with the drug Ibrance (palbociclib). It found that people who reduced their dose lived longer than those who didn’t—29.7 vs. 21.9 months—despite being older on average and having less frequent treatments. In other studies, scaling back the intensity appears to help some people stay on treatment longer.

Adding steps to a clinical trial’s design, like those needed to determine optimal dosage, increases its length and complexity, cautions Koffman, potentially delaying when a treatment would become available. For him, taking the plunge into traditional phase I trials was lifesaving. And while patients do worry about things like hair loss and nausea, he says, most are more concerned about whether a given treatment will give them a second type of cancer or perhaps affect their heart down the line. This type of long-term effect can’t be captured in a phase I trial, no matter how carefully constructed.

“For a nontrivial number of patients, a six- or 12-month or two-year delay in getting a med approved can be the difference between life and death. We’ve got to balance the speed of getting these things done versus the safety,” Koffman says.

Figg understands that research to determine optimal dosing will add time to the approval process and why that may concern people. But researchers are following FDA guidance to look at dosing before approval. “It’s better to do it right up front,” he says, rather than spending years after approval trying to walk it back to the optimal dose. He estimates that immunotherapy guidelines will change to less frequent dosing within the next few years.