Early this year, a medical journal article caught the attention of cancer patients and doctors worldwide because of its extraordinary conclusion. Simply changing the time of day that immunotherapy was administered appeared to produce a stunning benefit for lung cancer patients.
Those who received IV infusions in the morning had their cancer kept at bay for twice as long as those who got it in the afternoon, according to the results from a clinical trial in China and published in the journal Nature Medicine in February. The study also reported that the patients lived nearly twice as long.
Several oncologists said that in recent months they and their hospitals had received a flurry of calls from patients inquiring about switching to morning infusions.
But on Wednesday, Nature Medicine retracted the study, citing a list of inconsistencies and irregularities in the trial’s design and results.
“It was too good to be true,” said Dr. Toni Choueiri, an oncologist at the Dana-Farber Cancer Institute in Boston, who helped conduct the post-publication review that led to the retraction.
Among the issues that the journal cited in its retraction notice: Records that are supposed to be locked before the study started were changed midway through. There were discrepancies between the Chinese version of the study’s plan and the translated version. Every patient remained treated and tracked in the study’s first year, and no one dropped out because of side effects — highly unusual in an oncology study. And there were unusual patterns found in the timing of follow-up scans.
“Due to the amount and nature of the problems identified, the editors no longer have confidence in the integrity of the results,” the journal said.
Most of the study’s 28 authors were in China, with several collaborators in Europe. The study was funded by the Chinese government.
China has been pumping money into its hospitals and drug companies, fueling a surge of patents, publications and new clinical trials. In just a few years, the country has rapidly transformed into a powerhouse in drug development, a shift that some U.S. officials, doctors and executives see as a threat to longstanding American dominance in the field.
China’s critics often question the reliability of its biomedical research. Experts said that, similar to in the United States, China’s research output spans a wide range in quality: Some Chinese scientists run their studies at the most meticulous standards. Others were said to cut corners.
Dr. Yongchang Zhang, the study’s senior author, said in a statement that an internal review had “confirmed that part of the study execution and manuscript preparation might not reach the standards for publication in a high-impact journal.”
Dr. Zhang, a researcher at the Chinese hospital where the study was conducted, added: “We acknowledge these shortcomings and sincerely apologize for any inconvenience caused to the journal and its readers.” He did not provide an explanation for the problems cited by the journal.
The study had enrolled 210 patients with advanced lung cancer at Hunan Cancer Hospital in Changsha, a city in south-central China. Patients were randomly assigned to receive infusions of an immunotherapy — Merck’s blockbuster drug Keytruda or Tyvyt, which is not approved in the United States — either before or after 3 p.m.
The study reported that tumors did not progress for 11 months in patients who received the earlier infusions compared to six months for those given the later infusions. Patients receiving the earlier infusions lived for 28 months, compared to 17 months for those infused later in the day.
Those “were numbers we usually associate with new blockbuster drugs, not scheduling decisions,” wrote Dr. Gilberto Lopes, an oncologist at the University of Miami. And rescheduling a patient “costs nothing,” he noted.
Dr. Anil Makam, an epidemiologist and health services researcher at the University of California, San Francisco, said that such a drastic benefit, if real, would have prompted infusion clinics to overhaul staffing and scheduling to shift appointments to earlier in the day.
“If we believed the effects, it would be malpractice not to,” he said.
But within days after the study’s publication in Nature Medicine, online sleuths and physicians like Dr. Makam began raising concerns on social media and in blog posts. Less three weeks after the study was published, the journal published an editor’s note saying it was investigating the issues.
In a statement on Thursday, João Monteiro, chief editor of Nature Medicine, which is published by Springer Nature, said, “We are grateful to the research community for bringing these concerns to our attention.”
Some scientists have long been intrigued by the idea of harnessing the body’s circadian rhythms to try to make drugs more effective or less toxic. For example, enzymes that the body uses to break down certain medicines are more abundant at certain times of day.
But critics of the Chinese study argued that immunotherapy works very differently from fast-acting drugs like Tylenol. The drug Keytruda lingers in the body and takes effect over several weeks. The study did not identify a biological reason for a difference in treatment timing that would produce such a significant benefit.
“There wasn’t any sound scientific rationale behind it,” said Dr. Roy Herbst, the incoming director of the Dartmouth Cancer Center in New Hampshire and Vermont.
In March, a team led by European researchers reported the findings of an analysis that looked at whether more than 3,000 cancer patients across eight studies had received immunotherapy in the morning or the afternoon. Their study, funded by the drugmaker Roche, which sells a number of cancer drugs, concluded that timing is “unlikely to be a critical determinant” of how well patients do.
Other studies looking back at outcomes have found an association between the time of day that patients receive a cancer immunotherapy and how well they fare. But the why remains unclear.
Doctors said it was possible that more energetic, healthier patients might opt for morning slots. Poorer or rural patients who live far from an infusion center — and tend to fare worse — might ask for afternoon slots because they needed to spend the morning traveling to their appointment.
