Nature Retracts Cancer Study Linking Treatment Timing to Survival

After a 4-month investigation, Nature Medicine retracted a study that showed that the time of day in which immunochemotherapy was given for non-small cell lung cancer (NSCLC) had an effect on survival outcomes.

In the phase III trial known as LungTIME-C01, which was published in February, Chinese researchers reported that NSCLC patients who received immunochemotherapy in the morning or early afternoon had better survival outcomes compared with those who received treatment later in the day.

Nature Medicine editors announced that they were investigating concerns about some of the study’s findings and protocol weeks later.

Now, “due to the amount and nature of the problems identified, the editors no longer have confidence in the integrity of the results,” they wrote in a retraction note.

In the study of 210 patients with treatment-naive disease, median progression-free survival (PFS) was 11.3 months for those who received the first four cycles of immunochemotherapy before 3 p.m. compared with 5.7 months for those treated after 3 p.m. (HR 0.40, 95% CI 0.29-0.55, P<0.001). Median overall survival was 28.0 months in the early group and 16.8 months in the late group (HR 0.42, 95% CI 0.29-0.60, P<0.001).

The journal’s editors noted that concerns were raised about inconsistencies between the registration record of the trial on clinicaltrials.gov and the published version of the study protocol, and that key elements of the study — including endpoints, eligibility criteria, sample size, and study design — were inconsistently reported and modified over time.

Moreover, there were discrepancies between the original version of the study protocol in Chinese and the translated versions provided for peer review and publication.

There were also concerns about unexpected data patterns in the study, including:

• The shape of the PFS curve being smoother than what is most commonly observed in similar large phase III trials
• The absence of censoring in the first year of the study
• The absence of adverse events leading to treatment discontinuation throughout the trial
• Similar rates of immune-related adverse events in the trial’s two arms despite the differences in therapeutic efficacy

“These concerns were compounded by the source data provided by the authors indicating that randomization was performed on the day of treatment for almost all patients, which is uncommon; and their acknowledgement of deviations from fixed-calendar imaging schedules due to COVID-19 related delays and cycle-based assessment, indicating a lack of adherence to standard RECIST [Response Evaluation Criteria in Solid Tumors] timing,” the editors wrote.

According to the retraction note, a number of the study’s authors agreed with the retraction, while several others failed to respond to correspondence from Nature Medicine.