Cancer hates mornings too?

Via the pharmaceutical chemist Derek Lowe, and also various media outlets, there is a new cancer study that randomised patients with lung cancer to get their immunotherapy infusions in the morning or the afternoon/evening.  The motivation  will have been the various not-very-convincing correlational studies where patients getting morning treatment did better on average. In those studies the differences seen were large, but the studies were small enough that only large differences could have been seen.

The new study also saw a massive difference between morning and afternoon treatment, with the estimated rate of survival without disease progression being 60% lower in the morning group. That difference was 5.5 standard errors away from zero — almost physics levels of statistical surprise.

So, what  do we check?

First: dropout. Maybe the healthy patients in the afternoon or the sick patients in the morning dropped out? No, according to the research paper everyone who was randomised was included in the final analysis.

Second: did they report what they said they would report? Up to a point, yes.  The clinical trial registry says they started out with overall survival and response rate (tumour shrinkage) as their measurements of success. They changed to progression-free survival as their headline measurement after the trial had been running for a while, which is potentially dodgy.  On the other hand, they did report overall survival, and the results are almost as good as progression-free survival.  They also reported response rate, which had unimpressive favorable results, but which is a much less important measurement.  If things had gone the other way, with good response and bad survival data I would have believed the survival data.

We should now consider whether the results make sense.  This is immunology — as Ed Yong described it for the Atlantic, “where intuition goes to die”.  Looking at the experts (Derek Lowe and the people quoted in the news stories) it seems they don’t completely believe it, but they are also unwilling to entirely disbelieve it.  The drug hangs around in the body for weeks, making a time-of-day effect surprising, but who knows?  The result agrees with past correlational research, but that past research is not very convincing. The worst that the experts quoted by Stat (a medical news site) were willing to say is that only half the eligible patients were randomised, which might mean problems in generalising the results. Fortunately, this trial will be relatively easy to replicate, directly in lung cancer, or in the range of other conditions such as melanoma or head and neck cancer where this specific antibody is used, or in the wider world of immune checkpoint inhibitors.

The possibility that’s not mentioned by any of the news stories is fraud: either faking data or faking the tidiness of the randomisation and completeness of the data. Fraud happens; it’s a definite possibility.  On the other hand, this doesn’t look like an especially attractive place to try it. Other researchers are bound to redo the experiment, and look into the details, and Big Pharma hasn’t worked out how to manufacture more than one morning per day.

I expect these results to fail to replicate, but I wouldn’t bet large amounts of money on it.