Outcomes from the NHS-Galleri trial: the good, the bad, and the uncertain

It is good to now see long-awaited results [ 1 ] of the NHS-Galleri trial [ 2 ], an important and ground-breaking trial which was conducted with great care and to the highest scientific and statistical standards. This is the first randomised clinical trial of a multi-cancer early detection test. Trials in early detection of cancer are difficult and expensive, which is why we have so few of them. Cancer can develop over many years, from cellular and then tissue abnormalities into symptomatic disease, which at that point is often lethal or incurable. We don’t always know if what looks like early cancer will become lethal, or conversely if we find it early whether we can still cure it. This is why the only reliable evaluation for a cancer early detection test, in theory, is a lengthy randomised trial with mortality endpoints. The problem is that to run such a trial to completion would take many years, which means a long delay and high costs, and it means that by the time the trial is complete the technology will likely be obsolete and so much will change that it might no longer reflect the disease incidence or treatment path. So the design of this trial is by necessity a compromise. It tells us a lot about how the test performs, and it will continue to collect data which will tell us more about the impact of the test in the coming years. It is an ambitious project which was designed and initiated despite a high degree of uncertainty, which means that some decisions about the trial design were based on (optimistic) guesstimates of the effect of the intervention: blood-based screening for cancer detection using the Galleri test, which measures epigenetic signals in cell-free DNA in the blood circulation. To compensate for the lack of a mortality endpoint, and to keep the timelines shorter and costs contained, the primary endpoint goal was ambitiously set at an overall reduction in stage III-IV cancers over a fairly short period of 3 years.