Thursday, November 11, 2010

More thoughts on lung cancer screening

Today I want to continue in the vein of yesterday's post and discuss a slightly different aspect of the NLST study. But first, a story. I was at a meeting a couple of weeks ago, where we were discussing antibiotics in pneumonia. We were talking about mortality, and one of the docs said something that became a constant mosquito buzz in my brain, which I have been unable to swat away. He said that antibiotics never claimed to reduce all-cause mortality, only mortality associated with infection. Now, on the face of it, the statement makes perfect sense, particularly as you think mechanistically. But it also makes an important point from the perspective of population epidemiology. And it just happens to be related to the NLST study.

Yesterday we talked about the characteristics of the screening tests and in what populations it may make sense. But all of these current and future decisions rest on the results for the primary outcome, which was mortality from lung cancer, reaching an impressive 20% relative reduction. But what about all-cause mortality, and why should we care? Well, saving people from cancer deaths is great, and this is what early screening can mechanistically do. But it is only great if they are not at risk of dying of something else and can derive a meaningful benefit from a life not terminated by an undetected cancer. Unfortunately, as you well know, life does not work this way, and there are many other reasons that people die -- old age, cardiovascular disease, and the like. In epidemiology we call these "competing risks", and it is these risks that sometimes dilute the excitement over the effectiveness of our interventions to a Pyrrhic victory.

Let us apply this to the NLST, or at least what we know today. The results reported are so cursory at this time, that we have to make a lot of educated guesses. But when has that ever stopped us? The report, among other data, states "all-cause mortality was 7% lower" in the CT than in the CXR screening group. The report fails to say whether this is a relative or an absolute reduction, and, as you know, this is a critical distinction. It is critical because, if my calculations are correct, the 20% relative reduction in the cancer mortality detected represents only a 0.3% absolute reduction in deaths from cancer. Given a couple of other tid-bits peppering the report, a few numbers can be back-calculated:

So, again, if my calculations are correct, the all-cause mortality is ~6.4% in the CXR group and ~5.5% in the CT group, so no way can there be an absolute 7% reduction in mortality, and the absolute reduction then turns out to be 0.9% over the 5-year follow-up. And here is what it looks like graphically:

There actually is a reduction in non-cancer deaths in the CT arm. Why this is remains unclear so far, but may well be due to the observation bias, as the study was not blinded. If this is the case, the differences should smooth out over further follow-up period.

But here is my bottom line. Since we live in the world of competing risks, the question becomes "What is the value of screening with CT scans to prevent 0.3% of cancer-related deaths over 5 years?" And how much of this 0.3% benefit is due to lead time bias? This question cannot be answered yet, as we do not have the accounting of either the adverse events related to screening and follow-up, or of the financial costs, or of the patient utilities for either strategy. What we can guess is that the risks have to be miniscule in order not to overwhelm the very small benefit detected, even if it is real.

I am personally not that happy that this report was released the way it was -- no mention of absolute risk reductions, no explicit disclosure of the denominators, no hint as to what the comparative risks of the strategies are (both long- and short-term), and most importantly what implications either strategy has for the patients' quality of life. I guess all of these questions will be answered in the peer-reviewed publications that will result from this study. Fully and transparently. Without any politics or obfuscation. I am waiting with baited breath.

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