What is a reasonable cost to refute a preposterous hypothesis

British Journal of Cancer (2010) 102, 627–628. doi:10.1038/sj.bjc.6605523 www.bjcancer.comPublished online 5 January 2010& 2010 Cancer Research UKSir,This letter responds to editorials by SW Duffy and JM Reichcommenting on our recent publication ‘Cost of a 5-year lungcancer survivor: symptomatic tumour identification vs proactivecomputed tomography screening’ (Castleberry et al., 2009; Duffy,2009; Reich, 2009).Although we appreciate their efforts to analyse our methods andconclusions, we believe that the comments reflect preconceptionsand misunderstandings about lung cancer screening. Although ourmanuscript clearly states that the estimates are based on screeningwithin the context of the International Early Lung Cancer ActionProgram(IELCAP)Protocol,neitherDrDuffynorDrReichreference this document in their editorials or appear to appreciateits implications (IELCAP, 2009). This is an important omission.Furthermore, Dr Reich’s comments contain a number of inaccuratestatements regarding the published results of lung cancer screening.We thank Dr Duffy for his kind remarks on the innovativenature of our method of analysis. To address his comment thatsurvival of screen-detected cases is known to be potentiallyaffected by lead-time and length-time biases, we point out thatpublished IELCAP data demonstrate a flat actuarial survival curvewith no drop in survival consistent with delayed lead-time deathsout to 10 years (Henschke et al, 2006). IELCAP data also show anincidence of rapidly growing interval lung cancers occurringbetween annual CT screens of less than 1%, inconsistent withsubstantial length-time bias (Carter et al, 2007).The primary critique of both editorialists is that our costestimates may be inaccurate because we did not factor substantialproportions of theoretically non-lethal, overdiagnosed lungcancers in our model. Although Dr Duffy states that ‘it is difficultto avoid the conclusion that there must be some overdiagnosis inCT screening’, he hedges ‘if the hypothesis of a sizable populationof indolent lung tumors is correct, this is a fascinatingphenomenon, given the very poor prognosis of symptomaticdisease’. We believe that his scepticism is judicious.Reich, however, asks the reader to be sufficiently credulous toaccept that there might be sufficiently large numbers of non-lethalscreen-detected cancers that a double-arm trial could show afivefold difference in survival (between symptomatic lung cancersin the US or British national data (8–15%) and 80% actuarial10-year survival in the IELCAP study) and yet no reduction in lungcancer-specific mortality.To support this hypothesis, Reich estimates that the incidence ofoverdiagnosed lung cancer is around 50%. In fact, to explain thismarkedly improved survival without reduced deaths, more than75% of CT-screen detected lung cancers would have to be non-lethal.In the case of prostate cancer, for which the existence of asubstantial number of very slow-growing cancers has been wellestablished, a recent publication from the National CancerInstitute (NCI) estimates that the incidence of overdiagnosis isapproximately 23% (Welch and Albertsen, 2009). Reich thereforeasks the reader to accept that the incidence of overdiagnosed lungcancer could double that of prostate cancer. But there is no reliabledirect evidence to document any substantial lung cancer over-diagnosis. Three 1986 publications from Alvan Feinsteindescribing ‘postmortem-surprise lung cancers’ were funded bythe notorious Council for Tobacco Research and are often cited indefence against medical monitoring lawsuits (McFarlane et al,1986a,b, 1987). Symptom-detected but untreated stage I patientsdie, almost always, within 5 years (Raz et al, 2007). The same istrue of untreated patients detected by screening roentgenogramsand CT scans (Sobue et al, 1992).Reich’s hypothesis would be cause for amusement if notfor the cost. We refer not to the $200 million price tag ofthe NCI’s National Lung Screen Trial, but to the unneces-sary suffering and death of thousands of individuals from lungcancer who might have been salvaged by screening, betweentoday and the publication of prospective randomised trials. Isthis a reasonable and humane cost to refute a preposteroushypothesis?We suspect that a mindset that would consider such costjustifiable is what led Arthur Golleb to characterise epidemiologyas ‘the practice of medicine without the tears’.