International Early Lung Cancer Action Program Research Articles

Reducing the risk of overdiagnosis in lung cancer: A support from molecular biology

Early detection and swift treatment, when achievable, may significantly affect prognosis in lung cancer patients. Therefore, individuals with a high risk for lung cancer are invited to participate into international screening programs, such as the International Early Lung Cancer Action Program (I-ELCAP). An undesirable consequence of such massive enterprises is the detection of pulmonary nodules also in subjects who are unlikely to ultimately die from lung cancer. Nevertheless, the individuals with pulmonary nodule undergo stringent diagnostic procedures to assess the nature of the lesion. This implies a noticeable (physical and emotional) stress for our patients and the likelihood of overdiagnosis and, potentially, consequent overtreatment. Molecular markers, more specifically, microRNAs, might significantly add value to the workup process aiming at the distinction between benign and malignant lesions and, among the malignant ones, those concretely threatening for the patients' survival. We are confident that such a multidisciplinary approach would better suit our patients' diagnostic and/or therapeutic, actual needs.

The outcome differences of CT screening for lung cancer pre and post following an algorithm in Zhuhai, China

Purpose To evaluate the change in outcomes from CT screening for lung cancer before and after collaboration with the International Early Lung Cancer Action Program (I-ELCAP) as well as changing from a single-row detector to a multi-row detector CT scanner (MDCT). Methods and materials All participants in the screening program were 40 years of age and older. From 1994 to 2002, a single slice spiral CT was used, the screening protocol was established empirically at our institution. From 2003 to 2009 a 16 slice MDCT was used and our institute became the first I-ELCAP site in China. Collaboration included use of the I-ELCAP protocol, image reading training, teaching files training and attendance at international conferences. The clinical and CT characteristics of participants and diagnosed lung cancers pre and post-collaboration were summarized. The outcomes before and after collaboration were compared, including nodule positive rate, lung cancer frequency, stage distribution, pathology, intervals between last routine screening and surgery, the rate of surgery for benign disease and survival rate. Results 3348 participants were enrolled during 1994–2002 and 3582 participants during 2003–2009. Their age, gender, smoking and family cancer histories were comparable. The screening detection rate of lung cancer was 1.1% (36/3348) vs. 1.0% (34/3582) ( P = 0.6), mean size was 18.6 mm vs. 15.6 mm ( P = 0.04), stage I lung cancer was 67% vs. 91% ( P = 0.38), median intervals between last routine screening and surgery was 213 days vs. 96 days ( P < 0.001), 5-year survival rate due to lung cancer was 75% vs. 95% ( P = 0.032) in pre- and post collaboration group respectively. The nodule positive rate was 6.2% (208/3348) vs. 9.8% (351/3582) ( P < 0.001), the rate of surgery for benign disease was 18% (8/44) vs. 8% (3/37) ( P = 0.4) in pre- and post collaboration group respectively. Conclusion Smaller lung cancer were detected, interval between last routine screening and surgery was shorter, surgery for benign disease decreased, and survival rate increased in CT screening for lung cancer in Zhuhai after the collaboration with I-ELCAP and with MDCT. Technology improvements along with a well defined protocol improved outcomes of CT screening for lung cancer in Zhuhai, China.

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’.

Cautionary Note Regarding the Use of CIs Obtained From Kaplan-Meier Survival Curves

Cautionary Note Regarding the Use of CIs Obtained From Kaplan-Meier Survival Curves

Lung Cancer Screening Trial Financed by Tobacco-Funded Foundation, Sparks Debate

F or those who are worried about conflicts of interest in medical research, the news that a cigarette company helped fund a major lung cancer screening study, revealed in a front page story in the New York Times and in the Cancer Letter , represented a perfect storm of ethical issues that could further erode public confidence in the value of academic science. The story highlighted how two discrete issues that research institutions grapple with — fi nancial confl ict of interest and use of tobacco company money to fund research — came together in a highly unusual way, complicating the inter pretation of results from internationally known re searchers and a major medical institution. The Times and the Cancer Letter reported that Weill Cornell Medical College researchers Claudia Henschke, M.D., Ph.D., and David Yankelevitz, M.D., its dean, Antonio Gotto, M.D., D.Phil., and the vice chairman of the college board of overseers, Arthur J. Mahon, were offi cers of a charity called the Foundation for Lung Cancer: Early Detection, Prevention, and Treatment. That charity was almost exclusively funded by $3.6 million in funds donated by the Vector Group, the holding company for Liggett Tobacco, which makes several different brands of cigarettes. Henschke and Yankelevitz used the funds as seed money to help launch studies to test whether computed tomography (CT) screening of patients at risk for lung cancer can lead to early detection of the disease. Published studies from the group have shown a connection between CT screening and improved detection, and results from the Cornell-led International Early Lung Cancer Action Program (I-ELCAP), published in the New England Journal of Medicine in 2006, demonstrate that CT screening saves lives, according to Henschke. The fi ndings created controversy among lung cancer researchers, some of whom said that the nonrandomized study did not prove that such screening could reduce mortality. But the connection between Liggett Tobacco and the researchers was not transparent in the journals that published results of I-ELCAP and earlier studies. The foundation was listed as one of 32 funding sources in the NEJM publication, but not the fact that it contained Liggett Tobacco funds and little else.

Author’s Reply

I am grateful to David Yankelevitz, MD, for pointing out what he believes to be errors in my February editorial in JACR [ 1 Hillman B.J. CT screening for lung cancer: appearances can be deceiving. J Am Coll Radiol. 2007; 4: 83-85 Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar ]. However, his “Who? Us?” response to my concern over the International Early Lung Cancer Action Program (I-ELCAP) [ 2 Henschke C.I. Yankelevitz D.F. Libby D.M. Pasmantier M.W. Smith J.P. Miettinen O.S. International Early Lung Cancer Action Program InvestigatorsSurvival of patients with stage I lung cancer detected on CT screening. N Engl J Med. 2006; 355: 1763-1771 Crossref PubMed Scopus (1397) Google Scholar ] exhortation to promote generalized computed tomographic screening for lung cancer in high-risk populations on the basis of their findings seems to me naive. I leave it to the readers of JACR to reread the last paragraph of the discussion in the 2006 I-ELCAP report and review interviews [ 3 Goldberg P. Henschke says her observational study should change medical practice. Cancer Lett. 2006; 32: 1-8 Google Scholar ] given by I-ELCAP authors at the time of the publication to determine which of us more closely characterizes the situation. CT Screening for Lung Cancer: Editorials Can Be DeceivingJournal of the American College of RadiologyVol. 4Issue 6PreviewIn his editorial titled “CT Screening for Lung Cancer: Appearances Can Be Deceiving,” Bruce Hillman, MD, [1] addressed the most recent publication of the International Early Lung Cancer Action Program (I-ELCAP) [2]. The editorial’s title refers to Hillman’s point that the I-ELCAP investigators’ “simple message,” namely, that computed tomographic (CT) screening “works, and everyone at risk ought to undergo it,” has deceived an “unexpected” number of radiologists who “ought to better understand the flaws in drawing definitive conclusions from the I-ELCAP report.” Full-Text PDF

Lung Cancer Screening Debate Continues Despite International CT Study Results

Earlier this year, a lung cancer screening study received worldwide press when it found that computed tomography (CT) screening of patients at risk for lung cancer can lead to early detection. But the disputed report has not reduced the distance between two sparring groups of researchers. The critical issue is whether CT screening can reduce lung cancer deaths: the ultimate test of any effective cancer screening. Can a screening clinical trial with no control arm can prove a reduction in mortality? This study, the International Early Lung Cancer Action Program (I-ELCAP), had no control arm. Investigators

Meeting Summary of the 12th International Conference on Screening for Lung Cancer: Nara, Japan, April 2005

The 12th International Conference on Screening for Lung Cancer, hosted by the Screening Committee of the Japan Lung Cancer Society, was held in Nara, Japan on April 8–10, 2005. The International Early Lung Cancer Action Program (I-ELCAP) has conducted regular conferences semiannually both at Weil Cornell Medical College in New York, NY and at other I-ELCAP sites in the world. This 12th conference was a landmark of I-ELCAP activity for 6 years. Low-dose computed tomographic (LD-CT) scan was experimentally introduced for lung cancer screening in both Japan and the United States in 1993. Commemorating the pioneering work on LD-CT screening for lung cancer for a decade by both the ELCAP and the Japanese group, this I-ELCAP conference was hosted by the Screening Committee of the Japan Lung Cancer Society under the auspices of the Japan Lung Cancer Society, the Japanese Respiratory Society, the Japanese Society for Respiratory Surgery, the American Cancer Society, and the International Association for Studies of Lung Cancer (IASLC). The broadest mission of these conferences is the collective pursuit of avant-garde understanding of the issues surrounding screening for lung cancer, the broadest subissues being early diagnosis and early intervention. Any given conference focuses on issues that are of particular interest at the time. As always, the conference provides an update of research on and practice of screening for lung cancer, including updates of I-ELCAP protocols and results of research. For the conference, more than 180 attendees from eight countries, including non-members of the I-ELCAP, gathered in Nara, one of the ancient capitals of Japan in the seventh to eighth century (Figure 1). The 10th and 11th Conferences focused on the results on the diagnostic performance of the I-ELCAP protocol for CT screening and on alternatives to resection in early intervention. These conferences also focused on the discussion between individuals seeking screening and their physicians such as the potential benefit of a single round of screening. However, it requires the likelihood that early intervention could cure such a cancer, and that the patient would avoid death from another cause for a decade or another specified period. The 12th International Conference aimed to summarize the evaluation by I-ELCAP and Japanese groups as to the benefit of CT screening for lung cancer.

CT Screening for Lung Cancer

The International Early Lung Cancer Action Program (I-ELCAP) is an uncontrolled prospective study of annual lung cancer screening by spiral computed tomography. More than 31,000 people were enrolled from 1993 through 2005; all were at increased risk for lung cancer by virtue of smoking history or …

Screening for lung cancer: the early lung cancer action approach

Suddenly, screening for lung cancer has become a hot topic. Researchers are initiating projects to study it; the public is demanding it; and medical institutions are offering it. The sudden activity is also prompting reconsideration of the still-nihilistic North American public policies on lung-cancer screening. Out of the Fourth International Conference on Screening for Lung Cancer, held in February 2001 and only 16 months after the first one, arose a unanimous recommendation to quickly publish the current protocol of the International Early Lung Cancer Action Program (I-ELCAP) initiated by a resolution of the third Conference. The purpose here is to do just that, though only upon first outlining the origins of this initiative and also specifying its aims and broadest principles.