An Argument for a Large-Scale Low-Dose CT Lung Cancer Screening Trial in France

Source: http://www.raaonline.com/

By Bernard Milleron, MD, and Sébastien Couraud, MD, PhD

Large-scale lung cancer screening trials have been successfully conducted in several countries, and formal screening recommendations have been made based on this key research. For example, the U.S. National Lung Screening Trial (NLST) demonstrated in 2011 that annual screening by low-dose computed tomography (CT) was associated with a 20% reduction in lung cancer mortality in a high-risk population.1 Following these results, the U.S. Preventive Services Task Force recommended the implementation of such screening in the United States for adults aged 55 to 80 who are at high risk for lung cancer.2 Many initiatives and trials have been established in other countries such as Australia, the United Kingdom, and Canada. In Europe, final results from the Dutch-Belgian Randomized Lung Cancer Screening Trial (NELSON) are expected in 2019. NELSON was designed to investigate whether screening by lowdose CT in high-risk populations will lead to a decrease in 10-year lung cancer mortality of at least 25% when compared with an unscreened control group. Of note, the selected population appears slightly at lower risk than in the NLST trial (50-75 years; smoked >15cig/d >25y OR >10cig/d >30y; quit since less than 10y). This point may be kept in mind for interpretation of further results.3

The French National Authority for Health (Haute Autorité de Santé, HAS) published a report in 2016 on lung cancer screening, which was based on a literature analysis.4 Our group, gathering the French Pulmonology society, the French Thoracic Imaging society and the French intergroup IFCT, performed a similar literature analysis in 2013, which argued that lung cancer screening should be considered as a means to reduce lung cancer mortality and that comprehensive research in this field should be encouraged. 5 Interestingly, our conclusions were similar to those of many international societies but deeply different from those made by the later HAS report.

For example, HAS claimed that curative interventions for early-stage disease show limited success; however, data from a collaborative group, the International Early Lung Cancer Action Group, showed a survival rate of 92% for 302 patients with stage I disease who underwent surgical resection 1 month after diagnosis.6 In addition, HAS posited that the natural progression of lung cancer is too fast to allow for detection of disease in early stages. In contrast, the first lung cancer screening trial to take place in the United Kingdom, the UK Lung Cancer Screening Trial, detected stage I/II lung cancers in 36 of 42 (86%) screened participants.7 HAS reported that high-risk individuals who may benefit from screening are not characterized, whereas NLST demonstrated usefulness of screening in a wellcharacterized high-risk population (e.g., age and smoking history). An important and timely field of research in itself, these criteria could be optimized using biomarkers and/or risk-prediction models, such as the PLCO models.8,9

HAS reported that diagnostic interventions for false-positive cases identified by low-dose CT screening may result in severe complications or even death. However, very few patients identified in NLST underwent resection (4%), and diagnostic interventions for false-positive cases resulted in very few complications (0.4%) or death (less than 0.1%). However, it cannot be ignored that, of the total number of low-dose CT screening tests, 24.2% were classified as positive and 23.3% had false-positive results.1 In the NELSON trial, a new process for CT interpretation was successfully tested. Using volume measurement and doubling time, the rate of positive disease detection decreased drastically, compared with the NLST study, to approximately 6%.10

HAS also pointed out the potential risk of radiation exposure from repeated CT scan imaging in arguing against largescale screening, which is a valid point and should not be minimized. However, use of low-dose and very low-dose CT scanning decreased the radiation dose for each scan to an amount less than 6 months of environmental radiation in France. In addition, the target population for screening—individuals aged 55 to 80—is the population in which the risk of irradiation-induced cancer is lowest.11

Regarding prevention and mortality, HAS underscored the importance of tobacco smoking prevention, which is an obvious and significant way to reduce lung cancer incidence. HAS stated that the randomized trials it reviewed did not demonstrate a mortality reduction, but none of the trials was powered to detect a difference in this outcome.5 Interestingly, the ITALUNG trial—which was also not powered for demonstrating a survival benefit—recently released final data showing a non-significant trend towards mortality reduction in the screening arm.12

Extrapolating Data into the Real World
The HAS report stated that lung cancer screening should be tested in a French setting before recommendations, which would otherwise be based on data from other countries, are made. The importance of this point has led us and other researchers to submit several proposals to the French National Cancer Institute during the past decade. Unfortunately, no large lung cancer screening trial has been approved by French authorities despite the mention of screening-focused goals in the third Cancer Plan (2014-2019), launched by the former French President François Hollande in February 2014.13

Previous screening efforts in France have resulted in very poor participation rates.14 These existing data may affect health-policymakers’ decisions about the implementation of yet another cancer screening trial and any associated costs. However, the economic strategy for a lung cancer screening program is drastically different from that for other screening programs because tobacco is both a well-identified risk factor and a taxable product. Any large-scale lung cancer screening strategy may be fully subsidized by increasing existing taxes on tobacco products. We recently estimated that just a 1% increase of the cigarette tax in France would fund a screening program with a 45% participation rate.15

The current outlook regarding adoption of a large-scale lung cancer screening trial using low-dose CT is bleak due to the position presented in the HAS report. However, investigation of screening in relation to lung cancer mortality is an important area of research. Hopefully, through creative approaches to funding and trial participation, France will be able to contribute to the growing volume of international data on this topic within the next few years. Maybe recent renewal in policy makers in France will result in significant changes in preventive medicine.

References
1. National Lung Screening Trial Research Team, Aberle DR, Adams AM. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409.

2. U.S. Preventative Services Task Force. Lung Cancer Screening.https://www. uspreventiveservicestaskforce. org/Page/Document/UpdateSummaryFinal/ lung-cancer-screening. Published December 2013. Updated July 2015. Accessed May 1, 2017.

3. Ru Zhao Y, Xie X, de Koning HJ, Mali WP, Vliegenthart R, Oudkerk M. NELSON lung cancer screening study. Cancer Imaging. 2011;11(Spec No A):S79-S84.

4. Haute Autorité de Santé. Relevance of screening for bronchopulmonary cancer in France – Update on available data-Critical analysis of randomized controlled studies. http://www. has-sante.fr/portail/jcms/c_2001613/fr/ pertinence-du-depistage-du-cancer-bronchopulmonaire- en-france-point-de-situationsur- les-donnees-disponibles-analyse-critiquedes- etudes-controlees-randomisees. Published January 2016. Accessed May 1, 2017.

5. Couraud S, Cortot AB, Greillier L, et al. From randomized trials to the clinic: is it time to implement individual lung-cancer screening in clinical practice? A multidisciplinary statement from French experts on behalf of the french intergroup (IFCT) and the groupe d’Oncologie de langue francaise (GOLF). Ann Oncol. 2013;24(3): 586-597.

6. International Early Lung Cancer Action Program Investigators, Henschke CI, et al. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med. 2006;355(17):1763-1771.

7. Field JK, Duffy SW, Baldwin DR, et al. UK Lung Cancer RCT Pilot Screening Trial: baseline findings from the screening arm provide evidence for the potential implementation of lung cancer screening. Thorax. 2016;71(2):161-170.

8. Li K, Hüsing A, Sookthai D, et al. Selecting highrisk individuals for lung cancer screening – a prospective evaluation of existing risk models and eligibility criteria in the German EPIC cohort. Cancer Prev Res (Phila). 2015;8(9):777-785.

9. Tammemägi MC, Church TR, Hocking WG, et al. Evaluation of the Lung Cancer Risks at Which to Screen Ever- and Never-Smokers: Screening Rules Applied to the PLCO and NLST Cohorts. PLoS Med. 2014;11(12):e1001764.

10. van Klaveren RJ, Oudkerk M, Prokop M, et al. Management of lung nodules detected by volume CT scanning. N Engl J Med. 2009;361(23): 2221-2229.

11. Brenner DJ, Hall EJ. Computed tomography–an increasing source of radiation exposure. N Engl J Med. 2007;357(22):2277-2284.

12. Paci E, Puliti D, Lopes Pegna A, et al. Mortality, survival and incidence rates in the ITALUNG randomised lung cancer screening trial. Thorax. 2017. pii: thoraxjnl-2016-209825.

13. Institut National du Cancer. The Cancer Plan 2014-2019. http://en.e-cancer.fr/The-Cancer- Plan-2014-2019. Updated May 10, 2015. Accessed May 1, 2017.

14. Eisinger F, Pivot X, Greillier L, et al. Cancer screening in France: 10 years of analysis of behaviours by the EDIFICE surveys [Article in French]. Bull Cancer. 2017;104(3):258-266.

15. Gendarme S, Perrot É, Reskot F, et al. [Economic impact of lung cancer screening in France: A modeling study]. Rev Mal Respir. 2015. pii: S0761- 8425(15)00367-8.