Revised 15 March 2013
The current evidence regarding lung cancer screening using LDCT is recently reviewed by the Canadian Partnership Against Cancer Anticipatory Science Expert Panel. The document is designed to assist health professionals and policy-makers make an informed decision on lung cancer screening in Canada. The key issues are summarized below:
The National Lung Screening Trial (NLST) conducted by the U.S. National Cancer Institute is the first randomized trial of adequate sample size and follow-up to evaluate the efficacy of low dose computed tomography (LDCT) screening to reduce lung cancer mortality in heavy smokers. 53,454 current and former smokers between 55 and 74 years of age with a cigarette smoking history of 30 or more pack-years were randomized to receive a LDCT or chest-X-ray at study entry and annually for two years. Former smokers had to quit smoking within the 15 years prior to study entry. Those with treatment for cancer in the five years before eligibility assessment except non-melanoma skin cancer, history of lung cancer, history of removal of part of the lung (excluding needle biopsy), need for home oxygen supplementation, explained weight loss of more than 15 pounds in the last 12 months, recent hemoptysis, pneumonia or acute respiratory infection treated with antibiotics in the 12 weeks prior to eligibility assessment were excluded from the study. The trial found a shift to earlier stages and a significant 20% reduction in lung cancer mortality with LDCT compared to chest x-ray. There was also a 6.7% reduction in all cause mortality.
The Prostate, Lung, Colorectal, Ovarian (PLCO) trial published shortly after the NLST trial, provides good evidence that Chest X-ray is not effective for lung cancer screening, when compared to no screening. An analysis of only the participants with characteristics that matched eligibility for the National Lung Screening Trial (NLST) also found no significant impact of Chest X-ray screening compared to no screening. Since chest X-ray is not an effective screening test, it is likely that screening with LDCT is efficacious over no screening in high-risk heavy smokers similar to the NLST inclusion criteria.
Aside from NLST, the only large scale randomized trial is the NELSON trial (a Dutch acronym for a Dutch-Belgium lung cancer screening trial) comparing LDCT with no screening. Participants between 50 and 75 years of age, a smoking history of >15 cigarettes/day over 25 years or >10 cigarettes/day over 30 years underwent LDCT screening at baseline, 1 year later (second round), 3 years later (third round) and 5.5 years later (fourth round) or no screening. The study excluded persons who were unable to climb two flights of stairs; had a body weight of 140 kilograms or more; had a history of renal cancer, melanoma or breast cancer; had a history of lung cancer diagnosed less than five years ago; or had received a chest LDCT scan for any reason less than one year prior to enrolment. A total of 15,428 participants have been randomized. When the NELSON participants are pooled with the Danish Randomized Lung Cancer CT Screening Trial (DLCST) involving 4,104 participants, the trial is expected to have 80% power to show a lung cancer mortality reduction of ≥25%, 10 years after randomization. The NELSON trial was launched in April 2004. Recruitment was completed in October 2005. The DLCST enrolment and randomization ran from October 2004 to March 2006. The results of these trials are anticipated around 2015 – 2016.
Although the NLST results are encouraging, it should be recognized that lung cancer screening is a process, not a single event. It requires the use of tests to detect unrecognized cancer to permit timely intervention. For screening to demonstrate effectiveness at a population level, the screening test must be applied systematically on a large scale to distinguish between those apparently unaffected from those who may have lung cancer. A screening test is not intended to be diagnostic. The test results require confirmation through definitive diagnostic tests, followed by treatment of confirmed cases. Screening can only be effective if effective treatment is available for the disease revealed by screening. The potential benefits of screening must be balanced against possible harms of screening tests such as downstream investigations or therapeutic intervention for suspicious pulmonary lesions that turn out to be non-malignant. Such lesions are several times more frequent than true cancers. Implementation of lung cancer screening at the population level would require coordinated and specialized multi-disciplinary professional expertise to ensure the benefits of screening are maximized while the potential risks are minimized. For example, population penetration strategies for large-scale screening would have to be developed. As well, there would be a need for radiologists skilled in interpretation of lung cancer screening LDCT scans, biopsy and localization of small lung nodules; respirologists and thoracic surgeons experienced in management of lung nodules; interventional pulmonologists skilled in diagnosis of peripheral lung lesions and staging of lung cancer using endoscopic ultrasound; thoracic surgeons knowledgeable in staging, resection techniques and treatment methods; and pathologists experienced with interpretation of small biopsy specimens. The development of screening would need to be accompanied by a parallel process of quality assurance including radiologists, medical technologists, medical physicists, picture archiving and communications specialists as well as external evaluators.
Considerable expertise has been developed in BCCA and Vancouver Coastal Health over the last decade through support from the US NCI, the Terry Fox Research Institute and the Canadian Partnership Against Cancer (CPAC) to define the optimal population for screening as well as the management pathway of screen detected lung nodules using a novel lung nodule malignancy potential prediction model and calculator. A Canadian Lung Cancer Screening Network has been established by CPAC to develop Canadian guidelines for radiology, clinical work-up pathway for abnormal CT, pathology reporting, recommendations for surgical and therapeutic interventions and integration of smoking cessation practices. Before lung cancer screening can be adopted at the provincial level, it needs to be introduced in stages to ensure that adequate infrastructure is available as well as a robust program of quality assurance and performance management. Until such pilot programs are introduced, the BC Cancer Agency Lung Tumour Group advises against ad hoc/opportunistic screening by physicians. Ad hoc screening can cause net harm if performed on patients who have only a low risk of lung cancer and therefore low probability of benefit. The patient may receive a full dose/contrast enhanced CT instead of LDCT and hence significantly higher radiation exposure. Lack of expertise in interpreting screening CT can result in both false negative and false positive findings. Non-standardized protocols regarding diagnosis & management of CT detected lung nodules can also lead to unnecessary repeat imaging procedures, invasive diagnostic procedures or surgery with their associated potential for morbidity or even mortality.
Key References:
1. National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. June 29, 2011; 365:395-409.
2. Oken MM, Hocking WG, Kvale PA et al. Screening by chest radiograph and lung cancer mortality. The Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial. JAMA. 2011;306(17):doi:10.1001/jama.2011.1591.
3. van Iersel CA, de Koning HJ, Draisma G, et al. Risk-based selection from the general population in a screening trial: selection criteria, recruitment and power for the Dutch-Belgian randomised lung cancer multi-slice CT screening trial (NELSON). Int J Cancer. 2007;120:868–74.
4. Pedersen JH, Ashraf H, Dirksen A, et al. The Danish randomized lung cancer CT screening trial—overall design and results of the prevalence round. J Thorac Oncology. 2009;4:608–14.
5. van Klaveren RJ, Oudkerk M, Prokop M, Scholten et al. Management of Lung Nodules Detected by Volume CT Scanning. N Engl J Med 2009;361:2221-9.
6. Tammemagi M, Hormuzd K, Hocking W, et al. Selection Criteria for Lung-Cancer Screening. N Engl J Med, 2013;368:728-36
7. Tammemagi MC, Lam S, McWilliams A, Sin DD. Incremental value of pulmonary function and sputum DNA image cytometry in lung cancer risk prediction. Cancer Prev Res 2011; 4(4):552-61.
