Lung cancer probability in patients with CT-detected pulmonary nodules: a prespecified analysis of data from the NELSON trial of low-dose CT screening

Summary

Background

The main challenge in CT screening for lung cancer is the high prevalence of pulmonary nodules and the relatively low incidence of lung cancer. Management protocols use thresholds for nodule size and growth rate to determine which nodules require additional diagnostic procedures, but these should be based on individuals' probabilities of developing lung cancer. In this prespecified analysis, using data from the NELSON CT screening trial, we aimed to quantify how nodule diameter, volume, and volume doubling time affect the probability of developing lung cancer within 2 years of a CT scan, and to propose and evaluate thresholds for management protocols.

Methods

Eligible participants in the NELSON trial were those aged 50–75 years, who have smoked 15 cigarettes or more per day for more than 25 years, or ten cigarettes or more for more than 30 years and were still smoking, or had stopped smoking less than 10 years ago. Participants were randomly assigned to low-dose CT screening at increasing intervals, or no screening. We included all participants assigned to the screening group who had attended at least one round of screening, and whose results were available from the national cancer registry database. We calculated lung cancer probabilities, stratified by nodule diameter, volume, and volume doubling time and did logistic regression analysis using diameter, volume, volume doubling time, and multinodularity as potential predictor variables. We assessed management strategies based on nodule threshold characteristics for specificity and sensitivity, and compared them to the American College of Chest Physicians (ACCP) guidelines. The NELSON trial is registered at www.trialregister.nl, number ISRCTN63545820.

Findings

Volume, volume doubling time, and volumetry-based diameter of 9681 non-calcified nodules detected by CT screening in 7155 participants in the screening group of NELSON were used to quantify lung cancer probability. Lung cancer probability was low in participants with a nodule volume of 100 mm³ or smaller (0·6% [95% CI 0·4–0·8]) or maximum transverse diameter smaller than 5 mm (0·4% [0·2–0·7]), and not significantly different from participants without nodules (0·4% [0·3–0·6], p=0·17 and p=1·00, respectively). Lung cancer probability was intermediate (requiring follow-up CT) if nodules had a volume of 100–300 mm³ (2·4% [95% CI 1·7–3·5]) or a diameter 5–10 mm (1·3% [1·0–1·8]). Volume doubling time further stratified the probabilities: 0·8% (95% CI 0·4–1·7) for volume doubling times 600 days or more, 4·0% (1·8–8·3) for volume doubling times 400–600 days, and 9·9% (6·9–14·1) for volume doubling times of 400 days or fewer. Lung cancer probability was high for participants with nodule volumes 300 mm³ or bigger (16·9% [95% CI 14·1–20·0]) or diameters 10 mm or bigger (15·2% [12·7–18·1]). The simulated ACCP management protocol yielded a sensitivity and specificity of 90·9% (95% CI 81·2–96·1), and 87·2% (86·4–87·9), respectively. A diameter-based protocol with volumetry-based nodule diameter yielded a higher sensitivity (92·4% [95% CI 83·1–97·1]), and a higher specificity (90·0% [89·3–90·7). A volume-based protocol (with thresholds based on lung cancer probability) yielded the same sensitivity as the ACCP protocol (90·9% [95% CI 81·2–96·1]), and a higher specificity (94·9% [94·4–95·4]).

Interpretation

Small nodules (those with a volume <100 mm³ or diameter <5 mm) are not predictive for lung cancer. Immediate diagnostic evaluation is necessary for large nodules (≥300 mm³ or ≥10 mm). Volume doubling time assessment is advocated only for intermediate-sized nodules (with a volume ranging between 100–300 mm³ or diameter of 5–10 mm). Nodule management protocols based on these thresholds performed better than the simulated ACCP nodule protocol.

Funding

Zorgonderzoek Nederland Medische Wetenschappen and Koningin Wilhelmina Fonds.

Introduction

Several prominent medical associations have recommended regular low-dose CT screening for asymptomatic smokers and ex-smokers at high risk of developing lung cancer.1, 2 The main challenge faced by clinicians doing CT screening for lung cancer is that about half of people screened have one or more pulmonary nodules, but only a small percent of these people have lung cancer.3, 4 Validated guidelines to determine optimum patient management strategies based on characteristics of detected nodules are urgently needed.

When CT screening for lung cancer first began, the accepted standard of practice was to regard all non-calcified pulmonary nodules as potentially malignant lesions requiring follow-up screening until proven stable for a period of 2 years.5, 6, 7 Later, the Fleischner Society recommended that nodules of 4 mm in diameter or smaller in high-risk individuals (ie, history of smoking or other known risk factors) required no further follow-up if the nodule was unchanged at a 12-month follow-up examination, because the risk of the nodule being malignant was less than 1%.⁸ However, people with nodules 4–8 mm in size were still recommended to undergo two to three follow-up examinations over a period of 2 years. Individuals with nodules larger than 8 mm were recommended to undergo diagnostic work-up, which consisted of more invasive diagnostic procedures.⁸ Recently, the results of the Early Lung Cancer Action Project (ELCAP)⁹—which suggested raising of the threshold for initiation of follow-up CT examinations to nodules of 8 mm or larger—were supported by data from the National Lung Screening Trial (NLST).¹⁰ However, the ELCAP analyses were limited to screen detected lung cancers, and only false-positive values and time to diagnosis were taken into account when assessing new thresholds for nodule diameter. Increasing the protocol-screening thresholds for nodule diameter to determine which patients should undergo diagnostic follow-up reduces the potential harms of diagnostic procedures, exposure to ionising radiation, and costs.11, 12 However, it might also decrease the sensitivity for cancerous nodules, thus, in turn, increasing lung cancer mortality, and so it is important to balance these potential benefits and harms.⁴ Therefore, thresholds for negative, indeterminate, and positive screening results should be based on individual participants' probability of developing lung cancer, and should be assessed in terms of sensitivity, specificity, number of required CT examinations, and number of required invasive diagnostic procedures.

Recommendations of the latest American College of Chest Physicians (ACCP) guidelines for management of individuals with pulmonary nodules with a volume of 8 mm or larger were based on the consensus statement of the Fleischner Society.⁸ This statement has not been formally validated, and alternative management strategies might yield an improved performance in terms of sensitivity, specificity, and the number of required follow-up scans.

The NELSON trial is a randomised trial to assess whether low-dose CT screening with an increasing length of screening interval (1, 2, and 2·5 years) compared with no screening reduces lung cancer mortality.¹³ We used data from NELSON to quantify the probability of developing lung cancer within 2 years of CT screening, based on measurements of lung nodule diameters, volumes, and volume doubling times. We used lung cancer probabilities to assess the nodule management protocol recommended by the ACCP, and to propose improved management protocols.8, 14