Background
Screening for lung cancer assumes that the symptomatic illness is preceded by a period of pre-symptomatic disease that is detectable by chest radiography (CR), low dose computed tomography (LDCT) and sputum cytology (SC). The time interval between detection by screening and the onset of clinical manifestations is referred to as lead time (LT). Its duration has been inferred from longitudinal studies of populations at risk, randomized trials of screening for lung cancer, tumor doubling times (DT) and statistical analyzes of the results of screening trials.
Longitudinal studies have either followed prospectively populations at risk by SC [
1], or reviewed retrospectively CRs that had been performed before the clinical diagnosis of lung cancer [
2]. Estimates based on screening trials have inferred the duration of LT from the ratio between the prevalence of lung cancer at the first (baseline) screening round and the annual incidence of cancer during subsequent follow-up [
3]. Inferences from tumor DT assume that a single cell of 10 µm develops into a tumor by a succession of divisions at a constant DT. Therefore, one may derive the duration of LT from the tumor DT and the difference in tumor size at its detection in asymptomatic persons and in symptomatic patients [
4]. Statistical analyzes have applied probability estimates on the results of screening trials. The objective of this paper is to search the literature for estimates of the LT of lung cancer and update these estimates by those derived from published screening trials by SC, CR and LDCT.
Discussion
Derived LTs have fluctuated between 0.2 and 2.1 years since detection by CR 0.9 to 3.9 years since detection by LDCT; and 1.3 and 2.1 years since detection by SC in persons with normal chest x-ray (squamous cell cancer). The modes of LT and its range of probability density curves derived by probability modeling that includes interval cases were 0.24 (0–2.0) years since detection by CR [
31], and 0.9 (0–3.0) years since detection by LDCT [
30]. Table
4 summarizes the main findings of this survey.
Table 4
Estimates of lead time of lung cancer (years) by methods of study
Follow up (longitudinal studies) | 2.5a | | 0.8–1.1 |
Prevalence / incidence ratios all histologic types | | 1.1–3.5 | 0.6–2.1 |
Prevalence / incidence ratios squamous cell cancer only | 1.3–1.5 | | 1.2–1.8b |
Doubling time, all histologic types | | 3.9c | 0.2d |
Doubling time, squamous cell lung cancer only | 2.1e | 1.0f | 0.14g |
Statistical methods applied on controlled trials (modes and range of probability density curves, and means and standard errors) | | Mode: 0.9 (0–3.0) Mean: 0.87 (0.69) | Mode: 0.24 (0–2.0) Mean: 1.0 (1.7) |
The main limitations of this study are the methodological differences and possible erroneous assumptions of the approaches to the estimation of LT
. First, estimates of LT derived from screening trials may have been biased by the heterogeneity in their study populations (see footnotes of Tables
1 and
2). Some trials included men only, while others included men and women; some trials included smokers only, while others included current, former or never smokers. Some trials conducted a single round of follow up examinations, in addition to the baseline round, while other performed several annual examinations. There was also a marked heterogeneity of the histology of the detected lung cancers (data not shown), and histologically different cancers have different LTs.
Second, selection bias may have affected the findings by Saccomanno et al. [
1]. As noted by the authors, the restriction of their report to patients who developed invasive carcinoma during the period of observation, may have selected those with a shorter interval between carcinoma in situ to invasive carcinoma. Therefore, the observed 2.5-year interval may have underestimated the time interval between carcinoma in situ and invasive squamous cell cancer.
Third, the estimates of LTs may have been biased by erroneous assumptions when lung cancer becomes radiologically detectable. These assumptions are probably valid for extra-bronchial coin lesions, but not for endobronchial squamous cell cancers that become radiographically evident at a much larger size. Therefore, although LDCT is considered to be the most accurate mass screening modality, it is uncertain whether addition of SC can improve the sensitivity of screening by detecting squamous cell lung cancer before LDCT. It is also questionable whether the equation by Schwartz for extra-bronchial lesions [
28] may be applied for occult lung cancer.
A fourth limitation of this study is the uncertainty regarding tumor growth kinetics. On the one hand, a 2018 study that evaluated growth patterns of untreated lung cancer confirmed that the exponential model explains the development of both sub-solid and solid lung cancers [
32]. On the other hand, the proliferation curves of almost all animal tumors may be better described by a Gomperzian function [
33] that predicts progressively longer DTs as the tumor gets larger, and thereby, a shorter period of preclinical growth than the exponential model, and longer survival after diagnosis.
Both models assume that, if untreated, all cases detected by screening would eventually surface clinically. This assumption is supported by the finding that two thirds of the lung cancer patients detected by SC only [
34], and all clinical Stage I lung cancers detected by CR [
35] died from lung cancer within 10 years. On the other hand, the estimated average DT of 480 days of cancers detected by screening by LCDT [
27] predicts a median survival for lung cancer patients of more than 10 years, rather than the less than a year observed in patents with clinical lung cancer. Therefore, it is possible that LDCT detects mainly slow-growing cancers or tumors, which may not progress to advanced disease [
36].
Future research may first, consist of systematic reviews of the literature for screening trials for lung cancer. However, it seems that their heterogeneity with regard to study populations, control populations, and time intervals between screening preclude meta-analysis. Second, SC cytology may be considered again as a screening test, in addition to LDCT. Finally, an effort should be made to resolve the inconsistency between the observed survival of patients with lung cancer detected by LDCT and their calculated LT on the basis of their doubling time.
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