Despite the increased power obtained by combining data from the Johns Hopkins Lung Project and the Memorial Sloan-Kettering Lung Study and by considering all lung cancer deaths during nine years of follow-up, we were unable to demonstrate a statistically significant lung cancer mortality benefit associated with the addition of four-monthly sputum cytology screening to an annual chest x-ray regimen. However, there was a suggestion of both a modest benefit among the heaviest smokers and a moderate reduction in deaths due to squamous cell and large cell lung cancer.
The smoking-stratified efficacy estimates and the findings for squamous cell cancer were not surprising. Others have suggested that lung cancer screening would be expected to be most effective in the highest-risk groups (specifically heavy smokers with airflow obstruction)20
. Also, sputum cytology is most suited for the detection of squamous cell cancers, which tend to be located centrally and to exfoliate early in their natural history15
. Within these data, the findings for squamous cell carcinoma were remarkably consistent: over half of the squamous cancers in the dual-screen arm were detected by cytology, and there were larger numbers of squamous cancers detected earlier during follow-up and at earlier stages in the dual-screen arm (suggesting that these cancers were diagnosed earlier than they otherwise would have been, when they would potentially be more amenable to successful treatment). All of these findings are consistent with, though not conclusive of, the notion that the reduced squamous cell cancer mortality in the dual-screen arm could be due to a true, modest benefit of sputum cytology screening.
The large cell cancer results are more difficult to interpret. Although the efficacy estimates for large cell lung cancer mortality were similar for both trials, we did not see a stage shift for large cell cancers, and relatively few large cell cancers (less than 10 percent) were detected by cytology. At Hopkins, the observed difference in large cell cancer mortality seems likely to be because substantially fewer large cell cancers were diagnosed in the dual-screen group, which was unexpected. These findings suggest that the reduction in mortality observed for large cell lung cancers may be due to chance. This underscores the fact that we had limited power to conduct these histology-specific subanalyses, and therefore these findings (including those for squamous cell cancers) should be interpreted cautiously.
Because these findings are based on screening exams and lung cancer deaths from over 20 years ago, it is worthwhile to consider how changes in cancer incidence and technologic advances may impact the efficacy of lung cancer screening with sputum evaluation. Since the time of these trials, there has been a relative increase in the incidence of lung adenocarcinomas, and a resulting modest decrease in the proportion of squamous cell carcinomas21-23
. If, in fact, any benefit of sputum cytology is largely restricted to a reduction in squamous cell carcinoma mortality, then a decrease in the proportion of squamous cell lung cancers would tend to reduce the efficacy of cytology in preventing lung cancer death. On the other hand, a number of techniques have been developed which may make the detection of cancers using sputum evaluation more effective, and therefore may make earlier detection more likely as compared to the available technology from the 1970s and 1980s. For example, molecular analysis of archived sputum samples has detected p53 and ras mutations24
and promoter hypermethylation25
in patients who were later diagnosed with lung cancer. Recent studies have also suggested that chronic tobacco smoke exposure induces a persistent change in gene expression throughout the respiratory epithelium (a field effect), and that individuals who develop cancer may be distinguished by the pattern and extent of these changes in exfoliated cells26
. It should be emphasized, however, that none of these newer technologies has been tested in large-scale, well-designed randomized controlled trials.
There are a number of strengths and limitations to these analyses which should be considered. An obvious strength is that the efficacy estimates are based on populations that were randomized to a dual-screen versus x-ray only arm, and are therefore much less susceptible to bias than those of non-randomized studies of cancer screening. Additionally, the emphasis on mortality as a measure of screening efficacy eliminates the effects of lead-time, length, and overdiagosis biases, which are inherent to comparisons that examine case survival as a measure of screening efficacy27
. However, there are a number of limitations that should also be acknowledged. Most notably, even combining data from the two trials, we had limited statistical power to detect a benefit of cytology screening. Also, the fact that there was no unscreened comparison group complicates the interpretation of these results, as it is unclear what lung cancer mortality would have been in the absence of screening. Finally, there were numerous challenges in performing these analyses many years following the conduct of the trials. For example, we noted a much lower incidence of large cell carcinoma at Sloan-Kettering than at Hopkins. This is likely to be at least partially related to differences in how adenocarcinoma and large cell carcinoma were classified at the two sites28
. However, slides from the diagnosed lung cancers were not available, such that we could not base histologic subtype analyses on re-review of slides using a uniform classification scheme.
Despite these limitations, the Hopkins and the Sloan-Kettering trials represent the best information we have to date regarding the efficacy of lung cancer screening with sputum cytology. These results suggest that the use of sputum cytology may result in a modest (perhaps 10 percent) decrease in lung cancer mortality. However, given the uncertainty of any benefit, and given that, even if present, the benefit is likely to be small, the data presented here suggest that sputum cytomorphology has limited utility as a screening tool.