Progress in preventing lung cancer has been hampered by the lack of well established clinical trial models to provide preliminary evidence of efficacy in humans prior to proceeding to definitive efficacy phase III trials. Whereas multiple phase II lung cancer prevention trials have focused on bronchial dysplasia (the precursor to squamous cell carcinoma), the peripheral lung, which is beyond the reach of the bronchoscope, has previously been inaccessible to study. The current trial represents the first phase II study of a chemopreventive intervention focusing on the peripheral lung, where the majority of lung cancers arise. In addition to assessing the intervention, the study aimed to determine whether serial follow-up of CT-detected lung nodules is feasible and interpretable. We show that within the context of an ongoing CT screening study, 202 participants were accrued within a 16 month period in a single institution and 98% of these highly motivated individuals (198 participants) were evaluable. Using RECIST criteria modified to include very small lesions <1 cm in size, we were able to categorize nodule response rates and thereby assess the efficacy of the intervention.
The present study did not show a difference in nodule response rate in a per-person analysis. After excluding participants with nodules that were suspicious for lung cancer due to size or other characteristics, it is noteworthy that over 70% of the remaining nodules identified by CT was solid and that there was essentially no change in these nodules over the period of one year. On the contrary, the non-solid and, to a lesser extent, partially solid lesions decreased in size after budesonide treatment, although this trend was not significant, possibly due to the small number of lesions. Furthermore, none of the pre-existing lesions in the budesonide arm grew, in contrast to growth in approximately 5% of nodules in the placebo-treated arm. Non-solid nodules, which manifest as ground-glass opacities on CT scans, are increasingly being identified during CT screening studies. Accumulating data suggest that such ground-glass nodules are more likely to be malignant (59–73% of cases) than solid nodules (7–9% of cases)(26
The actual identity of CT detected ground-glass opacity cannot be ascertained without histologic analysis, but this is the category of nodule that is most likely to represent atypical alveolar hyperplasia, the putative precursor of pulmonary adenocarcinoma (27
). Kim et al. reported that of 53 persistent ground-glass opacities in 49 patients who underwent resection, 68% proved to be bronchoalveolar carcinoma, 7.5% were adenocarcinoma with predominant brochoalveolar components, 6% were atypical adenomatous hyperplasia, and 19% were nonspecific fibrosis or organizing pneumonia (28
). Similarly, Ohtsuka et al. reported that of 26 patients who underwent resection, bronchoalveolar carcinoma was diagnosed in 10 patients (38%), atypical adenomatous hyperplasia was diagnosed in 15 patients (58%), and focal scar was seen in 1 patient (4%)(29
). Although criteria such as size, the presence of air bronchograms, and nodule sphericity on CT scan have been used to differentiate carcinomas from atypical alveolar hyperplasia, histological analysis remains the gold standard for definitive categorization of nodules and there continues to be debate regarding the overlap between small bronchoalveolar carcinomas and atypical alveolar hyperplasia (30
Since resected nodules represent lesions that are suspicious enough to merit surgery, it is possible and even likely that the smaller nodules identified in the context of our CT screening study represent less advanced neoplasia than described in the above cited studies as well as non-neoplastic etiologies. In order to exclude from our intervention trial the small inflammatory lesions that resolve spontaneously, we instituted the requirement for persistence of nodules over two successive yearly CT scans. One would hypothesize that the persistent non-solid and partially solid nodules would therefore be enriched for preneoplasia and possibly for neoplasia. However, the lack of pathologic correlation remains a significant limitation of this study design.
Significant growth on CT scan is a well described feature of malignancy. Little is known, however, about differences in growth rates throughout the entire process of carcinogenesis and, specifically, about growth rates of premalignant lesions. Hasegawa et al. calculated the volume doubling time of cancers identified in a CT screening program (32
). These authors found that the mean volume doubling time ranges from 813 days for tumors characterized as ground-glass opacities (which were well differentiated adenocarcinomas) to 149 days for purely solid cancers (which included a range of adenocarcinoma differentiation as well as squamous and small cell lung cancers). The very early rates of growth of these lesions, however, cannot be ascertained from such cross-sectional studies that examine lesions that are pathologically identified as true cancers and therefore, by definition, represent the late stages of carcinogenesis. Presumably, rapidly growing tumors once started as slowly growing clones that eventually acquired the capacity for rapid uncontrolled proliferation. If, at least in some cases, the evolution of pulmonary adenocarcinoma does proceed from atypical adenomatous hyperplasia through the in situ bronchoalveolar carcinoma phase to invasive adenocarcinoma (27
), then serial CT scanning offers the opportunity to study the growth patterns during the early phases of carcinogenesis until well accepted clinical and radiologic criteria indicate the need for resection. The implication for a study such as ours, where small lesions were followed over a relatively short period of time, is that the lack of growth cannot necessarily be interpreted to mean that the CT-detected lesion is not premalignant or even malignant. Given the suggestion that approximately one quarter of GGOs may represent benign lesions, further follow-up of the present trial is underway to determine the association between non solid lesions and subsequent lung cancer in light of the expected long doubling-time.
The clinical intervention using budesonide was predicated on a body of consistent literature suggesting that glucocorticoids could inhibit cancer progression (8
). The mechanisms of action for this are not well understood (34
). Glucocorticoids have potent anti-inflammatory properties and profoundly affect the cellular microenvironment as well as epithelial cells. Direct effects mediated through the glucocorticoid receptor result in trans-activation and cis- and trans-repression of multiple genes, thereby affecting signal transduction pathways involved in inflammation. The animal and human data suggested that budesonide is most likely to be effective in the prevention of peripheral lung adenocarcinomas. However, our results do not confirm the multiple animal carcinogenesis studies, nor the positive preliminary data from the clinical trial by Lam and colleagues (12
). There are several potential reasons for this. In the study by Lam et al., a smaller number of individuals with bronchial pre-malignancy were studied and the nodules identified by CT scanning were mainly very small (<4 mm), frequently new, and only rarely non-solid. Such new nodules may well represent acute inflammation that resolves spontaneously or with inhaled corticosteroids. In contrast, our study showed that the solid lesions that persisted from a previous year showed little tendency to change over the course of an additional year of follow-up and we excluded participants with new nodules specifically to avoid the potential fleeting small inflammatory lesions. The disadvantage of this choice, however, was the decrease in likelihood that the nodules, in particular the solid ones, were malignant or premalignant.
As discussed above, the relatively short time frame of our trial as well as the preponderance of solid nodules that are less likely to represent pre-malignancy or invasive malignancy may be responsible for the difference between the animal models and the human trials. In contrast to animal studies where the intervention occurs early after carcinogen exposure, the human intervention is delivered relatively late, after lesions (in this case, nodules) already exist. It is possible that earlier intervention may be more efficacious, but it is difficult to identify the appropriately high risk population and, therefore, it is difficult to know how to best design such studies. It also remains possible that inhaled budesonide does not penetrate adequately into the peripheral lung (35
). To increase peripheral diffusion of budesonide, nanocluster technology is under development (36
Our trial also presented the opportunity to compare CT assessment of emphysema with spirometric determination of pulmonary function. It is known from the literature (37
) that treatment with inhaled corticosteroids has no effect in improving FEV1, but has a significant effect in reducing the number acute exacerbations in patients with severe COPD. CT assessment of emphysema showed a slight worsening in the treated group that was not appreciated by spirometry. Although it is highly unlikely that this small effect is clinically significant, a speculative explanation can be that the effect of Budesonide decreased the degree of inflammation even at the alveolar level reducing the density of the lung and not, per se
, increasing emphysema. Since resistance to steroids is well documented in patients with chronic obstructive pulmonary disease (34
), it is conceivable that CT is more sensitive than spirometry in the detection of ongoing deterioration of lung function in individuals who continue to smoke, as is true of the majority of our cohort.
In summary, this study for the first time showed the feasibility of performing a chemoprevention trial addressing the prevention of lung adenocarcinoma, measuring the effect of the intervention on persistent indeterminate CT-detected lung nodules. Lesion measurement performed using RECIST criteria allowed categorization of participants into responding vs. non-responding categories. As volumetric nodule assessment becomes more feasible, assessment of response is likely to become more precise. Although this study did not show a significant response to budesonide, subgroup analysis showed an intriguing decrease in the size of non-solid and partially solid nodules. As these are the nodules that are the most likely to represent premalignant lesions or overt cancer, these results suggest that subsequent trials should focus exclusively on the subgroup of participant with such nodules. Improved risk assessment, based on demographic, CT, and, eventually, molecular information is needed to optimize the identification of individuals with the highest short term lung cancer risk who stand to benefit the most from chemopreventive interventions.