Well established clinical trial models are mandatory to provide preliminary evidence of efficacy in humans and their development represents a major issue to proceed to definitive phase III trials for the progress in preventing lung cancer. Prior chemoprevention trials addressed central squamous carcinogenesis using of bronchial dysplasia as outcome measure, resulting the peripheral lung inaccessible to study.[5
The current trial represents the first phase II study of a chemopreventive intervention specifically focusing on the peripheral lung nodules, where the majority of lung cancers arise.
The effect of inhaled budesonide on lung nodules had in fact already been analyzed by Lam and colleagues[5
]. However the shrinkage of nodules was analyzed retrospectively as a secondary endpoint. As a consequence, compared to our current study, only eleven subjects in the budesonide group and nineteen subjects in the placebo group were analyzed; 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 order to exclude from our intervention trial the small inflammatory lesions that resolve spontaneously, we selected only persistent nodules over two successive yearly CT scans. Treatment duration is another important difference (six months vs. one year). All these features make our trial unique.
The real identity of these nodules cannot be established without histological examination. However, if previous authors [11
] considered these GGOs sufficiently suspicious to warrant surgery, it is possible that even smaller nodules, such as those identified in the context of our study of CT screening might represent less advanced cancers than those described in the literature.
Even though there are other causes for small lung nodules beside adenomatous hyperplasia, the aim of testing the potential activity of Budesonide on sub-solid nodules (partially solid and non solid) is an important issue, especially if we consider that these lesions represent a frequent finding of CT screening and have a higher probability to progress to lung malignancies. [11
] In addition, some of these lesions may represent multifocal indolent bronchoalveolar adenocarcinoma[23
] for which local systemic treatment is not always successful.
Our study was nested into a screening project with clear advantages in terms of participant accrual and reduction of costs. The study methodology was successful with a single center accrual of 13 cases per month showing that the screened population was highly motivated to participate into a chemoprevention trial.
Retention rate and compliance were extremely high. Treatment was well tolerated with the vast majority of adverse events being grade 1, according to the most recent version of the National Cancer Institute toxicity criteria (CTCAE version 3.0, published 12.12.03). The only significantly drug-related events were altered taste, voice change and cortisol suppression. No serious adverse event was considered drug related.
We estimate that the impact of our randomized trial on the outcomes of the screening study will be minimal, even in case of treatment success. The small number of subjects treated with budesonide (100), compared with the population of the COSMOS Study (more than 5000 subjects) being the main reason. However, a therapeutic success will lead us to develop new studies, possibly focusing exclusively on a subgroup of participants with such nodules.
Further studies are in fact needed to improve risk assessment, integrating demographic, CT, and eventually molecular information to optimize the identification of individuals with the highest short term lung cancer risk who may benefit the most from chemopreventive interventions.
The detailed results of the trial will be published shortly.