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E09 - Chemoprevention (ID 9)
- Event: WCLC 2013
- Type: Educational Session
- Track: Prevention & Epidemiology
- Presentations: 1
E09.3 - Study Design and Response Assessment in Chemoprevention Trials (ID 415)
14:00 - 15:30 | Author(s): E. Szabo
The goal of lung cancer chemoprevention is to prevent the development of invasive cancer, but designing early phase intermediate efficacy clinical trials to demonstrate that a strategy is effective remains a “work in progress”. Phase III prevention trials focus on individuals at high risk for cancer and have a lung cancer endpoint. By contrast, phase II trials depend on intermediate endpoints that are surrogates for cancer incidence, in a fashion analogous to shrinkage in tumor size being a surrogate for survival in phase II cancer treatment trials. Examples of such endpoints include premalignant lesions, proliferative indices, and various biomarkers of risk or malignant potential. To be useful, intermediate endpoints should be integrally involved in the process of carcinogenesis, differentially expressed in at-risk vs. normal epithelium, and modulated by effective interventions with little spontaneous fluctuation in expression. Although no intermediate endpoints have been validated as replacements for cancer incidence thus far, the assessment of a variety of such markers can significantly inform drug development and help make decisions regarding subsequent phase III trials. Lung cancer consists of a heterogeneous set of malignancies that presents with diverse molecular and histologic characteristics. The molecular evolution of tobacco related carcinogenesis is not well understood, but histologic evolution of squamous carcinogenesis, with progression from metaplasia through increasing grades of dysplasia and carcinoma in situ, is well described. This allows for a clinical trial design based on pre- and post-treatment bronchial biopsies to assess the response to chemopreventive interventions. Since the rate of progression of dysplasia to invasive cancer is variable, with higher progression rates associated with higher grades of dysplasia, studies assessing dysplasia as an endpoint need to be randomized such that the “spontaneous” reversion rate in the placebo arm can be used as a comparison to account for the effects of the biopsies and for true biologic reversion. This model has been successfully used to study a variety of interventions, including a recent trial of the prostacyclin analogue iloprost that showed improvement in bronchial histology after 6 months of treatment (Keith R et al., Cancer Prev Res 2011;4:793-802). In contrast, the study of the development of adenocarcinomas has been more difficult due to the inability to access tissues from the peripheral lung. The demonstration that helical CT screening reduces lung cancer mortality opens the opportunity to assess the peripheral lung for adenocarcinoma precursor lesions. Veronesi and colleagues (Veronesi G et al., Cancer Prev Res 2011;4;34-42) examined the effect of an inhaled steroid, budesonide, on CT-detected lung nodules, showing nonsignificant modulation of nonsolid lesions only. As persistent nonsolid (ground glass) lesions are more likely to represent lung cancer precursor lesions such as atypical adenomatous hyperplasia or early cancers than solid nodules, future studies should focus on nonsolid lesions only. Alternative designs for trials include a focus on individual biomarkers, panels of biomarkers, or pathways that are deregulated during carcinogenesis. As an example, Gustafson et al. demonstrated that the PI3K pathway is upregulated early during lung carcinogenesis and that an intervention with the drug myo-inositol that resulted in regression of bronchial dysplasia also inhibited PI3K activation in the bronchial epithelium (Gustafson AM et al., Science Trans Med 2010;2:26ra25). These data suggest that upregulated PI3K signaling could potentially identify smokers at increased risk for lung cancer and that pathway inhibition could serve as an endpoint for assessing treatment effect, a hypothesis that requires further testing. The rapidly increasing understanding of the pathogenesis of lung cancer provides an unprecedented opportunity to intervene in the process. Optimization of clinical trial design is required to translate the basic knowledge into clinical realities.
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