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E. Szabo
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MS 14 - Chemo Prevention Clinical Trials (ID 32)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Prevention and Tobacco Control
- Presentations: 1
- Moderators:Y.E. Miller, P.E. Postmus
- Coordinates: 9/08/2015, 14:15 - 15:45, 401-404
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MS14.04 - Chemoprevention Clinical Trials: How Do We Move Forward? How Do We Identify Valid End Points? (ID 1911)
15:20 - 15:40 | Author(s): E. Szabo
- Abstract
- Presentation
Abstract:
The ability to intervene in the process of carcinogenesis is predicated on an understanding of the pathways leading to invasive cancer and availability of targeted tools to abrogate the resulting processes. Thus, effective chemoprevention has been hampered by the evolving understanding of lung cancer as a heterogeneous set of malignancies arising from a multitude of diverse molecular deregulations. The simplistic view that early intervention (before the evolution of multiple complex mutational events that are characteristic of tobacco-related malignancies) is more likely to be effective than late intervention has been replaced by the realization that many complex abnormalities actually do occur early and we simply do not understand which individual abnormalities or combinations of abnormalities would derail the inevitable progression to invasive and metastatic cancer. To assess efficacy, well designed clinical trials need to have end points that are informative. For phase III trials, the ideal end point would be cancer-related mortality so that cancer overdiagnosis does not cloud the issue. Realistically, cancer incidence is a more achievable and sufficiently informative end point. Phase II trials, however, depend on intermediate end points that are surrogates for cancer incidence, in a manner analogous to tumor shrinkage or progression-free survival being a surrogate for survival in phase II cancer treatment trials. Examples of end points that have been used in a variety of phase II chemoprevention trials are premalignant lesions, proliferative indices, and a variety of biomarkers of risk or malignant potential. It must be emphasized that to be useful, intermediate end points should be integrally involved in the process of carcinogenesis, differentially expressed in at-risk vs. normal epithelium, and modulated by effective interventions well above the level of spontaneous fluctuation (1). To date, no intermediate end point has been validated to replace lung cancer incidence, but such biomarkers can significantly inform drug development and decision-making for subsequent phase III trials. Nevertheless, the histologic evolution of squamous carcinogenesis, with progression from bronchial metaplasia through varying grades of dysplasia to carcinoma in situ is well described (2). This knowledge has allowed for clinical trials based on pre- and post-treatment assessment of effect of interventions on bronchial histology. However, the rate of progression of dysplasia to invasive cancer is variable even though high grade histologies are associated with higher rates of progression. Therefore, studies assessing dysplasia need to have placebo controls to correct for spontaneous and biopsy-induced regression. A recent trial of a prostacyclin analogue, iloprost, showed improvement in bronchial histology in former smokers after 6 months of treatment (3). These results will be extended in a soon-to-open trial of inhaled iloprost in a similar population and will include analyses of potential molecular predictors of histologic progression. Ongoing efforts are focusing on understanding the process of carcinogenesis by profiling premalignant lesions, both in a cross-sectional manner with regard to lesions identified at time of lung cancer resection (4) and with longitudinal follow-up. Understanding the natural history of premalignant lesions will help determine which ones progress, why they progress, and, therefore, which end points are likely to be most informative. An alternative way to approach the issue is to examine the at-risk epithelial field to identify biomarkers associated with progressive carcinogenesis. Gustafson et al. showed that the PI3K pathway is upregulated early during lung carcinogenesis and that an intervention with a drug, myo-inositol, that resulted in regression of bronchial dysplasia also inhibited PI3K activation in the histologically normal bronchial epithelium obtained by bronchial brushings (5). These data suggest that upregulated PI3K could potentially identify smokers at increased lung cancer risk and that pathway inhibition could serve as an end point for assessing treatment effect. This hypothesis is undergoing further testing in a recently finished phase II trial of myo-inositol in current and former smokers with dysplasia, where normal bronchial epithelium was collected and will be tested for PI3K activation pre- and post-treatment. Similarly, Spira et al. showed that gene expression classifiers from bronchial brushings of histologically normal epithelium obtained from individuals undergoing bronchoscopy for suspect lung cancer can aid in the diagnosis of lung cancer and can serve as lung cancer biomarkers (6,7). These classifiers have potential to be adapted to surrogate tissues further up in the aerodigestive tract, such as the nasal epithelium, and are being tested in chemoprevention ongoing clinical trials (8; NCT02123849). How do we move forward? A better understanding of the early carcinogenic processes and which processes are operative in individual persons is key to designing clinical trials that bring the prospect of precision medicine to lung cancer chemoprevention. The focus on a molecular understanding of premalignant lesions and the at-risk field is at the center of current efforts to identify informative end points for chemoprevention clinical trials. References Szabo E. Phase II cancer prevention clinical trials. Semin Oncol 2010;37:359-66. Saccomanno G et al. Development of carcinoma of the lung as reflected in exfoliated cells. Cancer 1974;33:256-70. Keith R et al. Oral iloprost improves endobronchial dysplasia in former smokers. Cancer Prev Res 2011;4:793-802. Ooi AT et al. Molecular profiling of premalignant lesions in lung squamous cell carcinomas identifies mechanisms involved in stepwise carcinogenesis. Cancer Prev Res 2014;7:487-95. Gustafson AM et al. Airway PI3K pathway activation is an early and reversible event in lung cancer development. Sci Trans Med 2010;2:26ra25. Spira A et al. Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer. Nat Med 2007;13:361-6. Silvestri GA et al. A Bronchial Genomic Classifier for the Diagnostic Evaluation of Lung Cancer. N Eng J Med 2015 May 17 [Epub ahead of print]. Zhang X et al. Similarities and differences between smoking-related gene expression in nasal and bronchial epithelium. Physiol Genomics 2010;41:1-8.
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MTE 18 - Chemoprevention Trials: Past, Present, and Future (Ticketed Session) (ID 70)
- Event: WCLC 2015
- Type: Meet the Expert (Ticketed Session)
- Track: Prevention and Tobacco Control
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 07:00 - 08:00, 108+110+112
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MTE18.01 - Chemoprevention Trials: Past, Present, and Future (ID 2003)
07:00 - 08:00 | Author(s): E. Szabo
- Abstract
- Presentation
Abstract:
Outcomes for the majority of cancer prevention trials overall have been disappointing at best. Lung cancer remains the leading cause of cancer-related mortality worldwide, causing an estimated 156,000 deaths in the United States for 2013. Most lung cancers (>60%) are diagnosed at an advanced stage, with associated 5-year survival of less than 15%. Efforts in early diagnosis and cancer prevention remain crucial to reverse the impact of this deadly disease. For this session, I will be joined by Dr. Eva Szabo and Dr. Avi Spira to review perspectives on the past, present, and future of lung cancer chemoprevention trials. We will review a number of current concepts and important themes in lung cancer chemoprevention, including: 1. Genomic alterations in pre-malignant lesions for both lung adenocarcinoma and squamous cell carcinoma. 2. Patient stratification for applying chemoprevention. 3. Novel agents. 4. Strategies for individualized or precision chemoprevention. 5. Trial designs for rapid and efficient testing of chemoprevention hypotheses. 6. Priorities for further study. To reduce the mortality rate of lung cancer, and to prevent cancer initiation, progression and development, new techniques and approaches to cancer prevention must be developed. We will present both data and opinion regarding promising leads, routes to evaluation, and a vision for research priorities to advance the science of lung cancer chemoprevention.
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ORAL 23 - Prevention and Cancer Risk (ID 121)
- Event: WCLC 2015
- Type: Oral Session
- Track: Prevention and Tobacco Control
- Presentations: 2
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ORAL23.01 - A Randomized Phase IIb Trial of Myo-Inositol in Smokers with Bronchial Dysplasia (ID 856)
10:45 - 10:56 | Author(s): E. Szabo
- Abstract
- Presentation
Background:
Previous preclinical studies and a phase I clinical trial suggested myo-inositol may be a safe and effective lung cancer chemopreventive agent. We conducted a randomized, double blind, placebo-controlled, phase IIb study to determine the chemopreventive effects of myo-inositol in smokers with bronchial dysplasia.
Methods:
Smokers with ≥1 site of dysplasia identified by autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive oral placebo or myo-inositol, 9 g once/day for two weeks, and then twice/day for 6 months. The primary endpoint was change in dysplasia rate after six months of intervention on a per participant basis. Other trial endpoints reported herein include Ki-67 labeling index and pro-inflammatory, oxidant/anti-oxidant biomarker levels in blood and bronchoalveolar lavage fluid (BAL).
Results:
Seventy four (n=38 myo-inositol, n=36 placebo) participants with a baseline and 6-month bronchoscopy were included in all efficacy analyses. The complete response and the progressive disease rates were 26.3% versus 13.9% and 47.4% versus 33.3%, respectively, in the myo-inositol and placebo arms (p=0.76). The mean percent change in Ki67 labeling index in bronchial biopsies with dysplasia was -22.8% and -6.2%, respectively, in the myo-inositol and placebo arms (p=0.34). Compared with placebo, myo-inositol intervention significantly reduced IL-6 levels in BAL over 6 months (p=0.03) and had borderline significant effects on BAL myeloperoxidase (p= 0.06) level.
Conclusion:
The heterogeneous response to myo-inositol suggests a targeted therapy approach based on molecular alterations is needed in future clinical trials to determine the efficacy of myo-inositol as a chemopreventive agent.
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ORAL23.04 - Discussant for ORAL23.01, ORAL23.02, ORAL23.03 (ID 3357)
11:18 - 11:28 | Author(s): E. Szabo
- Abstract
- Presentation
Abstract not provided
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ORAL 25 - Biology and Other Issues in SCLC (ID 125)
- Event: WCLC 2015
- Type: Oral Session
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:J. Sage, L. Montuenga
- Coordinates: 9/08/2015, 10:45 - 12:15, 605+607
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ORAL25.01 - Screening for Small Cell Lung Cancer: Analysis of the National Lung Cancer Screening Trial Data (ID 2145)
10:45 - 10:56 | Author(s): E. Szabo
- Abstract
Background:
Given its widely metastatic nature at the time of diagnosis and the lack of effective therapies, early detection could theoretically have a beneficial impact on small cell lung cancer (SCLC) patient survival. However in the National Lung Screening Trial (NLST), there was no survival advantage for SCLC in the low dose computed tomography (LDCT) arm versus the chest radiography (CXR) arm. We investigated whether LDCT could detect SCLC and whether such screen detection offered a stage and/or survival benefit.
Methods:
Subjects randomized to the LDCT arm in NLST received three annual LDCT screens. Incident cancers were tracked with annual surveys and confirmed with medical records, with abstractors coding lung cancer stage and histology. “Best” stage was defined as pathologic stage if available, otherwise clinical stage. Deaths were tracked with the annual surveys and supplemented by the National Death Index. Cancer was denoted as screen-detected if it was diagnosed within one year of a positive screen or if it was diagnosed after a longer period but with no time gap between diagnostic procedures of more than one year. An interval cancer was defined as a cancer diagnosed within one year of a negative screen. Non-screen detected or interval cancers were denoted as non-screened if the subject did not receive any NLST screens or otherwise as post-screening.
Results:
26,722 subjects were randomized to the LDCT arm (median follow up 6.5 years; 59% men; median age at enrollment 62). 143 SCLCs were diagnosed [49 (34.2%) screen-detected, 15 (10.5%) interval, 79 (55.2%) non-screened/ post-screening]. The ratio of interval to screen detected cases was significantly higher for SCLC (15/49=0.31) than for NSCLC (29/591=0.05); p < 0.0001. 123 of 143 (86%) SCLCs were detected at late-stages (best stage III/IV); the unfavorable stage-distribution persisted among screen-detected, interval and non-screened/ post-screening cases with only 15 (10.5%) detected in early-stages. Three-year lung cancer-specific survival was 72% for early-stage versus 11% for late-stage disease. There was no significant difference in five-year survival between screen-detected, interval and non-screened/post-screening SCLCs (15.3%, 20.0% and 13.8%, respectively). Unlike NSCLC, even at small nodule sizes the proportion of screen-detected SCLCs that were late stage was very high.
Conclusion:
Analysis of SCLC detected in the NLST LDCT arm show that yearly LDCT screens do not detect a significant number of early stage SCLCs. Compared with NSCLC, a higher proportion of SCLCs are interval-detected than screen-detected. Further, there is no stage-shift or survival benefit for screen- detected SCLCs compared with interval or post-screen detected cases. To our knowledge this is the largest analysis to date of SCLC detected in a screening study. Our results indicate that in order for a screening modality to be successful for SCLC, it is necessary (but not sufficient) to be able to detect it earlier than does LDCT.
