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Randomized phase II trial of sulindac for lung cancer chemoprevention.

ABSTRACT: INTRODUCTION:Sulindac represents a promising candidate agent for lung cancer chemoprevention, but clinical trial data have not been previously reported. We conducted a randomized, phase II chemoprevention trial involving current or former cigarette smokers (?30 pack-years) utilizing the multi-center, inter-disciplinary infrastructure of the Cancer Prevention Network (CPN). METHODS:At least 1 bronchial dysplastic lesion identified by fluorescence bronchoscopy was required for randomization. Intervention assignments were sulindac 150mg bid or an identical placebo bid for 6 months. Trial endpoints included changes in histologic grade of dysplasia (per-participant as primary endpoint and per lesion as secondary endpoint), number of dysplastic lesions (per-participant), and Ki67 labeling index. RESULTS:Slower than anticipated recruitment led to trial closure after randomizing participants (n=31 and n=30 in the sulindac and placebo arms, respectively). Pre- and post-intervention fluorescence bronchoscopy data were available for 53/61 (87%) randomized, eligible participants. The median (range) of dysplastic lesions at baseline was 2 (1-12) in the sulindac arm and 2 (1-7) in the placebo arm. Change in dysplasia was categorized as regression:stable:progression for 15:3:8 (58%:12%:31%) subjects in the sulindac arm and 15:2:10 (56%:7%:37%) subjects in the placebo arm; these distributions were not statistically different (p=0.85). Median Ki67 expression (% cells stained positive) was significantly reduced in both the placebo (30 versus 5; p=0.0005) and sulindac (30 versus 10; p=0.0003) arms, but the difference between arms was not statistically significant (p=0.92). CONCLUSIONS:Data from this multi-center, phase II squamous cell lung cancer chemoprevention trial do not demonstrate sufficient benefits from sulindac 150mg bid for 6 months to warrant additional phase III testing. Investigation of pathway-focused agents is necessary for lung cancer chemoprevention.

SUBMITTER: Limburg PJ

PROVIDER: S-EPMC3566344 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Randomized phase II trial of sulindac for lung cancer chemoprevention.

Limburg Paul J PJ Mandrekar Sumithra J SJ Aubry Marie Christine MC Ziegler Katie L Allen KL Zhang Jun J Yi Joanne E JE Henry Michael M Tazelaar Henry D HD Lam Stephen S McWilliams Annette A Midthun David E DE Edell Eric S ES Rickman Otis B OB Mazzone Peter P Tockman Melvyn M Beamis John F JF Lamb Carla C Simoff Michael M Loprinzi Charles C Szabo Eva E Jett James J

Lung cancer (Amsterdam, Netherlands) 20121220 3

<h4>Introduction</h4>Sulindac represents a promising candidate agent for lung cancer chemoprevention, but clinical trial data have not been previously reported. We conducted a randomized, phase II chemoprevention trial involving current or former cigarette smokers (≥30 pack-years) utilizing the multi-center, inter-disciplinary infrastructure of the Cancer Prevention Network (CPN).<h4>Methods</h4>At least 1 bronchial dysplastic lesion identified by fluorescence bronchoscopy was required for rando ...[more]

PMID: 23261228

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Project description:Non-steroidal anti-inflammatory drugs (NSAIDs) are promising colorectal cancer (CRC) chemopreventive drugs; however, to overcome NSAIDs' associated side effects, there is a need to develop safer and efficacious approaches. The present study was designed to evaluate (i) the efficacy of nitric-oxide releasing (NO)-Sulindac as compared to Sulindac; (ii) whether NO-Sulindac is superior to Sulindac in enhancing low-dose difluoromethylornithine (DFMO)-induced chemopreventive efficacy, and (iii) assessing the key biomarkers associated with colon tumor inhibition by these combinations. In F344 rats, colonic tumors were induced by azoxymethane (AOM). At the adenoma stage (13 weeks post AOM), groups of rats were fed the experimental diets containing 0 ppm, 500 ppm DFMO, 150 ppm Sulindac, and 200 ppm NO-Sulindac, individually or in combinations, for 36 weeks. Colon tumors were evaluated histopathologically and assayed for expression levels of proliferative, apoptotic, and inflammatory markers. Results suggest that (except for NO-Sulindac alone), DFMO, Sulindac individually, and DFMO combined with Sulindac or NO-Sulindac significantly suppressed AOM-induced adenocarcinoma incidence and multiplicities. DFMO and Sulindac suppressed adenocarcinoma multiplicity by 63% (p < 0.0001) and 51% (p < 0.0011), respectively, whereas NO-Sulindac had a modest effect (22.8%, p = 0.09). Combinations of DFMO plus Sulindac or NO-Sulindac suppressed adenocarcinoma incidence (60%, p < 0.0001; 50% p < 0.0004), and multiplicity (81%, p < 0.0001; 62%, p < 0.0001). Rats that were fed the combination of DFMO plus Sulindac showed significant inhibition of tumor cell proliferation and induction of apoptosis. In addition, enhancement of p21, Bax, and caspases; downregulation of Ki-67, VEGF, and β-catenin; and modulation of iNOS, COX-2, and ODC activities in colonic tumors were observed. These observations show that a lower-dose of DFMO and Sulindac significantly enhanced CRC chemopreventive efficacy when compared to NO-Sulindac alone, and the combination of DFMO and NO-Sulindac was modestly efficacious as compared to DFMO alone.

Project description:The proteasome inhibitor bortezomib sensitizes tumor cells to chemotherapy-induced apoptosis. In preclinical non-small-cell lung cancer (NSCLC) models, p53-dependent growth arrest after bortezomib treatment resulted in reduced cytotoxicity if bortezomib preceded docetaxel. The reverse sequence of docetaxel before bortezomib was associated with increased apoptosis, cleavage of caspase-3 and PARP (poly [ADP-ribose] polymerase), and reduction in Bcl-2. A prospective randomized phase II trial of concurrent versus sequential docetaxel and bortezomib was conducted to assess whether administration sequence resulted in measurable clinical differences.Previously treated patients with advanced NSCLC were randomized to concurrent (CON) or sequential (SEQ) docetaxel (75 mg/m² intravenous [I.V.]) followed by bortezomib, every 3 weeks. In the CON arm, bortezomib (1.6 mg/m² I.V.) was given on days 1 and 8, and in the SEQ arm, it was given on days 2 and 8. Previous erlotinib as well as treated or controlled brain metastases were allowed. The primary endpoint was objective response rate (RR); progression-free (PFS) and overall survival (OS) were secondary endpoints.Eighty-one patients were randomized (40 CON and 41 SEQ). Grade 3+ toxicities were mostly due to myelosuppression. One patient each had grade 4 hyponatremia and syncope. Toxicities were similar between the arms. There was 1 treatment-related death in the SEQ arm. There were 8 partial responders, 4 in each arm, for an overall RR of 10%. Disease control rate was similar in both arms (50% vs. 49%). Median PFS was 12 weeks in the CON arm and 11 weeks in the SEQ arm. Median OS times in the CON and SEQ arms were 13.3 and 10.5 months, respectively.Docetaxel plus bortezomib given sequentially or concurrently has similar RR and PFS. Median survival in the SEQ arm exceeds published survival estimates for either agent alone or in combination. Any further studies in this population would require molecular characterization of a phenotype most likely to benefit from proteasome inhibitor therapy.

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Randomized phase II trial of sulindac for lung cancer chemoprevention.

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Randomized phase II trial of sulindac for lung cancer chemoprevention.

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