Eicosanoids in non-small cell lung cancer (NSCLC).

Abstract

7613 Background: COX-2 is frequently upregulated in NSCLC leading to high PGE2 levels that may play a role in NSCLC pathogenesis. PGE-M, the main urine metabolite of PGE2, accurately reflects changes in systemic and intratumoral PGE2 levels [CCR 11:6634, 2005]. A ≥ 70% decline in PGE-M in NSCLC pts treated with docetaxel (D) + celecoxib (C) 400 mg bid was associated with a possible survival benefit. In an ongoing trial, study pts are prospectively selected using a change in PGE-M levels before and after C 600 mg bid which is the dose needed to effect maximum COX-2 inhibition [CCR 12:3381, 2006]. Methods: Previously treated NSCLC pts, PS 0-2, evaluable/measurable disease, adequate marrow, renal and hepatic function, no current NSAID or sulfa allergy are eligible. Screened pts with ≥ 70% decline in PGE-M receive D 75 mg/m2 or pemetrexed 500 mg/m2 q3wk + continued C 600 mg bid × 4 cycles followed by C 400 mg bid until PD or excess toxicity. Results: Through 12/0930 pts (F = 13, M = 17) enrolled. At baseline men had higher PGE-M (median: 34.7 vs. 16.9 ng/mg Cr) and lower LTE4 levels (78.6 vs. 101.4 pg/mg Cr) (LTE4 is main leukotriene metabolite). Median PGE-M levels decreased from 21.4 to 8.1 ng/mg Cr (p = 0.000) pre- and post-C; LTE4 was unchanged (97.7 to 82.3 pg/mg Cr; p = 0.92); and PGI-M decreased from 119 to 47.5 pg/mg Cr (p = 0.004). In men PGE-M decreased post C whereas LTE4 increased (78.6 to 93.4 ng/mg Cr; p = 0.017) suggesting a possible shunting to the 5-LO/leukotriene pathway. Both PGE-M and LTE4 decreased in women. 13 pts received C + chemo; 10 evaluable; 6 SD and 4 PD. Treatment was well tolerated; no cardiac toxicities noted. Conclusions: These preliminary data indicate C 600 mg bid effectively inhibits intratumoral COX-2 in > 40% NSCLC pts. The effect is greatest in current smokers and males compared to never smokers and females. Post C, LTE4 increased in males (former smokers primarily). These data may have implications for chemoprevention trials. [Lung Cancer SPORE CA90949] No significant financial relationships to disclose.