Effect of anti-inflammatory therapy in patients with metastatic renal cell carcinoma on clinical response

14500 Background: Interaction among signalling networks from tumor and neighbouring stroma cells in complex disease traits is poorly understood. Methods: Two consecutive multi-centre phase II trials were designed (case calculation according response rate, T. Chen two stage design) to prove the hypothesis, whether the activation of presumably complementary receptor-triggered transcriptional cascades (via pioglitazone, and interferon alpha, IFNa) could result in synergistic clinical effects. Therapy in both trials consisted of low-dose capecitabine 1 g/m2 twice daily po for 14 days, every 3 weeks, day 1+, and rofecoxib 25 mg daily, day 1+ (from 11/04 etoricoxib 60 mg daily instead) plus pioglitazone 60 mg daily, day 1+. In study II low-dose IFNa 4.5 MU sc three times a week, week 1+, was added until disease progression. Results: Eighteen, and 33 patients (pts, 31 eligible for analysis), respectively, with clear cell carcinoma, progressive disease, and ECOG 0–2 were enrolled between 2/02 to 2/03 and 4/03 to 4/05, respectively. Mean Bradley score in both trials was not significantly different, 4.1(I)/4.9(II), however, the rate of previous systemic treatments 33%/19%. Objective response (48%) was exclusively observed in study II (PR 35%, CR 13%), and paralleled by a strong CRP response (after 4 weeks on treatment) in all 29 pts with elevated CRP levels (93%) (study I: no significant CRP response): CRP values decreased from mean 41.3 mg/l, range 8.1 to 221, to 5.1 mg/l, range 2.1 to 15.6, p = 0.005. Stable disease > 2 months (mos) occurred in 50%/48%. Median progression-free survival could be more than doubled from a median of 4.7 mos (95% CI, 1.0 to 10.4) to 11.5 mos (6.8 to 16.2) in study II, p = 0.0000. Median overall survival of population II has not been reached, yet. Toxicities > WHO grade II were reported (study I/II): Hand-foot syndrome (3/3), diarrhoea (2/2), depression (0/1), pneumonia (0/1). Conclusions: (1) Clinical results of anti-inflammatory/angiostatic therapy compare with available immuno-therapies. (2) Improved outcome with additive IFNa argues for a synergistic drug interaction. (3) Control of tumor-associated inflammation is an important therapeutic principle in metastatic clear cell carcinoma. No significant financial relationships to disclose.