Pharmacodynamic biomarkers in metronomic chemotherapy: multiplex cytokine measurements in gastrointestinal cancer patients.

Abstract

Metronomic chemotherapy has shown promising antitumor activity in a number of malignancies. We previously reported a phase II clinical trial of metronomic UFT (a 5-fluorouracil prodrug; 100mg/twice per day p.o.) and cyclophosphamide (CTX; 500mg/m2 i.v. bolus on day 1 and then 50mg/day p.o.) plus celecoxib (200mg/twice a day p.o.)in 38 patients with advanced refractory gastrointestinal tumors. The mechanisms of action of metronomic chemotherapy include inhibition of angiogenesis, direct cytotoxic effects on cancer cells, and, at least for drugs such as CTX, activation of the immune system. To further evaluate the latter, we carried out an immune system multiplex 14-cytokine profiling of plasma samples that were available (for day 0, day 28, and day 56) from 31 of the 38 patients in the above-noted clinical trial. Our results show that pre-treatment plasma-level cutoffs of interferon gamma (> 12.84pg/ml), sCD40L (< 2168pg/ml), interferon alpha 2 (> 55.11pg/ml), and IL-17a (< 15.1pg/ml) were predictive markers for those patients with better progression-free survival (p < .05 for each cytokine). After 28days of metronomic therapy, the plasma levels of sCD40L, IL-17a, and IL-6 (< 130pg/ml) could serve as predictors of improved progression-free survival, as could levels interferon gamma and sCD40L after 56days of therapy. We observed minimal changes in cytokine profiles, from baseline, as a consequence of the metronomic therapy, with the exception of an elevation of IL-6 and IL-8 levels 28days (and 56days) after treatment started (p < 0.05). Our results indicate that a selective cytokine elevation involves IL-6 and IL-8, following metronomic chemotherapy administration. In addition, interferon gamma and sCD40L may be potential biomarkers for gastrointestinal cancer patients that are likely to benefit from metronomic chemotherapy. Our study contributes to our understanding of the mechanisms of action of metronomic chemotherapy, and the cytokine profiling we describe may guide future selection of gastrointestinal cancer patients for UFT/CTX/celecoxib combination metronomic chemotherapy.