Abstract 784: 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. For example, we previously reported (Allegrini et al., Angiogenesis (2012) 15(2):275-86) a phase II clinical trial of metronomic UFT (a 5-fluorouracil prodrug; 100 mg/twice per day p.o.) and cyclophosphamide (CTX; 500 mg/mq2 i.v. bolus on day 1 and then 50 mg/day p.o.) plus celecoxib (200 mg/twice a day p.o.) in 38 patients with advanced refractory gastrointestinal tumors. The mechanisms of action of metronomic chemotherapy include upregulation of the angiogenesis inhibitor Thrombospondin-1, the suppression of bone marrow derived endothelial progenitor 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 (Allegrini et al) clinical trial. Our results show that pre-treatment plasma level cut-offs of interferon-gamma (>12.84pg/ml), sCD40L (<2168pg/ml), interferon-alpha2 (>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 28 days of metronomic therapy, the plasma levels of sCD40L, IL-17a, and of IL-6 (<130pg/ml) could serve as predictors of improved progression-free survival, as could levels interferon-gamma and sCD40L after 56 days 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 28 days (and 56 days) after treatment started (p<0.05). Our results indicate that a selective cytokine elevation, involving 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 may guide future patient selection criteria for metronomic chemotherapy for gastrointestinal cancers. Citation Format: Paloma Valenzuela, Karla Parra, Derrick Oaxaca, Luis Reza, Jose Lopez, Montserrat Garcia Arreguin, Diana Garcia, Georgialina Rodriguez, Alfredo Falcone, Giacomo Allegrini, Teresa Di Desidero, Guido Bocci, Robert Kirken, Giulio Francia. Pharmacodynamic biomarkers in metronomic chemotherapy: Multiplex cytokine measurements in gastrointestinal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 784. doi:10.1158/1538-7445.AM2017-784

Optimization of Biomarkers-Based Classification Scores as Progression-Free Survival Predictors: An Intuitive Graphical Representation

“…For the data of an immune system multiplex 14-cytokine profiling of plasma samples available from 31 patients with advanced refractory gastrointestinal tumors [ 8 , 11 ] ([V alenzuela P et al. , S ubmitted ), we showed that the scores derived from the suitably chosen combinations of three biomarkers has a classification power comparable to the RECIST criteria clinical classification.…”

“…plus celecoxib [ 8 ]. Experimental details as well as a discussion on the implications of cytokines levels for understanding the mechanism of action of metronomic therapy are provided elsewhere [ 8 , 11 , V alenzuela P et al. , S ubmitted ].…”

What is the real value of metronomic chemotherapy in the treatment of gastrointestinal cancer?

“…Efforts should focus on conducting large prospective trials (Table 1) [31] (ideally phase-III trials) incorporating MTC alone or in combination with synergetic drugs, to attain high-quality evidence supporting its use, specifically in earlier treatment settings [32]. It is important to identify patient-subpopulations for whom MTC would be best and establish the ideal predictive biomarkers that correlate with clinical outcomes [33]. Broader awareness of the potential of MTC should be acknowledged, with more investigations implemented in pursuit of the integration of MTC in cancer treatment algorithms.…”