 In regard of the two parts, the primary objective of the run-in phase n50 patients with conventional switch of chemotherapy together with the anti-angiogenic agent is the determination of a distinct cytokines and angiogenic factor CAF profile during treatment with FOLFOX and bevacizumab, which allows early detectionprediction of progressive disease. The primary objective of the marker-driven randomized part n150 patients with marker-driven switch of antiangiogenic agent and maintenance of chemotherapy is the evaluation of the efficacy of an early marker-driven switch of anti-angiogenic treatment bevacizumab to aflibercept 