Reversible tumor growth acceleration following bevacizumab interruption in metastatic colorectal cancer patients scheduled for surgery.

Inhibitors of vascular endothelial growth factor (VEGF) signaling can block angiogenesis and reduce tumor vascularity, but little is known regarding the reversibility of these changes after treatment withdrawal. In mice, after reversal of VEGF inhibition, implanted tumors were fully revascularized by 7 days, and the pericyte phenotype returned to baseline [1]. Importantly, the regrown vasculature regressed as much during a second treatment as it did in the first [1]. To address this issue, we prospectively focused on a cohort of seven metastatic colorectal cancer patients treated with chemotherapy, using following schedules FOLFOX6 or FOLFIRI [2], combined with the anti-VEGF mAb, bevacizumab (BV) at the dose of 5 mg/kg every 2 weeks. Given the long half-life of BV and the potential for anti-VEGF therapy to impede wound healing and/or liver regeneration, an interval of 6–8 weeks between BV administration and surgery has been recommended [3]. We took advantage of this subset of patients because any responding patients with potentially resectable liver metastases would have been consecutively on a ‘on therapy’ (chemotherapy + BV) period followed by a ‘off therapy’ during the perioperative period mimicking in the clinic the experiments made in mice [1]. We report here the kinetics of tumor growth before, during and after interruption of BV, and under BV reintroduction (Table 1). We measured either clinically, or using computed tomography, both the diameter of target lesions according to response evaluation criteria in solid tumors (RECIST) criteria, and the tumor doubling time. The median time between BV interruption and surgery was 8 weeks (range 3–12). Under BV, all patients experienced objective response with a median tumor reduction of 15% per month (range 5–25). After BV interruption, most of the patients experienced tumor growth of residual disease (Table 1) (Figure 1). Tumor growth doubling time after BV interruption ranged from 2 to 5 weeks. Reintroduction of BV reinduced a tumor response in five of seven patients, with a median time to response of 8 weeks and a median tumor diameter reduction of 5% per month. It is uncertain whether the main cause of tumor growth is the interruption per se or its association with surgeryinduced VEGF stimulation. Rebound in tumor growth and revascularization were previously documented in mice [1]. Furthermore, rebound following angiogenesis inhibitors’ interruption has also been described in the care of retinopathies [4]. Hence, BV might disregulate the balance between proand antiangiogenic signals, so that the proangiogenic one is broadly over-represented after BV withdrawal. This disregulation might as well be caused by the surgical resection. It is anticipated that VEGF plasma levels would increase after liver surgery and that such elevations may facilitate tumor growth. Both open and closed colorectal resection and gastric bypass are associated with significantly elevated plasma VEGF levels early after Annals of Oncology letter to the editor