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

Abstract

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 surgery-induced 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 pro- and 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 surgery [5]. Angiogenic cytokine perioperative levels could be increased from the fifth day after surgery and should induce perioperative stimulation of residual cancer cells [5]. This is the first clinical evidence of rapid regrowth after BV interruption in metastatic cancer patients with similar observations than previously reported preclinical experiments describing rapid reversal of antiangiogenic inhibitions in mice. Our observations suggest that, between 2 and 3 months after BV interruption, the tumor growth rate is faster than before BV and possibly also accelerated by surgery. On the basis of these observations, we suggest that the duration of BV interruption should be optimized and that the possibility to reintroduce BV 2 weeks after surgery rather than 30–45 days after surgical resection as presently routinely done should be studied.