Recombinant anti-VEGF monoclonal antibody(North China Pharmaceutical Co., Ltd.)

Background. New approaches are needed for patients newly diagnosed with bulky glioblastoma (GB) and/or with severe neurological impairment that cannot benefit from first line temozolomide (TMZ)-based chemoradiotherapy. Bevacizumab (BEV), an antiangiogenic anti-VEGF-R monoclonal antibody, has a rapid impact on tumor-related brain edema in recurrent GB. The present study reports the feasibility and efficacy of an induction treatment with TMZ and BEV to alleviate the initial neurological impairment and/or to reduce the tumor volume before a delayed chemoradiotherapy. Methods. We retrospectively analyzed tumor and target volumes and clinical neurological status in 39 patients with bulky GB and/or with severe neurological impairment after an induction treatment combining TMZ and BEV. Neurological and radiological responses were assessed according to RANO criteria. Calculating gross tumor and clinical target volumes (GTV and CTV) was done at diagnosis and before radiotherapy. Progression-free survival (PFS) and overall survival (OS) were determined by Kaplan Meier methods. Safety was reported according to NCTCAE. Results. A cohort of 39 patients was analyzed between December 2010 and April 2014. Upfront standard TMZ-based chemoradiotherapy was recused due either to tumor volume or impairment of neurological status and/or performance status. After TMZ/BEV induction (median time of 3 months), 6 (15%) patients achieved a partial response (PR), and 17 (44%) had a stable disease. 24 patients (62%) received a radical-intent chemoradiotherapy. TMZ-BEV induced median reduction of the clinical target volume (CTV) was 25.9% [-84.4%; - 4.8%]. The median PFS and OS were 8.4 months [95% CI: (6.6 - 9.9)] and 11.0 months [95% CI: (9.3 - 13.7)], respectively in the whole cohort and 10.8 [95% CI: (9.3 - 12.9)] and 15.0 [95% CI: (13.2 - 17.8)] for irradiated patients. Induction treatment led to corticosteroid dose reduction or cessation in 21 patients (54%). KPS improvement was observed in 38% of patients. Toxicity was mild with only 7/39 (18%) grade III-IV toxicity, including 1 digestive bleeding and 1 epistaxis. Conclusion. TMZ-BEV induction led to CTV reduction allowing for optimal chemoradiotherapy in a majority (62%) of patients for which radiotherapy was initially recused. A clinical benefit was obtained with improved KPS and a decrease in steroid dose.

Neuropathic pain is caused by the peripheral or central nervous system structure damage or dysfunction. VEGF is involved in nociception and inflammation. VEGF may target VEGF receptor-2 (VEGFR-2) on the surface of neurons. P2X(2/3) receptors play a crucial role in facilitating pain transmission at the spinal sites. Chronic constriction injury (CCI) rats were used as neuropathic pain model. Sprague-Dawley male rats were randomly divided into sham group, anti-recombinant VEGF antibody group with phosphate-buffer saline (anti-rVEGF+PBS group), CCI rats treated with phosphate-buffer saline group (CCI+PBS group) and CCI rats treated with anti-recombinant VEGF antibody group (CCI+anti-rVEGF group). The expressions of VEGFR-2, P2X(2) and P2X(3) protein in spinal dorsal horn (SDH) were detected by immunohistochemistry, double-label immunofluorescence and western blotting. The protein levels of VEGFR-2, P2X(2) and P2X(3) in L4/5 SDH of CCI+PBS group were higher than those in sham group. VEGFR-2 and P2X(2) or P2X(3) receptors were co-expressed in the cytoplasm and surface membranes of SDH. Anti-rVEGF treatment in CCI rats reduced the expression of VEGFR-2 and P2X(2/3) receptors in L4/5 SDH compared with those in CCI+PBS group. Therefore, VEGF may activate VEGFR-2 to participate the process of neuropathic pain. Anti-rVEGF treatment in CCI rats reduced the expression of VEGFR-2 and inhibited the transmission of neuropathic pain in L4/5 SDH via decreasing the expression of P2X(2/3). There is a cross-potentiation between VEGFR-2 and P2X(2/3) receptors in neuropathic pain state.