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Intragastric Injection of Botulinum Toxin a to Treat Gastric Cancer: An Open-Label Phase II Clinical Trial
Gøran Andersen*1,4, Chun-Mei Zhao4, Xing Cai4, Hanne-Line Rabben4, James G. Fox2, Timothy C. Wang3, Duan Chen4,1, Jon Erik Grønbech1,4
1Department of Surgery, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; 2Division of Comparative Medicine, Massachusetts Institute of Technology, Boston, MA; 3Division of Digestive and Liver Diseases, Columbia University College of Physicians and Surgeons, New York, NY; 4Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
Background/aims: Previously, we demonstrated that blocking vagal nerve signals surgically (by vagotomy) or with Botulinum toxin A (Botox) injection suppresses tumor growth in mice. In this study, we evaluated the safety and possible efficacy of endoscopic therapy with Botox for patients with advanced gastric cancer, and furthermore investigated a combination therapy of Botox plus oxaliplatin in cell culture and in an animal model of gastric cancer.
Methods: Patients eligible for this study included those (ECOG 0-2) with verified gastric adenocarcinomas that were locally non-resectable and/or with distant metastasis. The criteria also included a lack of response or non-tolerance to second line chemotherapy. Endoscopic Botox injection was performed under sedation with midazolam. One hundred units Botox were diluted into 14 ml saline. Patients received a total of 7 injections with 2 ml/14.3 units of Botox solution; 3 injections were made directly into the tumor and 4 injections around the tumor. The safety evaluation was performed based on the Common Toxicity Criteria. The study was conducted in accordance with the guidelines for Good Clinical Practice, and was approved by the Regional Committee for Medical and Health Research Ethics and the Norwegian Medicines Agency. A human gastric cancer cell line MKN74 and a well-established genetically engineered mouse model of gastric cancer (INS-GAS FVB mice) were used to test the combination therapy.
Results: During the time period from Aug. 2014 - Oct. 2015, six patients were treated with endoscopic injection of Botox. There were no complications in connection with the procedure and no adverse effects during or up to 20 weeks after the procedure. Four (4) out 6 patients survived for an average of 11.5 weeks after Botox treatment. One patient has been followed up for 20 weeks, with an absence of tumor growth between 8 to 20 weeks, while the last patient has significantly improved clinical condition and will have the 8-week postoperative CT scan on November 25, 2015. Botox directly inhibited cell proliferation in vitro by 10% and had an additive effect on oxaliplatin-induced inhibition. In INS-GAS mice with advanced gastric cancer (12 months of age, male:femal=1:1), local injections of Botox (once a month) had a synergistic effect with oxaliplatin treatment (given by i.p. injections for 2 months) in terms of pathological criteria (dysplasia and gastric histologic activity index) and tumor size.
Conclusions: The preliminary results of this clinical trial demonstrate the feasibility and the safety of this procedure as a potential treatment for advanced gastric cancer. To further demonstrate the efficacy of Botox endoscopic treatment in combination with chemotherapy, a randomized, double-blind, and placebo-controlled trial with an open-label extension study is in preparation.
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