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Induction Therapy for Locally Advanced, Resectable Esophagogastric Cancer

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Objectives:

Preoperative chemotherapy and radiation for localized esophageal cancer produces cure rates near 30% when combined with surgical resection. Vandetanib, a small molecule receptor tyrosine kinase inhibitor of VEGFR-2, VEGFR-3, RET, and EGFR, demonstrated synergy with radiation and chemotherapy in preclinical models. We conducted a phase I study to assess the safety and tolerability of vandetanib when combined with preoperative chemoradiation in patients with localized esophageal carcinoma who were surgical candidates.

Methods:

Patients with stage II-III esophageal and gastroesophageal junction carcinoma without prior therapy were enrolled in a 3+3 phase I design. Patients received once-daily vandetanib (planned dosing levels of 100, 200, and 300 mg) with concomitant daily radiotherapy (1.8 Gy/d, 45 Gy total) and chemotherapy, consisting of infusional 5-FU (225 mg/m2/d over 96 h, weekly), paclitaxel (50 mg/m2, days 1, 8, 15, 22, 29) and carboplatin (AUC of 5, days 1, 29).

Results:

A total 9 patients were enrolled with 8 having either distal esophageal or gastroesophageal junction carcinomas. All patients completed the planned preoperative chemoradiation and underwent esophagectomy. Nausea (44%) and anorexia (44%) were the most common acute toxicities of any grade. One grade 4 nonhematologic toxicity was observed (gastrobronchial fistula). One additional patient suffered a late complication, a fatal aortoenteric hemorrhage, not definitively related to the investigational regimen. Five (56%) patients achieved a pathologic complete response. Three (33%) additional patients had only microscopic residual disease. Five (56%) patients remain alive and disease free with a median follow-up of 3.7 years and median overall survival of 3.2 years. The maximum tolerated dose was vandetanib 100 mg/d.

Conclusions:

Vandetanib at 100 mg daily is tolerable in combination with preoperative chemotherapy (5-FU, paclitaxel, carboplatin) and radiation therapy with encouraging efficacy worthy of future study.
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Keywords: 5-fluorouracil; carboplatin; esophageal cancer; paclitaxel; radiotherapy; surgery; vandetanib

Document Type: Research Article

Affiliations: 1: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 2: Departments of Radiation Oncology 3: Department of Surgery, Thomas Jefferson University Hospital, Philadelphia, PA 4: Medical Oncology 5: Pathology 6: Protocol Management Office, Fox Chase Cancer Center 7: Department of Surgical Oncology, Brigham and Women’s Hospital, Boston, MA 8: Department of Medical Oncology, Yale University School of Medicine, New Haven, CT 9: Surgical Oncology

Publication date: August 1, 2017

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