title: Induction Therapy for Locally Advanced, Resectable Esophagogastric Cancer: A Phase I Trial of Vandetanib (ZD6474), Paclitaxel, Carboplatin, 5-Fluorouracil, and Radiotherapy Followed by Resection.
abstract: OBJECTIVE
  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/m/d over 96 h, weekly), paclitaxel (50 mg/m, 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.
authors.affiliation: *Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY Departments of †Radiation Oncology §Medical Oncology ∥Pathology ††Surgical Oncology ¶Protocol Management Office, Fox Chase Cancer Center ‡Department of Surgery, Thomas Jefferson University Hospital, Philadelphia, PA #Department of Surgical Oncology, Brigham and Women's Hospital, Boston, MA **Department of Medical Oncology, Yale University School of Medicine, New Haven, CT ‡‡Department of Biochemistry, Kazan Federal University, Kazan, Russia.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Boland
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Meyer
authors.forename: Adam C
authors.initials: AC
authors.lastname: Berger
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Cohen
authors.forename: Tzahi
authors.initials: T
authors.lastname: Neuman
authors.forename: Harry S
authors.initials: HS
authors.lastname: Cooper
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Olszanski
authors.forename: Monica
authors.initials: M
authors.lastname: Davey
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Cheng
authors.forename: Abraham
authors.initials: A
authors.lastname: Lebenthal
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Burtness
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Scott
authors.forename: Igor A
authors.initials: IA
authors.lastname: Astsaturov
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000401:mortality / Q000628:therapy; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000401:mortality / Q000628:therapy*; D016629:Esophagectomy; D004943:Esophagogastric Junction / Q000473:pathology / Q000601:surgery; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D017239:Paclitaxel / Q000008:administration & dosage; D010880:Piperidines / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D010880:Piperidines; D011799:Quinazolines; D016190:Carboplatin; D017239:Paclitaxel; D005472:Fluorouracil; C452423:vandetanib