title: Phase I Trial of Dose-escalated Whole Liver Irradiation With Hepatic Arterial Fluorodeoxyuridine/Leucovorin and Streptozotocin Followed by Fluorodeoxyuridine/Leucovorin and Chemoembolization for Patients With Neuroendocrine Hepatic Metastases.
abstract: We have previously shown that refractory neuroendocrine tumors can respond to moderate doses of chemoradiotherapy. We completed a dose-escalation phase I/II trial combining hepatic arterial (HA) chemotherapy, chemoembolization, and dose-escalated whole liver radiotherapy to determine the maximum safe dose of radiation that could be delivered and to make a preliminary assessment of response.
  
  
  
  From 2002 to 2009, 19 patients with symptomatic neuroendocrine liver metastases who failed somatostatin analog therapy were enrolled. HA fluorodeoxyuridine, leucovorin, and streptozotocin were delivered, as concurrent whole liver radiotherapy was dose escalated from 24 to 32 Gy in 2 Gy fractions, with a target rate of dose-limiting grade ≥3 radiation-induced liver disease of 10%. Eight weeks later, for patients without grade ≥3 liver or grade ≥4 any toxicity, a 72-hour infusion of HA fluorodeoxyuridine and leucovorin was given, followed by transarterial chemoembolization.
  
  
  
  Eleven patients completed the entire protocol and received 24 to 32 Gy. No patients developed radiation-induced liver disease; 7 had grade 3 to 4 transiently increased liver function tests, and 4 had other grade 4 toxicities. Three patients (14%) had partial response, 16 (84%) stable disease. Median freedom from local progression and overall survival were 35.3 and 54.6 months, respectively.
  
  
  
  Thirty-two in 2 Gy daily fractions can be delivered safely when combined with HA chemotherapy and subsequent transarterial chemoembolization. However, although objective responses were observed, this combination was not significantly better than our prior approaches. Further treatment intensification strategies, including individualized dose escalation for radiation-tolerant livers, and improved radiosensitization should be investigated, along with improved systemic therapy.
authors.affiliation: Departments of Radiation Oncology.
authors.forename: Mark
authors.initials: M
authors.lastname: Shilkrut
authors.affiliation: Departments of Radiation Oncology.
authors.forename: Eli
authors.initials: E
authors.lastname: Sapir
authors.affiliation: Departments of Radiation Oncology.
authors.forename: Sheela
authors.initials: S
authors.lastname: Hanasoge
authors.affiliation: Departments of Radiation Oncology.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Schipper
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Normolle
authors.affiliation: Departments of Radiation Oncology.
authors.forename: Edgar
authors.initials: E
authors.lastname: Ben-Josef
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI.
authors.forename: William
authors.initials: W
authors.lastname: Ensminger
authors.affiliation: Departments of Radiation Oncology.
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Lawrence
authors.affiliation: Departments of Radiation Oncology.
authors.forename: Mary
authors.initials: M
authors.lastname: Feng
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018278:Carcinoma, Neuroendocrine / Q000473:pathology / Q000628:therapy*; D016461:Chemoembolization, Therapeutic; D003131:Combined Modality Therapy; D005260:Female; D005467:Floxuridine / Q000008:administration & dosage; D005500:Follow-Up Studies; D006499:Hepatic Artery; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000556:secondary / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011879:Radiotherapy Dosage; D013311:Streptozocin / Q000008:administration & dosage; D015996:Survival Rate
chemical_list: D005467:Floxuridine; D013311:Streptozocin; D002955:Leucovorin