OBJECTIVES: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
OBJECTIVES: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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: Philipp M Paprottka; Ralf-T Hoffmann; Alexander Haug; Wieland H Sommer; Franziska Raessler; Christoph G Trumm; Gerwin P Schmidt; Nima Ashoori; Maximilian F Reiser; Tobias F Jakobs Journal: Cardiovasc Intervent Radiol Date: 2011-08-17 Impact factor: 2.740
Authors: Yue Cao; Hesheng Wang; Timothy D Johnson; Charlie Pan; Hero Hussain; James M Balter; Daniel Normolle; Edgar Ben-Josef; Randall K Ten Haken; Theodore S Lawrence; Mary Feng Journal: Int J Radiat Oncol Biol Phys Date: 2012-04-18 Impact factor: 7.038
Authors: Eric Raymond; Laetitia Dahan; Jean-Luc Raoul; Yung-Jue Bang; Ivan Borbath; Catherine Lombard-Bohas; Juan Valle; Peter Metrakos; Denis Smith; Aaron Vinik; Jen-Shi Chen; Dieter Hörsch; Pascal Hammel; Bertram Wiedenmann; Eric Van Cutsem; Shem Patyna; Dongrui Ray Lu; Carolyn Blanckmeister; Richard Chao; Philippe Ruszniewski Journal: N Engl J Med Date: 2011-02-10 Impact factor: 91.245
Authors: Anja Rinke; Hans-Helge Müller; Carmen Schade-Brittinger; Klaus-Jochen Klose; Peter Barth; Matthias Wied; Christina Mayer; Behnaz Aminossadati; Ulrich-Frank Pape; Michael Bläker; Jan Harder; Christian Arnold; Thomas Gress; Rudolf Arnold Journal: J Clin Oncol Date: 2009-08-24 Impact factor: 44.544
Authors: Frederike G I van Vilsteren; Edwina S Baskin-Bey; David M Nagorney; Schuyler O Sanderson; Walter K Kremers; Charles B Rosen; Gregory J Gores; Timothy J Hobday Journal: Liver Transpl Date: 2006-03 Impact factor: 5.799
Authors: Philipp C Manegold; Carmen Paringer; Ulrike Kulka; Klaus Krimmel; Martin E Eichhorn; Ralf Wilkowski; Karl-Walter Jauch; Markus Guba; Christiane J Bruns Journal: Clin Cancer Res Date: 2008-02-01 Impact factor: 12.531