F A Lévi1, V Boige2, M Hebbar3, D Smith4, C Lepère5, C Focan6, A Karaboué7, R Guimbaud8, C Carvalho9, S Tumolo10, P Innominato11, Y Ajavon12, S Truant3, D Castaing13, T De Baere2, F Kunstlinger12, M Bouchahda7, M Afshar14, P Rougier15, R Adam7, M Ducreux16. 1. UMRS 776 'Biological Rhythms and Cancers', INSERM, Villejuif Université Paris Sud 11, Orsay Assistance Publique-Hopitaux de Paris, Department of Medical Oncology, Department of Hepatobiliary Center and Radiology, Paul Brousse Hospital, Villejuif, France Cancer Chronotherapy Unit, Warwick Medical School, Coventry, UK f.levi@warwick.ac.uk. 2. Service d'Oncologie Digestive, Institut Gustave Roussy, Villejuif. 3. Department of Medical Oncology, Hôpital Huriez, Lille. 4. Hôpital Saint-André, Department of Medical Oncology, Centre Hospitalo-Universitaire, Bordeaux. 5. Service d'Hépato-Gastro-Entérologie, Hôpital Européen Georges Pompidou, Paris, France. 6. Department of Oncology, Centre Hospitalier Chrétien, Clinique Saint-Joseph, Liège, Belgium. 7. UMRS 776 'Biological Rhythms and Cancers', INSERM, Villejuif Université Paris Sud 11, Orsay Assistance Publique-Hopitaux de Paris, Department of Medical Oncology, Department of Hepatobiliary Center and Radiology, Paul Brousse Hospital, Villejuif, France. 8. Department of Oncology, University Hospital of Purpan, Toulouse, France. 9. Medical Oncology Unit, Hospital Fernando Foncesca, Amadora, Portugal. 10. Department of Oncology, Santa Maria Degli Angeli General Hospital, Pordenone, Italy. 11. UMRS 776 'Biological Rhythms and Cancers', INSERM, Villejuif Université Paris Sud 11, Orsay Assistance Publique-Hopitaux de Paris, Department of Medical Oncology, Department of Hepatobiliary Center and Radiology, Paul Brousse Hospital, Villejuif, France Cancer Chronotherapy Unit, Warwick Medical School, Coventry, UK. 12. Assistance Publique-Hopitaux de Paris, Department of Medical Oncology, Department of Hepatobiliary Center and Radiology, Paul Brousse Hospital, Villejuif, France. 13. Université Paris Sud 11, Orsay Assistance Publique-Hopitaux de Paris, Department of Medical Oncology, Department of Hepatobiliary Center and Radiology, Paul Brousse Hospital, Villejuif, France. 14. Cancer Chronotherapy Unit, Warwick Medical School, Coventry, UK. 15. Service d'Hépato-Gastro-Entérologie, Hôpital Européen Georges Pompidou, Paris, France Université René Descartes, Paris V, France. 16. Université Paris Sud 11, Orsay Assistance Publique-Hopitaux de Paris, Department of Medical Oncology, Department of Hepatobiliary Center and Radiology, Paul Brousse Hospital, Villejuif, France Service d'Oncologie Digestive, Institut Gustave Roussy, Villejuif.
Abstract
BACKGROUND: Systemic chemotherapy typically converts previously unresectable liver metastases (LM) from colorectal cancer to curative intent resection in ∼15% of patients. This European multicenter phase II trial tested whether hepatic artery infusion (HAI) with triplet chemotherapy and systemic cetuximab could increase this rate to 30% in previously treated patients. PATIENTS AND METHODS: Participants had unresectable LM from wt KRAS colorectal cancer. Main non-inclusion criteria were advanced extra hepatic disease, prior HAI and grade 3 neuropathy. Irinotecan (180 mg/m(2)), oxaliplatin (85 mg/m(2)) and 5-fluorouracil (2800 mg/m(2)) were delivered via an implanted HAI access port and combined with i.v. cetuximab (500 mg/m(2)) every 14 days. Multidisciplinary decisions to resect LM were taken after every three courses. The rate of macroscopic complete resections (R0 + R1) of LM, progression-free survival (PFS) and overall survival (OS) were computed according to intent to treat. RESULTS: The patient population consisted of 42 men and 22 women, aged 33-76 years, with a median of 10 LM involving a median of six segments. Up to 3 extrahepatic lesions of <1 cm were found in 41% of the patients. A median of six courses was delivered. The primary end point was met, with R0-R1 hepatectomy for 19 of the 64 previously treated patients, 29.7% (95% confidence interval 18.5-40.9). Grade 3-4 neutropenia (42.6%), abdominal pain (26.2%), fatigue (18%) and diarrhea (16.4%) were frequent. Objective response rate was 40.6% (28.6-52.3). Median PFS and OS reached 9.3 (7.8-10.9) and 25.5 months (18.8-32.1) respectively. Those with R0-R1 hepatectomy had a median OS of 35.2 months (32.6-37.8), with 37.4% (23.6-51.2) alive at 4 years. CONCLUSION: The coordination of liver-specific intensive chemotherapy and surgery had a high curative intent potential that deserves upfront randomized testing. PROTOCOL NUMBERS: EUDRACT 2007-004632-24, NCT00852228.
BACKGROUND: Systemic chemotherapy typically converts previously unresectable liver metastases (LM) from colorectal cancer to curative intent resection in ∼15% of patients. This European multicenter phase II trial tested whether hepatic artery infusion (HAI) with triplet chemotherapy and systemic cetuximab could increase this rate to 30% in previously treated patients. PATIENTS AND METHODS: Participants had unresectable LM from wt KRAS colorectal cancer. Main non-inclusion criteria were advanced extra hepatic disease, prior HAI and grade 3 neuropathy. Irinotecan (180 mg/m(2)), oxaliplatin (85 mg/m(2)) and 5-fluorouracil (2800 mg/m(2)) were delivered via an implanted HAI access port and combined with i.v. cetuximab (500 mg/m(2)) every 14 days. Multidisciplinary decisions to resect LM were taken after every three courses. The rate of macroscopic complete resections (R0 + R1) of LM, progression-free survival (PFS) and overall survival (OS) were computed according to intent to treat. RESULTS: The patient population consisted of 42 men and 22 women, aged 33-76 years, with a median of 10 LM involving a median of six segments. Up to 3 extrahepatic lesions of <1 cm were found in 41% of the patients. A median of six courses was delivered. The primary end point was met, with R0-R1 hepatectomy for 19 of the 64 previously treated patients, 29.7% (95% confidence interval 18.5-40.9). Grade 3-4 neutropenia (42.6%), abdominal pain (26.2%), fatigue (18%) and diarrhea (16.4%) were frequent. Objective response rate was 40.6% (28.6-52.3). Median PFS and OS reached 9.3 (7.8-10.9) and 25.5 months (18.8-32.1) respectively. Those with R0-R1 hepatectomy had a median OS of 35.2 months (32.6-37.8), with 37.4% (23.6-51.2) alive at 4 years. CONCLUSION: The coordination of liver-specific intensive chemotherapy and surgery had a high curative intent potential that deserves upfront randomized testing. PROTOCOL NUMBERS: EUDRACT 2007-004632-24, NCT00852228.
Authors: Linda M Pak; Nancy E Kemeny; Marinela Capanu; Joanne F Chou; Taryn Boucher; Andrea Cercek; Vinod P Balachandran; T Peter Kingham; Peter J Allen; Ronald P DeMatteo; William R Jarnagin; Michael I D'Angelica Journal: J Surg Oncol Date: 2017-11-22 Impact factor: 3.454
Authors: Annabelle Ballesta; Pasquale F Innominato; Robert Dallmann; David A Rand; Francis A Lévi Journal: Pharmacol Rev Date: 2017-04 Impact factor: 25.468
Authors: Hordur M Kolbeinsson; Randa Preihs; Alexandra Bengel; Sreenivasa Chandana; M Mura Assifi; Mathew H Chung; G Paul Wright Journal: J Gastrointest Oncol Date: 2022-02