title: Acute and delayed toxicity of gemcitabine administered during isolated lung perfusion: a preclinical dose-escalation study in pigs.
abstract: OBJECTIVE
  Colorectal cancer is the third most commonly diagnosed cancer worldwide, with up to 25% of patients presenting with metastases at the time of diagnosis. Despite pulmonary metastasectomy many patients go on to develop pulmonary recurrence, which might be linked to the presence of lung micrometastases. In this setting, the adjuvant administration of high-dose chemotherapy by isolated lung perfusion (ILP) has shown encouraging results. However, the tolerance to and efficacy of modern gemcitabine (GEM)-based chemotherapy regimens during adjuvant ILP remain unknown. We conducted a dose-escalating preclinical study to evaluate the immediate and delayed toxicity of GEM in a pig model to define dose-limiting toxicity (DLT) and maximum tolerated concentration.
  
  
  METHODS
  Twenty-three pigs were given increasing concentrations of GEM during ILP, and were awakened at the end of the procedure. The concentrations of GEM were 40, 80, 160, 320, 640 and 1280 µg/ml. Serum and lung samples were taken to measure GEM concentrations. Pulmonary damage was evaluated by histological examination and cleaved caspase-3 detection. Immediate and delayed (1 month) toxicity were recorded.
  
  
  RESULTS
  All of the animals underwent successful ILP with GEM. No systemic leak was observed. The three pigs that received a concentration of GEM of 1280 µg/ml died of hypoxia after lung recirculation at the end of the procedure. Eleven pigs survived for 1 month. Major lung toxicity was observed for the concentration of GEM of 640 µg/ml, both at the end of the procedure and after 1 month. DLT was defined at the concentration of 640 µg/ml and the maximum tolerated dose (MTD) was defined at the concentration of 320 µg/ml.
  
  
  CONCLUSIONS
  ILP with GEM is a safe and reproducible technique in this large-animal model, which includes 1 month of survival. The MTD in this pig model was a concentration of GEM of 320 µg/ml.
authors.affiliation: INSERM UMR 866, CHU Bocage, University of Burgundy, Dijon, France Department of Thoracic and Cardiovascular Surgery, CHU Bocage, University of Burgundy, Dijon, France pierrebenoit.pages@chu-dijon.fr pb.pages@live.fr.
authors.forename: Pierre-Benoit
authors.initials: PB
authors.lastname: Pagès
authors.affiliation: INSERM UMR 866, CHU Bocage, University of Burgundy, Dijon, France.
authors.forename: Valentin
authors.initials: V
authors.lastname: Derangere
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, CHU Bocage, University of Burgundy, Dijon, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Bouchot
authors.affiliation: Department of Anesthesiology, CHU Bocage, University of Burgundy, Dijon, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Magnin
authors.affiliation: Department of Pathology, Georges-Francois Leclerc Center, University of Burgundy, Dijon, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Charon-Barra
authors.affiliation: Department of Pharmacology, Centre René Huguenin, Saint-Cloud, France.
authors.forename: François
authors.initials: F
authors.lastname: Lokiec
authors.affiliation: INSERM UMR 866, CHU Bocage, University of Burgundy, Dijon, France Department of Medical Oncology, Georges-Francois Leclerc Center, University of Burgundy, Dijon, France.
authors.forename: François
authors.initials: F
authors.lastname: Ghiringhelli
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, CHU Bocage, University of Burgundy, Dijon, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Bernard
mesh_terms: D000208:Acute Disease; D055371:Acute Lung Injury / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D000768:Anesthesia, General / Q000379:methods; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000009:adverse effects* / Q000379:methods; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary*; D034421:Sus scrofa; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: Colorectal cancer; Gemcitabine; Isolated lung perfusion; Lung metastases