Annals of Oncology 13:267-272, 2002
© 2002 European Society for Medical Oncology
Heated intra-operative intraperitoneal oxaliplatin after complete resection of peritoneal carcinomatosis: pharmacokinetics and tissue distribution
Department of Surgical Oncology, Department of Clinical Biology, Department of Pharmacy, Department of Medical Oncology and Biostatistics, Institut Gustave Roussy Comprehensive Cancer Center, France
Received 14 May 2001; revised 25 July 2001; accepted 17 August 2001.
Purpose: This article reports the pharmacokinetics (PK) of heated intra-operative intraperitoneal oxaliplatin and its tolerance profile. Oxaliplatin has demonstrated significant activity in advanced colorectal cancer, and this is the first publication concerning its intraperitoneal administration.
Methods: Twenty consecutive patients with peritoneal carcinomatosis (PC) of either gastrointestinal or uniquely peritoneal origin underwent complete cytoreductive surgery followed by intra-operative intraperitoneal chemo-hyperthermia (IPCH) with increasing doses of oxaliplatin. We performed IPCH using an open procedure (skin pulled upwards), at an intraperitoneal temperature of 42–44°C, with 2 l/m2 of 5% dextrose instillate in a closed circuit. The flow-rate was 2 l/min for 30 min. Patients received intravenous leucovorin (20 mg/m2) and 5-fluorouracil (400 mg/m2) just before the IPCH to maximize the effect of oxaliplatin. We treated at least three patients at each of the six intraperitoneal oxaliplatin dose levels (from 260 to 460 mg/m2) before progressing to the next. We analysed intraperitoneal, plasma and tissue samples with atomic absorption spectrophotometry.
Results: The mean duration of the entire procedure was 8.4 ± 2.7 h. Half the oxaliplatin dose was absorbed in 30 min at all dose levels. Area under the curve (AUC) and maximal plasma concentration (Cmax) increased with dose. At the highest dose level (460 mg/m2), peritoneal oxaliplatin concentration was 25-fold that in plasma. AUCs following intraperitoneal administration were consistently inferior to historical control AUCs after intravenous oxaliplatin (130 mg/m2). Intratumoral oxaliplatin penetration was high, similar to absorption at the peritoneal surface and 17.8-fold higher than that in non-bathed tissues. Increasing instillate volume to 2.5 l/m2 instead of 2 l/m2 dramatically decreased oxaliplatin concentration and absorption. There were no deaths, nor severe haematological, renal or neurological toxicity, but we observed two fistulas and three deep abscesses.
Conclusions: Heated intraperitoneal chemotherapy gives high peritoneal and tumour oxaliplatin concentrations with limited systemic absorption. We recommend an oxaliplatin dose of 460 mg/m2 in 2 l/m2 of 5% dextrose for intraperitoneal chemo-hyperthermia, at a temperature of 42–44°C over 30 min. We may be able to improve these results by increasing the intraperitoneal perfusion duration or by modifying the instillate composition.
Key words: colorectal cancer, cytoreductive surgery, hyperthermia, intraperitoneal chemotherapy, oxaliplatin, peritoneal carcinomatosis
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. Elias, J. H. Lefevre, J. Chevalier, A. Brouquet, F. Marchal, J.-M. Classe, G. Ferron, J.-M. Guilloit, P. Meeus, D. Goere, et al. Complete Cytoreductive Surgery Plus Intraperitoneal Chemohyperthermia With Oxaliplatin for Peritoneal Carcinomatosis of Colorectal Origin J. Clin. Oncol., February 10, 2009; 27(5): 681 - 685. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Marcotte, L. Sideris, P. Drolet, A. Mitchell, S. Frenette, G. Leblanc, Y. E. Leclerc, and P. Dube Hyperthermic Intraperitoneal Chemotherapy with Oxaliplatin for Peritoneal Carcinomatosis Arising from Appendix: Preliminary Results of a Survival Analysis Ann. Surg. Oncol., October 1, 2008; 15(10): 2701 - 2708. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Stewart IV, P. Shen, G. Russell, J. Fenstermaker, L. McWilliams, F. M. Coldrun, K. E. Levine, B. T. Jones, and E. A. Levine A Phase I Trial of Oxaliplatin for Intraperitoneal Hyperthermic Chemoperfusion for the Treatment of Peritoneal Surface Dissemination from Colorectal and Appendiceal Cancers Ann. Surg. Oncol., August 1, 2008; 15(8): 2137 - 2145. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. P. Ceelen, M. Peeters, P. Houtmeyers, C. Breusegem, F. De Somer, and P. Pattyn Safety and Efficacy of Hyperthermic Intraperitoneal Chemoperfusion with High-Dose Oxaliplatin in Patients with Peritoneal Carcinomatosis Ann. Surg. Oncol., February 1, 2008; 15(2): 535 - 541. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Benoit, N. Cheynel, P. Ortega-Deballon, G. Di Giacomo, B. Chauffert, and P. Rat Closed Hyperthermic Intraperitoneal Chemotherapy with Open Abdomen: a Novel Technique to Reduce Exposure of the Surgical Team to Chemotherapy Drugs Ann. Surg. Oncol., February 1, 2008; 15(2): 542 - 546. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Gesson-Paute, G. Ferron, F. Thomas, E. C. de Lara, E. Chatelut, and D. Querleu Pharmacokinetics of Oxaliplatin During Open Versus Laparoscopically Assisted Heated Intraoperative Intraperitoneal Chemotherapy (HIPEC): An Experimental Study Ann. Surg. Oncol., January 1, 2008; 15(1): 339 - 344. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Lim, J. N. Cormier, B. W. Feig, P. F. Mansfield, R. S. Benjamin, J. R. Griffin, J. L. Chase, P. W. T. Pisters, R. E. Pollock, and K. K. Hunt Toxicity and Outcomes Associated with Surgical Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Patients with Sarcomatosis Ann. Surg. Oncol., August 1, 2007; 14(8): 2309 - 2318. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Elias, D. Goere, F. Blot, V. Billard, M. Pocard, N. Kohneh-Shahri, and B. Raynard Optimization of Hyperthermic Intraperitoneal Chemotherapy With Oxaliplatin Plus Irinotecan at 43{degrees}C After Compete Cytoreductive Surgery: Mortality and Morbidity in 106 Consecutive Patients Ann. Surg. Oncol., June 1, 2007; 14(6): 1818 - 1824. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Elias, E. Benizri, D. DiPietrantonio, P. Menegon, D. Malka, and B. Raynard Comparison of Two Kinds of Intraperitoneal Chemotherapy Following Complete Cytoreductive Surgery of Colorectal Peritoneal Carcinomatosis Ann. Surg. Oncol., February 1, 2007; 14(2): 509 - 514. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Elias, G. Liberale, D. Vernerey, M. Pocard, M. Ducreux, V. Boige, D. Malka, J.-P. Pignon, and P. Lasser Hepatic and Extrahepatic Colorectal Metastases: When Resectable, Their Localization Does Not Matter, But Their Total Number Has a Prognostic Effect Ann. Surg. Oncol., November 1, 2005; 12(11): 900 - 909. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Stewart IV, P. Shen, and E. A. Levine Intraperitoneal Hyperthermic Chemotherapy for Peritoneal Surface Malignancy: Current Status and Future Directions Ann. Surg. Oncol., October 1, 2005; 12(10): 765 - 777. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Elias, L. Sideris, M. Pocard, T. de Baere, C. Dromain, N. Lassau, and P. Lasser Incidence of Unsuspected and Treatable Metastatic Disease Associated With Operable Colorectal Liver Metastases Discovered Only at Laparotomy (and Not Treated When Performing Percutaneous Radiofrequency Ablation) Ann. Surg. Oncol., April 1, 2005; 12(4): 298 - 302. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Elias, T. Matsuhisa, L. Sideris, G. Liberale, L. Drouard-Troalen, B. Raynard, M. Pocard, J. M. Puizillou, V. Billard, P. Bourget, et al. Heated intra-operative intraperitoneal oxaliplatin plus irinotecan after complete resection of peritoneal carcinomatosis: pharmacokinetics, tissue distribution and tolerance Ann. Onc., October 1, 2004; 15(10): 1558 - 1565. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Elias, J.-R. Delperro, L. Sideris, E. Benhamou, M. Pocard, O. Baton, M. Giovannini, and P. Lasser Treatment of Peritoneal Carcinomatosis From Colorectal Cancer: Impact of Complete Cytoreductive Surgery and Difficulties in Conducting Randomized Trials Ann. Surg. Oncol., May 1, 2004; 11(5): 518 - 521. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Elias, L. Sideris, M. Pocard, C. Ede, D. Ben Hassouna, M. Ducreux, V. Boige, J. F. Cote, and P. Lasser Efficacy of intraperitoneal chemohyperthermia with oxaliplatin in colorectal peritoneal carcinomatosis. Preliminary results in 24 patients Ann. Onc., May 1, 2004; 15(5): 781 - 785. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. J. Verwaal, S. van Ruth, E. de Bree, G. W. van Slooten, H. van Tinteren, H. Boot, and F. A.N. Zoetmulder Randomized Trial of Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy Versus Systemic Chemotherapy and Palliative Surgery in Patients With Peritoneal Carcinomatosis of Colorectal Cancer J. Clin. Oncol., October 15, 2003; 21(20): 3737 - 3743. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Mohamed, P. Marchettini, O. A. Stuart, M. Urano, and P. H. Sugarbaker Thermal Enhancement of New Chemotherapeutic Agents at Moderate Hyperthermia Ann. Surg. Oncol., May 1, 2003; 10(4): 463 - 468. [Abstract] [Full Text] [PDF]
|
|