Application of cisplatin as intraoperative hyperthermic peritoneal lavage (IHPL) in patients with locally advanced gastric cancer: analysis of pharmacokinetics and of nephrotoxicity.
The purpose of this study was to assess the extent of the systemic absorption of cisplatin during intraoperative hyperthermic peritoneal lavage (IHPL) in patients with locally advanced gastric cancer.


METHODS
The pharmacokinetics and nephrotoxicity of cisplatin were analyzed in patients receiving IHPL (8000 ml of Ringer's solution containing 150 mg/m2 cisplatin and 15 mg/m2 mitomycin C for one hour at 43.5 degrees C). Levels of ultrafiltrable platin were determined by flameless atomic absorption spectrometry. Nephrotoxicity was assessed by nephelometric analyses of urinary marker-proteins. The data were compared to respective analyses in patients receiving intravenous cisplatin.


RESULTS
Twenty-four patients received five applications of cisplatin as IHPL (five patients) and 53 applications of intravenous cisplatin (21 patients). Platin levels within the lavage fluid declined monophasically (half-life, 0.48 +/- 10 hours; area under curve (AUC) 29,274 +/- 9075 ng/ml*h). The pharmacokinetic parameters calculated for IHPL vs. intravenous application of cisplatin were: maximum plasma levels 2392 +/- 407 vs. 1349 +/- 692 ng/ml; terminal half-lives 93 +/- 73 vs. 36 +/- 9 hours; AUC 9508 +/- 856 vs. 11,627 +/- 3372 ng/ml*h; total urinary excretion of platinum 24 +/- 6 vs. 49 +/- 13% of dose; renal clearance 127 +/- 34 vs. 145 +/- 35 ml/min. Pathologic urinary albumin excretion occurred on days 9 +/- 0 vs. 5 +/- 2 (maximum 232 +/- 179 vs. 20 +/- 20 mg/l). Plasma creatinine levels rose to 1.5 +/- 0.4 vs. 0.9 +/- 0.1 mg/dl on days 15 +/- 4 vs. 16 +/- 26. The degree of albuminuria was related to the clearance of platin from the lavage fluid (p = 0.048).


CONCLUSIONS
A significant amount of intraperitoneally applied cisplatin is available systemically and probably adds to the nephrotoxicity of IHPL.
Kern
Wolfgang
W
University Hospital Grosshadern, Department of Internal Medicine III, Ludwig-Maximilians-University, 81366 München, Germany. wolfgang.kern@med3.med.uni-muenchen.de
Braess
Jan
J
Kotschofsky
Marion
M
Samel
Stefan
S
Becker
Heinz
H
Hiddemann
Wolfgang
W
Schleyer
Eberhard
E
D000042:Absorption; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods*; D007275:Injections, Intravenous; D007430:Intraoperative Care / Q000379:methods; D007674:Kidney Diseases / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism; D010533:Peritoneal Lavage / Q000379:methods; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000601:surgery; D013736:Testicular Neoplasms / Q000188:drug therapy / Q000378:metabolism
D000970:Antineoplastic Agents; D016685:Mitomycin; D002945:Cisplatin