Cisplatin tumor concentrations after intra-arterial cisplatin infusion or embolization in patients with oral cancer.
BACKGROUND
One neoadjuvant course of intra-arterial high-dose cisplatin (cis-diamminedichloroplatinum [CDDP]) tumor perfusion combined with intravenous sodium thiosulfate (STS) (cisplatin neutralizer) infusion is part of a multimodality concept for treatment of oral cancer. Recently, crystalline cisplatin embolization has been described as a novel treatment variant with increased tumor response rates.


METHODS
We have compared tumor and plasma concentrations of cisplatin and STS by means of microdialysis in 10 patients with oral cancer treated with intra-arterial cisplatin perfusion (150 mg/m(2) in 500 mL of 0.9% sodium chloride) and 6 patients with oral cancer treated with crystalline cisplatin embolization (150 mg/m(2) in 45-60 mL of 0.9% sodium chloride), respectively. The microdialysis catheter was placed into the tumor, and the intra-arterial catheter into the tumor-feeding artery. Cisplatin was rapidly administered through the intra-arterial catheter and STS (9 g/m(2)) was infused intravenously to reduce the systemic toxicity of cisplatin. STS infusion was started 10 seconds after the cisplatin infusion was started.


RESULTS
After embolization, cisplatin tumor maximum concentration (C(max)) and tumor area under the concentration-time curves (AUCs) were about 5 times higher than those achieved after intra-arterial perfusion (C(max), 180.3 +/- 62.3 micromol/L versus 37.6 +/- 8.9 micromol/L), whereas the opposite was true for plasma concentrations (C(max), 0.9 +/- 0.2 micromol/L versus 4.7 +/- 0.6 micromol/L). STS plasma levels were about 3 times higher than its tumor concentrations (C(max) tumor, 1685 +/- 151 micromol/L; C(max) plasma, 5051 +/- 381 micromol/L). After the standard intra-arterial perfusion, the average STS/CDDP AUC ratios for tumor and plasma were 211 +/- 75 and 984 +/- 139, respectively. After cisplatin embolization, the respective ratios were 48.5 +/- 29.5 and 42966 +/- 26728.


CONCLUSIONS
Molar STS/CDDP ratios of greater than 500 are required outside the tumor to neutralize cisplatin, whereas tumor ratios should be lower than 100 to avoid a loss of tumor cell killing. The first goal is achieved with both treatment modalities and the second only with cisplatin embolization, suggesting that crystalline cisplatin embolization is superior to intra-arterial cisplatin perfusion in terms of tumor cisplatin concentrations. Whether this translates into higher tumor response rates needs to be investigated further.
Tegeder
Irmgard
I
Pharmazentrum Frankfurt, Klinik und Poliklinik für Kiefer und Plastische Gesichtschirugie, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany. tegeder@em.uni-frankfurt.de
Bräutigam
Lutz
L
Seegel
Maic
M
Al-Dam
Ahmed
A
Turowski
Bernd
B
Geisslinger
Gerd
G
Kovács
Adorján F
AF
D000328:Adult; D000368:Aged; D000931:Antidotes / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D002138:Calibration; D002404:Catheterization; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004621:Embolization, Therapeutic; D005260:Female; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D017551:Microdialysis; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D018307:Neoplasms, Squamous Cell / Q000188:drug therapy / Q000378:metabolism*; D010984:Platinum / Q000097:blood; D013885:Thiosulfates / Q000627:therapeutic use
D000931:Antidotes; D000970:Antineoplastic Agents; D013885:Thiosulfates; D010984:Platinum; C017717:sodium thiosulfate; D002945:Cisplatin