Pharmacokinetics of doxorubicin and cisplatin used in intraoperative hyperthermic intrathoracic chemotherapy after cytoreductive surgery for malignant pleural mesothelioma and pleural thymoma

Our plain-English summary of Pharmacokinetics of doxorubicin and cisplatin used in intraoperative hyperthermic intrathoracic chemotherapy after cytoreductive surgery for malignant pleural mesothelioma and pleural thymoma, by S. van Ruth, O. van Tellingen, C.M. Korse, et al (Anti-cancer Drugs, 2003).

The study

• Authors: S. van Ruth, O. van Tellingen, C.M. Korse, V.J. Verwaal, F.A. Zoetmulder
• Journal: Anti-cancer Drugs
• Published: 2003;14(1):57-65
• Cited by: 30 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Cytoreductive surgery combined with intraoperative hyperthermic intrathoracic chemotherapy (HITHOC) is studied in a phase I study in the treatment of malignant pleural mesothelioma and pleural thymoma. We studied the pharmacokinetics of doxorubicin and cisplatin used during the HITHOC procedure. Furthermore, the penetration characteristics of doxorubicin were examined. Between 1998 and 2001, 24 perfusions were performed with a solution containing doxorubicin and cisplatin for 90 min at 40-41 degrees C. The dose was first based on square meters body surface, whereas in later studies a fixed concentration of the perfusion fluid was used. Samples of blood and perfusion fluid were collected for doxorubicin and cisplatin measurements. The penetration characteristics of doxorubicin in tissue were determined by fluorescence microscopy. The mean AUC(perfusate):AUC(plasma) ratios for doxorubicin and cisplatin (ultrafiltration for plasma) were 99 and 59, respectively. During perfusion the concentration in the perfusate declined essentially according to first-order elimination kinetics for both doxorubicin and cisplatin with half-lives of 74 and 138 min, respectively. At the end of the perfusion, about 35 and 52% of the dose of doxorubicin and cisplatin, respectively, was recovered in the perfusion fluid. One patient developed a nephrotoxicity grade II. No leukopenia or hair loss was seen. Doxorubicin penetrated into the intercostal muscle specimen, albeit that there was considerable variation in distribution throughout the specimen. We conclude that HITHOC with doxorubicin and cisplatin is relatively a safe procedure with the advantage of high intrathoracic cytostatic drug concentrations, while having limited systemic side effects.

Copyright 2003 Lippincott Williams & Wilkins

In plain English

This pharmacokinetic study was part of a phase I trial in Amsterdam. Between 1998 and 2001, 23 patients (20 with malignant pleural mesothelioma, three with pleural thymoma) had 24 procedures: surgery to remove visible tumor, then heated fluid containing doxorubicin and cisplatin circulated through the chest for a planned 90 minutes. Drug exposure over time (area under the curve) was far higher in chest fluid than blood: mean ratios were 99 for doxorubicin and 59 for cisplatin. The authors thought the cisplatin figure probably overestimated. By the end, about 35% of the doxorubicin dose, and in the last six patients 52% of the cisplatin dose, remained in the fluid. The first patient had temporary grade II kidney toxicity; no hair loss or low white-cell counts occurred. Major surgical complications affected 14 patients (58%); none died within 30 days. Doxorubicin reached chest-wall muscle unevenly; in tumor from two patients it was mainly in the outer rim, with some clusters farther in. The authors concluded the procedure was relatively safe, with high drug levels in the chest and limited exposure elsewhere.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Pharmacokinetic study within a phase I clinical treatment study (cytoreductive surgery followed by intraoperative hyperthermic intrathoracic chemotherapy, HITHOC)
• Who was studied: 23 patients (20 with malignant pleural mesothelioma, 3 with pleural thymoma; 19 males, 4 females) who had 24 procedures at the Netherlands Cancer Institute, Amsterdam, 1998 to 2001. One thymoma patient was treated twice for recurrence on the other side.
• Exposure: Not asbestos exposure. The article studied the chemotherapy drugs doxorubicin and cisplatin, circulated in heated fluid (40 to 41 degrees C) through the chest for a planned 90 minutes. The first 18 procedures used cisplatin 80 mg/m2 and doxorubicin starting at 15 mg/m2, rising in 5 mg/m2 steps. The last six patients received fixed concentrations: doxorubicin 18 or 21 mg/l and cisplatin 40 mg/l.
• Main results:
  • One of the 24 perfusions was stopped after 80 minutes instead of the planned 90, because the patient became hemodynamically unstable.
  • The mean ratio of the area under the concentration-time curve (AUC) in the chest perfusion fluid to the AUC in plasma was 99 for doxorubicin and 59 for cisplatin. For cisplatin, the plasma measurement was in ultrafiltrate.
  • Cisplatin in plasma ultrafiltrate was measured only in the last six patients, and only during the 90-minute perfusion.
  • The authors considered the cisplatin ratio of 59 probably an overestimate.
  • In the perfusion fluid, the doxorubicin and cisplatin levels fell with half-lives of about 74 and 138 minutes. By the end of perfusion, about 35% of the doxorubicin dose and 52% of the cisplatin dose was recovered in the fluid. The cisplatin figures come from the last six patients, who received a fixed concentration.
  • At the highest doxorubicin concentration (21 mg/l), the authors calculated that systemic exposure was only 1/10 to 1/15 of that reported after a therapeutic intravenous dose. The intravenous figure comes from other studies.
  • Systemic toxicity occurred only in the first patient, as transient grade II nephrotoxicity. No leukopenia or hair loss was observed.
  • Major surgical complications occurred in 14 patients (58%). There was no 30-day mortality.
  • Doxorubicin was seen in intercostal muscle cells in all examined cases, but its penetration was not uniform throughout the tissue.
  • Residual tumor was resected for analysis in two patients.
  • In the tumor sample, doxorubicin was detected in the outer rim, although some clusters of doxorubicin-containing nuclei were also found in some areas farther from the surface.
  • No relation was found between drug exposure in perfusate or plasma and either the volume of perfusion fluid or whether a pneumonectomy was performed.
• The authors' conclusion: The authors concluded that HITHOC with doxorubicin and cisplatin is a relatively safe procedure that gives high drug concentrations in the chest with limited systemic exposure. They also preferred dosing based on a fixed concentration in the perfusion fluid.
• Limitations the authors state:
  • Results of the first four procedures were excluded because of technical problems in sample collection.
  • A late plasma sample needed to calculate the doxorubicin elimination half-life accurately was missing in a number of patients.
  • For cisplatin, only plasma exposure during the 90-minute perfusion was available, not total exposure.
  • The lack of a relation between plasma exposure and pneumonectomy may be due to the limited number of patients.
  • Nausea and vomiting were not scored, because they could not be separated from post-operative symptoms.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Doxorubicin, Cisplatin, Intrathoracic, Chemotherapy, Cytoreductive Surgery, Pleural Mesothelioma, Nephrotoxicity.

Related studies

• Cytoreductive surgery and intraoperative hyperthermic intrathoracic chemotherapy in patients with malignant pleural mesothelioma or pleural metastases of thymoma — E. de Bree, S. van Ruth, et al. (2002)
• Local and systemic exposure of cisplatin during hyperthermic intrathoracic chemotherapy perfusion after pleurectomy and decortication for treatment of pleural malignancies — M. Ried, T. Potzger, et al. (2013)
• Cytoreductive surgery and hyperthermic intrathoracic chemotherapy perfusion for malignant pleural tumours: perioperative management and clinical experience — M. Ried, T. Potzger, et al. (2013)
• Acute kidney injury after cytoreductive surgery and hyperthermic intraoperative cisplatin chemotherapy for malignant pleural mesothelioma — T. Hod, K.J. Freedberg, et al. (2021)
• Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among low-risk patients with malignant pleural mesothelioma undergoing surgical macroscopic complete resection — D.J. Sugarbaker, R.R. Gill, et al. (2013)
• Anesthetic management and renal function in pediatric patients undergoing cytoreductive surgery with continuous hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin — P. Owusu-Agyemang, R. Arunkumar, et al. (2012)

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