Intrapleural cisplatin and mitomycin for malignant mesothelioma following pleurectomy: pharmacokinetic studies

Our plain-English summary of Intrapleural cisplatin and mitomycin for malignant mesothelioma following pleurectomy: pharmacokinetic studies, by V.W. Rusch, D. Niedzwiecki, Y. Tao, et al (Journal of Clinical Oncology, 1992).

The study

• Authors: V.W. Rusch, D. Niedzwiecki, Y. Tao, C. Menendez-Botet, A. Dnistrian, D. Kelsen, L. Saltz, M. Markman
• Journal: Journal of Clinical Oncology
• Published: 1992;10(6):1001-6
• Cited by: 88 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Purpose: Intrapleural cisplatin-based chemotherapy has been used in the treatment of patients with malignant pleural mesothelioma and malignant pleural effusions, but the pharmacokinetics of this form of chemotherapy have not been previously evaluated. We performed pharmacokinetic studies on 12 patients who received both intrapleural cisplatin and mitomycin immediately following pleurectomy/decortication for malignant pleural mesothelioma.

Patients And Methods: Simultaneous pleural fluid and plasma samples were collected at 15 and 30 minutes, and at 1, 2, 3, 4, and 24 hours after administration of the intrapleural chemotherapy (cisplatin 100 mg/m2 and mitomycin 8 mg/m2), and after cisplatin (total and free) and mitomycin levels were measured. The mean peak levels, the areas under the concentration-time curve (AUC) and the drug half-lives (t1/2s) in plasma and pleural fluid were compared using the paired t test. Differences were considered significant if P less than or equal to .05.

Results: Systemic absorption was rapid, with peak plasma levels being reached within 1 hour of administration of the intrapleural chemotherapy. Peak plasma levels measured after intrapleural chemotherapy approximated those reportedly attained during systemic administration of these drugs at similar doses. However, the mean peak cisplatin and mitomycin levels, and their mean AUCs, were significantly higher in the pleural fluid than in the plasma. There was a three- to fivefold advantage (on a logarithmic scale) for pleural to plasma AUCs for both cisplatin and mitomycin. The mean t1/2s for cisplatin and mitomycin were significantly longer in the plasma than in the pleural fluid.

Conclusions: The pharmacokinetics of intrapleural cisplatin-based chemotherapy are analogous to those of intraperitoneal chemotherapy. Our findings show that intrapleural cisplatin-based chemotherapy has a distinct local pharmacologic advantage, but also produces significant and sustained drug plasma levels.

In plain English

This study measured how two chemotherapy drugs, cisplatin and mitomycin, behaved in the body when placed directly into the chest cavity. The 12 patients had malignant pleural mesothelioma and were enrolled in an ongoing phase II trial at Memorial Sloan-Kettering Cancer Center in New York. Immediately after surgery to remove the pleura and visible tumor (pleurectomy/decortication), cisplatin 100 mg/m2 and mitomycin 8 mg/m2 were instilled into the pleural space. Pleural fluid and blood plasma were sampled at set times up to 24 hours. Both drugs entered the bloodstream quickly, with peak plasma levels within 1 hour in all patients. Total drug exposure over time (AUC) was much higher in pleural fluid than in plasma. For total platinum the mean was 1,841.0 in pleural fluid versus 64.2 µg/mL/h in plasma. Drug half-lives were longer in plasma than in pleural fluid, for example 27.8 versus 4.0 hours for total platinum. The authors concluded that this treatment has a distinct local drug advantage but also produces significant and sustained blood drug levels. The article does not discuss asbestos.

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 carried out within a prospective phase II treatment trial
• Who was studied: 12 patients with resectable malignant pleural mesothelioma treated with pleurectomy/decortication at Memorial Sloan-Kettering Cancer Center, New York. The article gives no study dates; it was submitted in November 1991.
• Exposure: The exposure studied was chemotherapy, not asbestos: intrapleural cisplatin 100 mg/m2 and mitomycin 8 mg/m2, each in 100 mL normal saline, given into the pleural space right after surgery and retained for 4 hours. The article does not address asbestos exposure.
• Main results:
  • Both drugs were absorbed into the bloodstream rapidly. Peak plasma levels were reached within 1 hour in all patients.
  • Peak levels were higher in pleural fluid than in plasma. The mean difference was 273.2 plus or minus 41 µg/mL for total platinum (P less than .001), 231 plus or minus 46 µg/mL for free platinum (P less than .001), and 17,429.4 plus or minus 2,356 µg/mL for mitomycin (P less than .001).
  • Mean AUC for total platinum was 1,841.0 plus or minus 1,351.5 µg/mL/h in pleural fluid, compared with 64.2 plus or minus 30.5 µg/mL/h in plasma. Patient 9 was excluded from the means.
  • Mean AUC for free platinum was 1,252.2 plus or minus 1,469.7 µg/mL/h in pleural fluid and 26.3 plus or minus 14.2 µg/mL/h in plasma.
  • Mean AUC for mitomycin was 128,994.7 plus or minus 79,325.9 µg/mL/h in pleural fluid, compared with 659.1 plus or minus 278.6 in plasma.
  • On a logarithmic scale, mean pleural-to-plasma AUC ratios were three times greater for total and free platinum and five times greater for mitomycin. The pleural–plasma differences were statistically significant: P = .0001 for total platinum, P = .0004 for free platinum, and P = .0001 for mitomycin.
  • Mean half-lives were longer in plasma than in pleural fluid. For total platinum they were 27.8 plus or minus 14.3 hours in plasma versus 4.0 plus or minus 1.3 hours in pleural fluid (P = .0003). For free platinum they were 23.5 plus or minus 13.0 hours versus 2.9 plus or minus 0.7 hours (P = .009).
  • Mitomycin mean half-life was 5.5 plus or minus 4.0 hours in plasma and 2.3 plus or minus 1.0 hours in pleural fluid (P = .05).
• The authors' conclusion: The authors concluded that the pharmacokinetics of intrapleural cisplatin-based chemotherapy are analogous to those of intraperitoneal chemotherapy. In their view, it has a distinct local pharmacologic advantage but also produces significant and sustained plasma drug levels. They suggested this supports using the same precautions as for intravenous cisplatin (for example prehydration), and that patients may remain at risk for kidney toxicity for longer.
• Limitations the authors state:
  • Patient 9 was excluded from the AUC means because only two samples (at 15 and 30 minutes) were available.
  • Half-life means were calculated on fewer than 12 patients (9 to 11, depending on the measure) because data were not available at all time points. Patient 3 was also excluded from one plasma free-platinum value because of poor regression.

Topics

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

Medical terms in this study, explained in our Lexicon: Cisplatin, Malignant Mesothelioma, Chemotherapy, Pleural Mesothelioma, Pleural Effusion, Pleurectomy/Decortication (P/D).

Related studies

• A phase II trial of pleurectomy/decortication followed by intrapleural and systemic chemotherapy for malignant pleural mesothelioma — V. Rusch, L. Saltz, et al. (1994)
• Pharmacokinetic evaluation of intrapleural perfusion with hyperthermic chemotherapy using cisplatin in patients with malignant pleural effusion — H. Sakaguchi, H. Ishida, et al. (2017)
• Interim results of pleurectomy/decortication and intraoperative intrapleural hyperthermic cisplatin perfusion for patients with malignant pleural mesothelioma intolerable to extrapleural pneumonectomy — H. Ishibashi, M. Kobayashi, et al. (2015)
• Pleurectomy/decortication and hyperthermic intrapleural chemotherapy for malignant pleural mesothelioma: initial experience — M. Migliore, D. Calvo, et al. (2015)
• Optimal management of malignant mesothelioma after subtotal pleurectomy: revisiting the role of intrapleural chemotherapy and postoperative radiation — E.R. Sauter, C. Langer, et al. (1995)
• Cytoreductive surgery with intraperitoneal hyperthermic chemotherapy for malignant peritoneal mesothelioma: mitomycin versus cisplatin — A.U. Blackham, P. Shen, et al. (2010)

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