Intraoperative hyperthermic chemotherapy perfusion for malignant pleural mesothelioma: an in vitro evaluation

Our plain-English summary of Intraoperative hyperthermic chemotherapy perfusion for malignant pleural mesothelioma: an in vitro evaluation, by R.B. Cameron, D. Hou (The Journal of Thoracic and Cardiovascular Surgery, 2013).

The study

• Authors: R.B. Cameron, D. Hou
• Journal: The Journal of Thoracic and Cardiovascular Surgery
• Published: 2013;145(2):496-504
• Cited by: 25 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objectives: Hyperthermic chemotherapy perfusion has been used in the treatment of both pleural and peritoneal mesothelioma without an extensive basic science foundation. Clinical data are limited with no prospective randomized trials to support the use of this potentially toxic therapy. We sought to generate basic scientific support for this clinical practice and to define the optimal conditions for use in future clinical trials.

Methods: Growth of a variety of in vitro established cell lines, including a hyperthermia-sensitive Chinese hamster ovary (CHO)-K1 cell line, a normal lung fibroblast line (MRC-5), a lung cancer line (A549), and 3 human mesothelioma cell lines (NCI-H28, NCI-H2052, and MSTO-211H), was assessed using a novel tetrazolium compound (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt [MTS]) and an electron coupling reagent (phenazine methosulfate), which measures the absorbance at 490 nm of a formazan product reduced from MTS by living cells (MTS metabolic assay), or a standard dilution clonogenic assay, which enumerates colony-forming units of more than 50 cells. Each cell line was plated into flasks and then exposed to varying combinations of chemotherapy agents and hyperthermia (37°C-45°C). The cells then were harvested and assessed in either assay. The role of chemotherapeutic agents currently most commonly used in clinical practice, including cisplatin, gemcitabine, and pemetrexed, was assessed with and without simultaneous heat exposure.

Results: Conditions initially were explored using hyperthermia alone in CHO-K1, A549, and NCI-H28 cell lines using temperatures of 37°C, 42°C, and 45°C for 20, 40, and 60 minutes, respectively. This showed a reproducible dose-response curve in CHO-K1 cells with increasing temperature producing lower survival to only 1.5% of the control at 45°C for 60 minutes (P < .01). The A549 cells also showed a response but only at the highest temperature, and the NCI-H28 cells showed a more modest reduction to 65% at 45°C for 60 minutes (P < .01). When the 2 assays were directly compared, the MTS assay failed to detect differences between groups and therefore was discontinued from the remainder of these experiments. Next, hyperthermia was limited to the physiologic limit of 42°C, and the addition of chemotherapy was assessed. Doses were chosen on the basis of prior pharmacokinetic data from studies showing a maximum tissue/blood level of 200 ng/mL for cisplatin pleural instillation and were thought to more accurately reflect actual tumor levels. Cisplatin alone modestly reduced the clonogenic potential to 26%, 16.4%, and 13.6% at 42°C, respectively, for 60 minutes (P < .01); however, this was only a further reduction of 29.6%, 33.8%, and 34.2%, respectively, from the cisplatin alone control. Therefore, most of the reduction was attributable to chemotherapy and not hyperthermia. With combinations of cisplatin/gemcitabine and cisplatin/pemetrexed, the effect was larger, with reduction to 9.6%, 0%, and 0%, respectively (P < .01) (incremental reduction of 16.5%, 0%, and 0%, respectively, due to hyperthermia). Cisplatin/pemetrexed produced essentially identical results.

Conclusions: Intrapleural chemotherapy seems to be most effective when using 2 drug combinations. All mesothelioma cell lines showed no particular sensitivity to heat. The use of hyperthermia alone or with chemotherapy produces at best only a modest effect and does not necessarily support its current clinical use.

Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

In plain English

This laboratory study tested whether heat, alone or with chemotherapy, kills malignant pleural mesothelioma cells in culture. The authors first heated one mesothelioma cell line, a heat-sensitive hamster line and a lung cancer line at 37, 42 or 45 degrees C for up to 60 minutes. They then heated three mesothelioma lines and three comparison lines, including normal lung cells, at 42 degrees C. Some cells also received cisplatin alone, or cisplatin combined with pemetrexed or gemcitabine. No asbestos exposure or patients were studied. At 45 degrees C for 60 minutes, survival of the mesothelioma line fell to 65%, a smaller drop than in the lung cancer line. With heat alone at 42 degrees C, none of the mesothelioma lines showed a statistically meaningful drop. With cisplatin at 42 degrees C, most of the cell killing came from the drug, not the heat. Two-drug combinations cut mesothelioma cell survival to between 0% and 9.6%; heat added only 0% to 28.4% to their effect. The authors concluded that, under current clinical conditions, heat with or without chemotherapy had at best a modest effect.

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: Laboratory (in vitro) experiment on cultured cell lines
• Who was studied: Six established cell lines from the American Type Culture Collection. Three were human mesothelioma lines (NCI-H28, NCI-H2052, MSTO-211H). The comparison lines were a heat-sensitive Chinese hamster ovary line (CHO-K1), a normal human lung fibroblast line (MRC-5) and a human lung cancer line (A549). No patients or animals were studied. Only CHO-K1, A549 and NCI-H28 were tested at all three temperatures. All six lines were tested at 42 degrees C.
• Exposure: Heat (hyperthermia) at 37, 42 or 45 degrees C for 0 to 60 minutes. Some cells also received the chemotherapy drugs cisplatin, cisplatin plus pemetrexed, or cisplatin plus gemcitabine. No asbestos exposure was studied.
• Main results:
  • The first experiment tested heat alone at 37, 42 and 45 degrees C on three lines only: CHO-K1, A549 and the NCI-H28 mesothelioma line.
  • With heat alone at 45 degrees C for 60 minutes, survival fell to 1.5% of control in the heat-sensitive CHO-K1 hamster cells and to 65% in the NCI-H28 mesothelioma cells. The A549 lung cancer cells responded only at the highest temperature.
  • With heat alone at 42 degrees C, tested across all six cell lines, none of the three mesothelioma cell lines showed a statistically meaningful reduction in survival, even after 60 minutes.
  • At 45 degrees C, the heat effect was more marked in the lung cancer line than in the NCI-H28 mesothelioma line. The authors wrote that the mesothelioma cell lines may, if anything, be more resistant to heat.
  • With the highest cisplatin concentration at 42 degrees C for 60 minutes, survival of the three mesothelioma lines (NCI-H28, NCI-H2052, MSTO-211H) fell to 26%, 16.4% and 13.6% respectively. The authors attributed most of this reduction to the chemotherapy rather than the heat.
  • Cisplatin plus gemcitabine with heat reduced survival of the three mesothelioma lines (NCI-H28, NCI-H2052, MSTO-211H) to 9.6%, 0% and 0% respectively.
  • Cisplatin plus pemetrexed with heat reduced survival of the three mesothelioma lines to 0%, 7.2% and 4.5% respectively.
  • At 42 degrees C for 60 minutes, heat added between 0% and 28.4% to the effect of the two-drug platinum-based combinations.
  • The MTS metabolic assay detected no differences between experimental conditions, so the authors dropped it and used the clonogenic (colony-counting) assay instead.
• The authors' conclusion: The authors concluded that, under current clinical conditions, heat alone or with chemotherapy produced only a modest effect at best.
• Limitations the authors state:
  • Results in flat layers of cultured cells do not necessarily predict what happens in three-dimensional tumors and normal tissues.
  • Heat-induced inflammation, immune responses and changes in blood vessels do not occur in cell cultures and could not be measured.

Topics

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

Medical terms in this study, explained in our Lexicon: Chemotherapy, Pleural Mesothelioma, Peritoneal Mesothelioma, Clinical Trial, Fibroblast, Lung Cancer, Mesothelioma, Cisplatin.

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• 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)
• Cytoreductive surgery and hyperthermic intrathoracic chemotherapy perfusion for malignant pleural tumours: perioperative management and clinical experience — M. Ried, T. Potzger, et al. (2013)
• Malignant peritoneal mesothelioma treated by continuous hyperthermic peritoneal perfusion chemotherapy — E. de Bree, M. Christodoulakis, et al. (2000)
• PI3K/mTOR signaling in mesothelioma patients treated with induction chemotherapy followed by extrapleural pneumonectomy — B.K. Bitanihirwe, M. Meerang, et al. (2014)
• 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)

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