Combined hyaluronate-based films loaded with pemetrexed and cisplatin for the treatment of malignant pleural mesothelioma: Preliminary evaluation in an orthotopic tumor recurrence model

Our plain-English summary of Combined hyaluronate-based films loaded with pemetrexed and cisplatin for the treatment of malignant pleural mesothelioma: Preliminary evaluation in an orthotopic tumor recurrence model, by F. Sonvico, S. Barbieri, P. Colombo, et al (European Journal of Pharmaceutical Sciences, 2018).

The study

• Authors: F. Sonvico, S. Barbieri, P. Colombo, E. Barocelli, C. Mucchino, A.M. Cantoni, P.G. Petronini, M. Rusca, P. Carbognani, L. Ampollini
• Journal: European Journal of Pharmaceutical Sciences
• Published: 2018;123:89-97
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is a rare malignancy characterized by a long latency period of 20-50 years after exposure to the main aetiology agent that is asbestos. MPM treatments include surgery, chemotherapy, and radiation therapy, with the combination pemetrexed and cisplatin being the standard chemotherapy approach. Despite this multimodality therapy one of the major issues after surgery is the high rate of local recurrence of the tumor. One possible approach would be the intrapleural application of implants loaded with anticancer drug to be applied during surgery to prevent local tumor recurrence. The implant proposed in the present work is a polymeric film of hyaluronic acid loaded with pemetrexed. The film developed is a hydrophilic, thin and flexible film sufficiently resistant to be applied intrapleurally adhering to the mesothelial surface. The release of pemetrexed from the film was found to be complete within2 h in phosphate buffered saline. In an orthotopic model of mesothelioma recurrence in rats, pemetrexed loaded films showed the same antitumor efficacy of pemetrexed disodium solutions administered intravenously or intrapleurally, while when administered in combination with cisplatin-loaded hyaluronate film, the implants almost completely prevented tumor recurrence. The local administration of drug-loaded polymer implants appears an ideal chemotherapy strategy especially for patients in which surgery is already selected as a viable therapeutic option.

Copyright © 2018 Elsevier B.V. All rights reserved.

In plain English

This was a laboratory and animal study. It did not study people or asbestos exposure. University of Parma authors made thin hyaluronic acid films carrying the cancer drug pemetrexed. The films are meant to be laid in the chest during surgery for malignant pleural mesothelioma to prevent regrowth. Films with 20% pemetrexed formed drug crystals, so only 2% films were tested further. In lab solution these released nearly 80% of their drug within an hour. Thirty male rats had tumors, grown from rat cell line IL-45 (derived from asbestos-induced peritoneal mesothelioma), surgically removed. The rats were randomly assigned to five treatments, given after surgery. Six days after treatment, rats given drug-free films averaged over 2000 cubic millimetres of regrown tumor; all treatments significantly reduced tumor volume. Pemetrexed films (average 216 cubic millimetres) did not differ significantly from pemetrexed into a vein (557) or into the chest (997). Combined pemetrexed and cisplatin films gave an average regrown tumor volume of 1.7 cubic millimetres (standard error of the mean 1.6), with no visible tumor in 4 of 6 rats. The authors noted their preliminary experiments used few animals.

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 formulation study of drug-loaded films plus an animal experiment in an orthotopic rat model of mesothelioma recurrence after surgery
• Who was studied: 30 male Fisher 344 inbred rats (280-300 g), University of Parma, Italy, randomly assigned to five treatment groups. Tumors were grown from the IL-45 rat mesothelioma cell line, derived from asbestos-induced peritoneal mesothelioma in rats, injected under the pleura.
• Exposure: Not an asbestos exposure study. After tumor removal and pneumonectomy, the five groups received: drug-free (blank) hyaluronate films; pemetrexed 10 mg/kg into a vein; pemetrexed 10 mg/kg into the chest cavity; pemetrexed-loaded films (2% w/w, 10 mg/kg); or pemetrexed films combined with cisplatin-loaded films (cisplatin 3 mg/kg).
• Main results:
  • Films with a high pemetrexed load (20% w/w) were covered in drug crystals, so only the 2% w/w films were used further.
  • In laboratory release tests, the 2% pemetrexed films released nearly 80% of the drug in the first hour, and release levelled off from the second hour.
  • In the group given blank (drug-free) films, the recurrent tumor volume (reported as a group mean) was larger than 2000 mm3 at the end of the experiment.
  • All treatments significantly reduced recurrent tumor volume compared with blank films.
  • Mean recurrence volume was 216 mm3 with pemetrexed films, 557 mm3 with intravenous pemetrexed and 997 mm3 with intrapleural pemetrexed. These differences were not statistically significant.
  • With combined pemetrexed and cisplatin films, the average recurrence volume was 1.7 mm3, with a standard error of the mean of 1.6 mm3 (the article reports tumor volumes as mean and standard error of the mean).
  • The combined-film volume was significantly lower than that of the blank-film control and of intrapleural pemetrexed.
  • In the combined-film group, no visible tumor recurrence was found in 4 of the 6 treated rats.
  • Pemetrexed in blood serum was below the detection limit from 24 to 144 hours. Cisplatin in the combined-film group stayed above 1000 ng/ml up to 72 hours.
• The authors' conclusion: The authors concluded that, in this rat model, pemetrexed-loaded films were as effective as pemetrexed solution given into a vein or into the chest in preventing tumor recurrence. They concluded that combining pemetrexed and cisplatin films gave superior antitumor efficacy, completely preventing recurrence in 4 of 6 treated animals.
• Limitations the authors state:
  • The authors said the lack of significant differences between pemetrexed treatments may partly reflect the small number of animals in these preliminary experiments.
  • The authors noted the hyaluronate film did not control the release of pemetrexed well.

Topics

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

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Cisplatin, Pleural Mesothelioma, Latency, Chemotherapy, Multimodal Therapy, Hyaluronic Acid, Mesothelioma.

Related studies

• 2-Deoxy-glucose Enhances the Effect of Cisplatin and Pemetrexed in Reducing Malignant Pleural Mesothelioma Cell Proliferation But Not Spheroid Growth — I. Gerogianni, E. Pitaraki, et al. (2019)
• Nintedanib in combination with pemetrexed and cisplatin for chemotherapy-naive patients with advanced malignant pleural mesothelioma (LUME-Meso): a double-blind, randomised, placebo-controlled phase 3 trial — G.V. Scagliotti, R. Gaafar, et al. (2019)
• A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma — E.M.J. van Brummelen, E. Levchenko, et al. (2020)
• A Case Report of Primary Pericardial Malignant Mesothelioma Treated with Pemetrexed and Cisplatin — J.S. Kim, S.Y. Lim, et al. (2017)
• Local recurrence model of malignant pleural mesothelioma for investigation of intrapleural treatment — I. Opitz, D. Lardinois, et al. (2007)
• Interaction and cross-resistance of cisplatin and pemetrexed in malignant pleural mesothelioma cell lines — M. Kitazono-Saitoh, Y. Takiguchi, et al. (2012)

Browse return to medical research.