Targeting interleukin-6 as a treatment approach for peritoneal carcinomatosis

Our plain-English summary of Targeting interleukin-6 as a treatment approach for peritoneal carcinomatosis, by N. Dadgar, C. Sherry, J. Zimmerman, et al (Journal of Translational Medicine, 2024).

The study

• Authors: N. Dadgar, C. Sherry, J. Zimmerman, H. Park, C. Lewis, A. Donnenberg, A.H. Zaidi, Y. Fan, K. Xiao, D. Bartlett, V. Donnenberg, P.L. Wagner
• Journal: Journal of Translational Medicine
• Published: 2024;22(1):402
• Type of article: Review
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Peritoneal carcinomatosis (PC) is a complex manifestation of abdominal cancers, with a poor prognosis and limited treatment options. Recent work identifying high concentrations of the cytokine interleukin-6 (IL-6) and its soluble receptor (sIL-6-Rα) in the peritoneal cavity of patients with PC has highlighted this pathway as an emerging potential therapeutic target. This review article provides a comprehensive overview of the current understanding of the potential role of IL-6 in the development and progression of PC. We discuss mechansims by which the IL-6 pathway may contribute to peritoneal tumor dissemination, mesothelial adhesion and invasion, stromal invasion and proliferation, and immune response modulation. Finally, we review the prospects for targeting the IL-6 pathway in the treatment of PC, focusing on common sites of origin, including ovarian, gastric, pancreatic, colorectal and appendiceal cancer, and mesothelioma.

© 2024. The Author(s).

In plain English

This article was a review, not a new study. The authors summarized published laboratory, animal and clinical research on interleukin-6 (IL-6), an immune signaling protein, in peritoneal carcinomatosis, cancer spread across the lining of the abdomen. They covered ovarian, gastric, colorectal, pancreatic and appendiceal cancer, and malignant peritoneal mesothelioma. The article did not study asbestos or any fiber exposure. One cited ovarian cancer trial reported a 5.6% overall response rate in 18 patients given the IL-6 drug siltuximab alone. In a cited siltuximab trial including 35 colorectal cancers, only three colorectal patients had stable disease for more than 6 weeks, and none had an objective response. The authors wrote that, to their knowledge, no clinical trials had tested anti-IL-6 therapy in mesothelioma. They judged that IL-6 blockade used alone is unlikely to give meaningful benefit against the cancer. The authors concluded that combining IL-6 blockade with other treatments had shown promise in preclinical and clinical studies. They reported opening a safety and drug-level trial of tocilizumab given into the abdominal or chest cavity in patients with malignant fluid buildup.

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: narrative review of published laboratory, animal and clinical studies
• Who was studied: No new study population. The review covered published pre-clinical studies and clinical trials in cancers commonly associated with peritoneal carcinomatosis (ovarian, gastric, colorectal, pancreatic and appendiceal cancer, and malignant peritoneal mesothelioma).
• Exposure: No asbestos or fiber exposure was studied. The subject was the IL-6 signaling pathway and drugs that block it, such as tocilizumab and siltuximab.
• Main results:
  • The authors stated that, to their knowledge, no clinical trials had investigated anti-IL-6 therapy in malignant mesothelioma (MM) or malignant peritoneal mesothelioma (MPM).
  • The review cited earlier work reporting elevated IL-6 levels in peritoneal fluid from patients with malignant peritoneal mesothelioma.
  • In a cited phase II trial (Coward et al.) in platinum-resistant recurrent ovarian cancer, 18 patients received siltuximab alone, with a 5.6% overall response rate.
  • In a cited siltuximab trial in solid tumors that included 35 colorectal cancers, only three colorectal cancer patients (less than 10%) had stable disease for more than 6 weeks, and there were no objective responses.
  • Across cancer types, the authors judged that the clinical data suggest IL-6 inhibition used alone is unlikely to give meaningful oncologic (anti-cancer) benefit; they separately discussed possible relief of fibrosis, adhesions and other complications of peritoneal carcinomatosis.
  • The authors reported opening a clinical trial (NCT06016179) examining the safety and pharmacokinetic profile of tocilizumab delivered into the peritoneal and pleural cavities, for patients with malignant pleural or peritoneal effusions or ascites.
• The authors' conclusion: The authors concluded that targeting IL-6 and its downstream signaling in combination regimens had shown promise in preclinical and clinical studies of cancers that commonly cause peritoneal carcinomatosis.

Topics

Medical terms in this study, explained in our Lexicon: Prognosis, Cytokine, Peritoneal Cavity, Mesothelioma.

Related studies

• Interleukin-6 involvement in mesothelioma pathobiology: inhibition by interferon alpha immunotherapy — H. Bielefeldt-Ohmann, A.L. Marzo, et al. (1995)
• Interleukin-6 as a therapeutic target in candidate inflammatory diseases — N. Nishimoto (2010)
• Multicenter comprehensive methodological and technical analysis of 832 pressurized intraperitoneal aerosol chemotherapy (PIPAC) interventions performed in 349 patients for peritoneal carcinomatosis treatment: An international survey study — M. Nowacki, M. Alyami, et al. (2018)
• The role of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the treatment of peritoneal carcinomatosis: a systematic review including evidence from Japan — T. Kitai (2021)
• Cytoreduction and HIPEC in the treatment of "unconventional" secondary peritoneal carcinomatosis — M. Cardi, P. Sammartino, et al. (2015)
• Evolution of locoregional treatment for peritoneal carcinomatosis: single-center experience of 308 procedures of cytoreductive surgery and perioperative intraperitoneal chemotherapy — T.C. Chua, W. Liauw, et al. (2011)

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