Biological Pathways Associated With the Development of Pulmonary Toxicities in Mesothelioma Patients Treated With Radical Hemithoracic Radiation Therapy: A Preliminary Study

Our plain-English summary of Biological Pathways Associated With the Development of Pulmonary Toxicities in Mesothelioma Patients Treated With Radical Hemithoracic Radiation Therapy: A Preliminary Study, by S. Crovella, A. Revelant, E. Muraro, et al (Frontiers in Oncology, 2021).

The study

• Authors: S. Crovella, A. Revelant, E. Muraro, R.R. Moura, L. Brandão, M. Trovò, A. Steffan, P. Zacchi, G. Zabucchi, E. Minatel, V. Borelli
• Journal: Frontiers in Oncology
• Published: 2021;11:784081
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Radical hemithoracic radiotherapy (RHR), after lung-sparing surgery, has recently become a concrete therapeutic option for malignant pleural mesothelioma (MPM), an asbestos-related, highly aggressive tumor with increasing incidence and poor prognosis. Although the toxicity associated to this treatment has been reduced, it is still not negligible and must be considered when treating patients. Genetic factors appear to play a role determining radiotherapy toxicity. The aim of this study is the identification of biological pathways, retrieved through whole exome sequencing (WES), possibly associated to the development of lung adverse effects in MPM patients treated with RHR. The study included individuals with MPM, treated with lung-sparing surgery and chemotherapy, followed by RHR with curative intent, and followed up prospectively for development of pulmonary toxicity. Due to the strong impact of grade 3 pulmonary toxicities on the quality of life, compared with less serious adverse events, for genetic analyses, patients were divided into a none or tolerable pulmonary toxicity (NoSTox) group (grade ≤2) and a severe pulmonary toxicity (STox) group (grade = 3). Variant enrichment analysis allowed us to identify different pathway signatures characterizing NoSTox and Stox patients, allowing to formulate hypotheses on the protection from side effects derived from radiotherapy as well as factors predisposing to a worst response to the treatment. Our findings, being aware of the small number of patients analyzed, could be considered a starting point for the definition of a panel of pathways, possibly helpful in the management of MPM patients.

Copyright © 2021 Crovella, Revelant, Muraro, Moura, Brandão, Trovò, Steffan, Zacchi, Zabucchi, Minatel and Borelli.

In plain English

This preliminary study looked for inherited genetic differences linked to lung side effects of radiation in patients with malignant pleural mesothelioma, which the authors call asbestos-related. Asbestos exposure itself was not studied. The authors sequenced the protein-coding DNA (exome) from blood of 49 patients treated in Aviano, Italy, from August 2014 to May 2018. Patients had partial pleurectomy/decortication or biopsy only, then chemotherapy and radical hemithoracic radiotherapy. Patients were grouped as having no or tolerable lung toxicity (grade 0 to 2; 40 patients) or severe toxicity (grade 3; 9 patients). Fibrosis occurred in 3 patients (2 severe), pneumonitis in 7 (4 grade 3). Survival did not differ significantly between groups. No specific genetic variant or overall signature separated the groups, and no variant that earlier genome-wide studies linked to radiotherapy toxicity was found. Pathway analysis found 47 pathways with extra functional variants only in the tolerable group, four only in the severe group. The authors concluded these patterns allow hypotheses about protection from, or predisposition to, side effects. They noted the small number of patients and the lack of RNA data.

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: Prospective study with whole exome sequencing of germline (blood) DNA and a pathway-based (variant enrichment) analysis; described by the authors as preliminary
• Who was studied: 49 patients with malignant pleural mesothelioma (40 male, 9 female; median age 69) at the Centro di Riferimento Oncologico di Aviano, Italy, between August 2014 and May 2018. They were treated with nonradical surgery (partial pleurectomy/decortication or biopsy only), platinum-based plus pemetrexed chemotherapy, and radical hemithoracic radiotherapy.
• Exposure: The exposure studied was radiotherapy to the whole affected side of the chest: 50 Gy in 25 fractions, with a possible boost to 60 Gy on PET-positive areas. Asbestos exposure was not studied.
• Main results:
  • 40 patients had no or tolerable lung toxicity (grade 0 to 2) and 9 had severe lung toxicity (grade 3)
  • Among all 49 patients, fibrosis developed in 3 (2 severe) and pneumonitis in 7 (4 of grade 3)
  • Among all 49 patients, dyspnea was reported in 37% as acute toxicity, mainly low grade, and was severe in 8% as a late event
  • Among all 49 patients, median overall survival was 25 months and 2-year overall survival was 51.4%. There were no significant survival differences between the two toxicity groups.
  • Principal component analysis showed a homogeneous distribution of variants in both groups, and no specific genetic signature was observed
  • For functional variants, 47 pathways showed a significantly increased number of variants only in the no or tolerable toxicity group, and four pathways only in the severe toxicity group
  • None of the genetic variants previously identified through genome-wide studies as associated with radiotherapy toxicity were detected in either group
  • In the severe toxicity group, one patient (#2) who had a pulmonary thromboembolic event carried a stopgain variant in the SERPINF2 gene
• The authors' conclusion: The authors concluded that sequencing did not show any specific genetic variant associated with the two toxicity groups. They said the variant enrichment analysis indicated different pathway signatures in each group, allowing hypotheses on protection from radiotherapy side effects and on factors predisposing to a worse response.
• Limitations the authors state:
  • Small number of patients analyzed
  • No transcriptomic (RNA) data, because lung or pleural samples could not be collected to check the hypotheses

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Prognosis, Chemotherapy, Quality of Life.

Related studies

• Disease-Related Outcomes and Toxicities of Intensity Modulated Radiation Therapy After Lung-Sparing Pleurectomy for Malignant Pleural Mesothelioma: A Systematic Review — R. Patel, E.B. Ludmir, et al. (2020)
• Patterns of failure, toxicity, and survival after extrapleural pneumonectomy and hemithoracic intensity-modulated radiation therapy for malignant pleural mesothelioma — D.R. Gomez, D.S. Hong, et al. (2013)
• Hemithoracic radiation therapy after extrapleural pneumonectomy for malignant pleural mesothelioma: Toxicity and outcomes at an Australian institution — A. Bece, M.M. Tin, et al. (2015)
• Impact of induction therapy on postoperative outcome after extrapleural pneumonectomy for malignant pleural mesothelioma: does induction-accelerated hemithoracic radiation increase the surgical risk? — P. Mordant, K. McRae, et al. (2016)
• Geometric dose prediction model for hemithoracic intensity-modulated radiation therapy in mesothelioma patients with two intact lungs — L. Kuo, E.D. Yorke, et al. (2016)
• Hemithoracic radiation therapy after extrapleural pneumonectomy for malignant pleural mesothelioma: Applicable to all and by all? — R. Haas, P. Baas (2015)

Browse more research in Frontiers in Oncology, or return to medical research.