Radical Hemithoracic Radiotherapy Induces Systemic Metabolomics Changes That Are Associated with the Clinical Outcome of Malignant Pleural Mesothelioma Patients

Our plain-English summary of Radical Hemithoracic Radiotherapy Induces Systemic Metabolomics Changes That Are Associated with the Clinical Outcome of Malignant Pleural Mesothelioma Patients, by E. Di Gregorio, G. Miolo, A. Saorin, et al (Cancers, 2021).

The study

• Authors: E. Di Gregorio, G. Miolo, A. Saorin, E. Muraro, M. Cangemi, A. Revelant, E. Minatel, M. Trovò, A. Steffan, G. Corona
• Journal: Cancers
• Published: 2021;13(3)
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Radical hemithoracic radiotherapy (RHRT) represents an advanced therapeutic option able to improve overall survival of malignant pleural mesothelioma patients. This study aims to investigate the systemic effects of this radiotherapy modality on the serum metabolome and their potential implications in determining the individual clinical outcome. Nineteen patients undergoing RHRT at the dose of 50 Gy in 25 fractions were enrolled. Serum targeted metabolomics profiles were investigated at baseline and the end of radiotherapy by liquid chromatography and tandem mass spectrometry. Univariate and multivariate OPLS-DA analyses were applied to study the serum metabolomics changes induced by RHRT while PLS regression analysis to evaluate the association between such changes and overall survival. RHRT was found to affect almost all investigated metabolites classes, in particular, the amino acids citrulline and taurine, the C14, C18:1 and C18:2 acyl-carnitines as well as the unsaturated long chain phosphatidylcholines PC ae 42:5, PC ae 44:5 and PC ae 44:6 were significantly decreased. The enrichment analysis showed arginine metabolism and the polyamine biosynthesis as the most perturbed pathways. Moreover, specific metabolic changes encompassing the amino acids and acyl-carnitines resulted in association with the clinical outcome accounting for about 60% of the interpatients overall survival variability. This study highlighted that RHRT can induce profound systemic metabolic effects some of which may have a significant prognostic value. The integration of metabolomics in the clinical assessment of the malignant pleural mesothelioma could be useful to better identify the patients who can achieve the best benefit from the RHRT treatment.

In plain English

This Italian study measured blood chemistry changes in people with malignant pleural mesothelioma given radical hemithoracic radiotherapy (high-dose radiation to one side of the chest). Nineteen patients from a randomized trial (2014 to 2018) gave blood before and after 50 Gy in 25 fractions; residual active disease received 60 Gy through a simultaneous integrated boost. The test targeted 188 small molecules (metabolites). Afterwards, 14 metabolites rose and 69 fell by 10% or more, and citrulline dropped by 33%. The most affected pathways included polyamine biosynthesis, the urea cycle, and arginine and proline metabolism. In 15 reference patients given low-dose palliative radiotherapy, only citrulline fell slightly (under 10%), significant only before multiple-testing correction (p = 0.04, q = 0.72). Median overall survival after high-dose treatment was 24 months (95% CI, 17 to 43 months); all these patients had died of mesothelioma. Changes in certain amino acids and acyl-carnitines were associated with survival, explaining about 60% of between-patient survival differences. The authors concluded their exploratory results support adding metabolomics to clinical evaluation, noting the small sample prevented proper validation. Asbestos exposure was not studied.

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: Exploratory translational study comparing serum metabolite profiles before and after radiotherapy, with a reference group, nested within an ongoing randomized phase III trial
• Who was studied: 34 patients with histologically confirmed malignant pleural mesothelioma were referred to Centro di Riferimento Oncologico of Aviano, Italy, from 2014 to 2018 after nonradical surgery and chemotherapy. The test group was 19 nonmetastatic patients given RHRT: median age 70, 89% male, all treated with pemetrexed and cisplatin. The reference group was 15 patients given palliative local radiotherapy.
• Exposure: The exposure studied was radiotherapy, not asbestos. RHRT was given at 50 Gy in 25 fractions, and residual active disease received 60 Gy through a simultaneous integrated boost within the same course. The reference group received palliative local radiotherapy at 21 Gy in 3 fractions.
• Main results:
  • After RHRT, 52% of the investigated metabolites changed by 10% or more: 14 increased and 69 decreased (19 RHRT patients).
  • Citrulline was the most altered metabolite in the RHRT group. Its mean fell from 33.22 to 22.19 micromolar, a 33% drop. Taurine, the acyl-carnitines C14, C18:1 and C18:2, and the phosphatidylcholines PC ae C42:5, C44:5 and C44:6 also decreased significantly.
  • Enrichment analysis identified polyamine biosynthesis, the urea cycle, and arginine and proline metabolism as the pathways most significantly perturbed by RHRT.
  • In the reference group given palliative local radiotherapy, no metabolites changed significantly except citrulline. Citrulline showed a slight (less than 10%) decrease with p = 0.04 and q = 0.72. The study's significance threshold was q less than 0.05, so this was significant only before correction for multiple testing. Mean absolute variation in amino acid derivatives was 11.8% for RHRT and 4.0% for LRT.
  • Median overall survival in the RHRT group was 24 months (95% CI, 17 to 43 months). All investigated patients had died of mesothelioma by last follow-up. Survival was not associated with age, tumour stage or performance status.
  • In the RHRT group, metabolite fold changes explained about 60% of the variation in overall survival between patients. Changes in ADMA, threonine, SDMA, putrescine, serine, asparagine and the acyl-carnitines C2, C10:1, C16:2 and C18:1 were positively correlated with survival.
  • The mean fold changes of these metabolites were 0.77 for patients who survived under 16.9 months, 1.01 for those who survived 16.9 to 28.8 months, and 1.23 for those who survived over 28.8 months.
• The authors' conclusion: The authors concluded that the results of this first exploratory study support integrating metabolomics into the clinical evaluation of MPM patients. They suggested it may help explain differences in survival after RHRT and help identify frail patients.
• Limitations the authors state:
  • The small sample size did not allow proper validation of the results. Longitudinal studies with larger cohorts are needed before clinical use.
  • Further studies need time-series analyses during treatment and follow-up to distinguish acute from long-term effects.
  • Only serum was analysed; other samples such as urine would give a fuller view.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Overall Survival.

Related studies

• Radical hemithorax radiotherapy induces an increase in circulating PD-1+ T lymphocytes and in the soluble levels of PD-L1 in malignant pleural mesothelioma patients: a possible synergy with PD-1/PD-L1 targeting treatment? — A. Revelant, F. Gessoni, et al. (2025)
• Biological Pathways Associated With the Development of Pulmonary Toxicities in Mesothelioma Patients Treated With Radical Hemithoracic Radiation Therapy: A Preliminary Study — S. Crovella, A. Revelant, et al. (2021)
• Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study — T. Treasure, L. Lang-Lazdunski, et al. (2011)
• Clinical outcome of postoperative highly conformal versus 3D conformal radiotherapy in patients with malignant pleural mesothelioma — J. Krayenbuehl, P. Dimmerling, et al. (2014)
• Hemithoracic radiotherapy for mesothelioma: lack of benefit or lack of statistical power? — A. Rimner, C.B. Simone, et al. (2016)
• Hemithoracic intensity-modulated radiotherapy using helical tomotherapy for patients after extrapleural pneumonectomy for malignant pleural mesothelioma — T. Ebara, H. Kawamura, et al. (2012)

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