bims-mesote 2023-11-26 papers

bims-mesote

Biomed News

on Mesothelioma

Issue of 2023–11–26
seven papers selected by
Laura Mannarino, Humanitas Research

Safety and efficacy of helical tomotherapy following lung-sparing surgery in locally advanced malignant pleural mesothelioma.
Targeted Approaches to Treatment of Pleural Mesothelioma: A Review.
Pleural Mesothelioma: Advances in Blood and Pleural Biomarkers.
Long-Term Survival Analysis of Pleural Mesothelioma Patients Undergoing Surgery: Brief Report From a Tertiary Referral Centre.
Evaluating niraparib versus active symptom control in patients with previously treated mesothelioma (NERO): a study protocol for a multicentre, randomised, two-arm, open-label phase II trial in UK secondary care centres.
International Prognostic Modeling: A Platform for Collaborative Approach for Patients With Mesothelioma.
The Interplay between the Immune System, Tumor Suppressor Genes, and Immune Senescence in Mesothelioma Development and Response to Immunotherapy.

Strahlenther Onkol. 2023 Nov 22.

Safety and efficacy of helical tomotherapy following lung-sparing surgery in locally advanced malignant pleural mesothelioma.

Julian P Layer, Pascal Fischer, Cas S Dejonckheere, Gustavo R Sarria, Rebekka Mispelbaum, Sandra Tessa Hattenhauer, Shari Wiegreffe, Andrea R Glasmacher, Katharina Layer, Youness Nour, Lara Caglayan, Franziska Grau, Thomas Müdder, Mümtaz Köksal, Davide Scafa, Frank A Giordano, Alberto Lopez-Pastorini, Erich Stoelben, Leonard Christopher Schmeel, Christina Leitzen.

   PURPOSE: To assess the value of radiation therapy (RT) with helical tomotherapy (HT) in the management of locally advanced malignant pleural mesothelioma (MPM) receiving no or lung-sparing surgery.
METHODS: Consecutive MPM cases not undergoing extrapleural pneumonectomy and receiving intensity-modulated (IM) HT were retrospectively evaluated for local control, distant control, progression-free survival (PFS), and overall survival (OS). Impact of age, systemic treatment, RT dose, and recurrence patterns was analyzed by univariate and multivariate analysis. As a secondary endpoint, reported toxicity was assessed.
RESULTS: A total of 34 localized MPM cases undergoing IMHT were identified, of which follow-up data were available for 31 patients. Grade 3 side effects were experienced by 26.7% of patients and there were no grade 4 or 5 events observed. Median PFS was 19 months. Median OS was 20 months and the rates for 1‑ and 2‑year OS were 86.2 and 41.4%, respectively. OS was significantly superior for patients receiving adjuvant chemotherapy (p = 0.008).
CONCLUSION: IMHT of locally advanced MPM after lung-sparing surgery is safe and feasible, resulting in satisfactory local control and survival. Adjuvant chemotherapy significantly improves OS. Randomized clinical trials incorporating modern RT techniques as a component of trimodal treatment are warranted to establish an evidence-based standard of care pattern for locally advanced MPM.

Keywords:  Adjuvant radiotherapy; Intensity-modulated radiotherapy; Local tumor control; Survival; Trimodal therapy

DOI:  https://doi.org/10.1007/s00066-023-02174-7
JCO Precis Oncol. 2023 Sep;7 e2300344

Targeted Approaches to Treatment of Pleural Mesothelioma: A Review.

Ibiayi Dagogo-Jack.

Pleural mesothelioma is an aggressive disease that is enriched for inactivating alterations in tumor suppressor genes. Systemic therapeutic strategies for pleural mesothelioma generally involve chemotherapies and immunotherapies that are chosen without consideration of the tumor's molecular profile. As this generalized approach to treatment rarely yields durable responses, alternative therapeutic regimens are urgently indicated. Preclinical studies have identified synthetic lethal protein and metabolic interactions, recurrently overexpressed proteins, and frequent pathway perturbations that may be therapeutically exploited in mesothelioma. This review discusses the mechanism of action of emerging investigational therapies and summarizes findings from phase I-II clinical trials exploring selective, biomarker-driven therapeutic strategies for mesothelioma, with a focus on five common targets. Finally, using lessons learned from these clinical trials, imperatives for successful implementation of targeted therapy in mesothelioma are discussed.

DOI: https://doi.org/10.1200/PO.23.00344
J Clin Med. 2023 Nov 09. pii: 7006. [Epub ahead of print]12(22):

Pleural Mesothelioma: Advances in Blood and Pleural Biomarkers.

Claudio Sorino, Michele Mondoni, Giampietro Marchetti, Sergio Agati, Riccardo Inchingolo, Federico Mei, Sara Flamini, Filippo Lococo, David Feller-Kopman.

  Pleural mesothelioma (PM) is a type of cancer that is highly related to exposure to asbestos fibers. It shows aggressive behavior, and the current therapeutic approaches are usually insufficient to change the poor prognosis. Moreover, apart from staging and histological classification, there are no validated predictors of its response to treatment or its long-term outcomes. Numerous studies have investigated minimally invasive biomarkers in pleural fluid or blood to aid in earlier diagnosis and prognostic assessment of PM. The most studied marker in pleural effusion is mesothelin, which exhibits good specificity but low sensitivity, especially for non-epithelioid PM. Other biomarkers found in pleural fluid include fibulin-3, hyaluronan, microRNAs, and CYFRA-21.1, which have lower diagnostic capabilities but provide prognostic information and have potential roles as therapeutic targets. Serum is the most investigated matrix for biomarkers of PM. Several serum biomarkers in PM have been studied, with mesothelin, osteopontin, and fibulin-3 being the most often tested. A soluble mesothelin-related peptide (SMRP) is the only FDA-approved biomarker in patients with suspected mesothelioma. With different serum and pleural fluid cut-offs, it provides useful information on the diagnosis, prognosis, follow-up, and response to therapy in epithelioid PM. Panels combining different markers and proteomics technologies show promise in terms of improving clinical performance in the diagnosis and monitoring of mesothelioma patients. However, there is still no evidence that early detection can improve the treatment outcomes of PM patients.

Keywords:  biomarkers; fibulin-3; mesothelin; mesothelioma; pleural effusion

DOI:  https://doi.org/10.3390/jcm12227006
Clin Lung Cancer. 2023 Oct 24. pii: S1525-7304(23)00223-1. [Epub ahead of print]

Long-Term Survival Analysis of Pleural Mesothelioma Patients Undergoing Surgery: Brief Report From a Tertiary Referral Centre.

Riccardo Orlandi, Giovanni Leuzzi, Luigi Rolli, Michele Ferrari, Alessia Stanzi, Camilla Valsecchi, Ugo Pastorino.

   OBJECTIVES: to date, no consensus has been reached on the surgical gold-standard in pleural mesothelioma (PM). We retrospectively reviewed our experience as a tertiary referral centre, to compare short- and long-term survival of PM patients undergoing different types of surgery.
METHODS: in retrospective, observational, single-centre study, we analysed all the patients histologically diagnosed with PM undergoing surgical procedures with palliative or curative intent at IRCCS Istituto Nazionale dei Tumori of Milan, Italy, from January 2003 to December 2020. The primary study endpoint was 10-year overall survival (OS) in three different types of resections: extra-pleural-pneumonectomy (EPP), pleurectomy/decortication (P/D), partial-pleurectomy/pleural-biopsy (PP/B). Secondary endpoints were postoperative hospital stay and postoperative 30-day and 90-day mortality rates. The survival function was estimated using Kaplan-Meier, and the Log-rank test was used for testing differences. Univariable and Multivariable Cox regression models were implemented to estimate Hazard Ratio (HR) for all variables of interest.
RESULTS: 243 consecutive patients were enrolled, EPP was performed in 49 (20.2%), P/D in 58 (23.8%), PP/B in 136 (56.0%) patients. The median follow-up time was 19.8 months. 10-year OS was significantly better for P/D group (16%, Log-Rank test p<0.0001) compared to PP/B (1.8%) and EPP (0%). No statistically significant differences were found among the 3 surgical groups in 30- and 90-day mortality rates. At multivariable analysis, gender (male, HR=1.58), type of resection (P/D, HR=0.55) and surgery date (recent years, HR=0.61) were found to be independent prognostic factors for OS.
CONCLUSIONS: in PM, lung-sparing curative approach (e.g. P/D) should be preferred in highly selected patients and in highly experienced centres, whenever appropriate. Anyway, when P/D is not indicated, adopting palliative/conservative management (e.g. PP/B) could ensure comparable results as extremely aggressive surgeries (e.g. EPP). The aim of surgery in PM should not be reaching complete resection, but rather accomplishing significant resection allowing to complete the multimodality treatment in highly selected patients in experienced centers.

Keywords:  Extrapleural pneumonectomy; Pleura; Pleural mesothelioma; Pleurectomy/decortication; Surgical oncology; Thoracic surgery

DOI:  https://doi.org/10.1016/j.cllc.2023.10.010
BMJ Open. 2023 11 22. 13(11): e073120

Evaluating niraparib versus active symptom control in patients with previously treated mesothelioma (NERO): a study protocol for a multicentre, randomised, two-arm, open-label phase II trial in UK secondary care centres.

Dean Fennell, Daniel Griffiths, Zina Eminton, Abigail Morgan-Fox, Kayleigh Hill, Sean Ewings, Charlotte Stuart, Lucy Johnson, Kim Mallard, Mavis Nye, Liz Darlison, Sean Dulloo, Judith Cave, Jin-Li Luo, Paul Taylor, Jake Spicer, Charlotte Poile, Aleksandra Bzura, Gareth Griffiths.

   BACKGROUND: Malignant mesothelioma is a rapidly lethal cancer that has been increasing at an epidemic rate over the last three decades. Targeted therapies for mesothelioma have been lacking. A previous study called MiST1 (NCT03654833), evaluated the efficacy of Poly (ADP-ribose) polymerase (PARP) inhibition in mesothelioma. This study met its primary endpoint with 15% of patients having durable responses exceeding 1 year. Therefore, there is a need to evaluate PARP inhibitors in relapsed mesothelioma patients, where options are limited. Niraparib is the PARP inhibitor used in NERO.
METHODS: NERO is a multicentre, two-arm, open-label UK randomised phase II trial designed to evaluate the efficacy of PARP inhibition in relapsed mesothelioma. 84 patients are being recruited. NERO is not restricted by line of therapy; however, eligible participants must have been treated with an approved platinum based systemic therapy. Participants will be randomised 2:1, stratified according to histology and response to prior platinum-based chemotherapy, to receive either active symptom control (ASC) and niraparib or ASC alone, for up to 24 weeks. Participants will be treated until disease progression, withdrawal, death or development of significant treatment limiting toxicity. Participants randomised to niraparib will receive 200 or 300 mg daily in a 3-weekly cycle. The primary endpoint is progression-free survival, where progression is determined by modified Response Evaluation Criteria in Solid Tumors (mRECIST) or RECIST 1.1; investigator reported progression; or death from any cause, whichever comes first. Secondary endpoints include overall survival, best overall response, 12-week and 24 week disease control, duration of response, treatment compliance and safety/tolerability. If NERO shows niraparib to be safe and biologically effective, it may lead to future late phase randomised controlled trials in relapsed mesothelioma.
ETHICS AND DISSEMINATION: The study received ethical approval from London-Hampstead Research Ethics Committee on 06-May-2022 (22/LO/0281). Data from all centres will be analysed together and published as soon as possible.
TRIAL REGISTRATION NUMBER: ISCRTN16171129; NCT05455424.

Keywords:  clinical trial; oncology; quality of life; thoracic medicine

DOI:  https://doi.org/10.1136/bmjopen-2023-073120
J Thorac Oncol. 2023 Dec;pii: S1556-0864(23)02243-8. [Epub ahead of print]18(12): 1618-1620

International Prognostic Modeling: A Platform for Collaborative Approach for Patients With Mesothelioma.

Cristian G Medina, Yuan Xu, R Taylor Ripley.

DOI: https://doi.org/10.1016/j.jtho.2023.09.1441
J Thorac Oncol. 2023 Nov 22. pii: S1556-0864(23)02373-0. [Epub ahead of print]

The Interplay between the Immune System, Tumor Suppressor Genes, and Immune Senescence in Mesothelioma Development and Response to Immunotherapy.

Andre E Nel, Elizabeth N Pavlisko, Victor L Roggli.

  Despite efforts to ban asbestos mining and manufacturing, mesothelioma deaths in the United States have remained stable around 2500 cases annually. This trend is not unique to the US but is also a global phenomenon, associated with increased aging of populations worldwide. While geo-economic factors such as lack of regulations and continued asbestos manufacturing in resource-poor countries play a role, it is essential to consider biological factors such as immune senescence and increased genetic instability associated with aging. Recognizing that mesothelioma shares genetic instability and immune system effects with other age-related cancers is crucial because the impact of aging on mesothelioma is frequently assessed in the context of disease latency following asbestos exposure. However, the long latency period, often cited as a reason for mesothelioma's elderly predominance, should not overshadow the shared mechanisms. This communication focuses on the role of immune surveillance in mesothelioma, particularly exploring the impact of immune escape resulting from altered tumor suppressor gene (TSG) function during aging, contributing to the phylogenetic development of gene mutations and mesothelioma oncogenesis. The interplay between the immune system, TSGs, and aging not only shapes the immune landscape in mesothelioma but also contributes to the development of heterogeneous tumor microenvironments, significantly influencing responses to immunotherapy approaches and survival rates. By understanding the complex interplay between aging, TSG decline, and immune senescence, healthcare professionals can pave the way for more effective and personalized immunotherapies, ultimately offering hope for better outcomes in the fight against mesothelioma.

Keywords:  immune landscapes; immune senescence; immunotherapy; mesothelioma; tumor suppressor genes

DOI:  https://doi.org/10.1016/j.jtho.2023.11.017