Clinical Lung Cancer

Our medical research library holds 38 studies published in Clinical Lung Cancer (2003–2026). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 35 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it. For 1 study PubMed has no abstract for, we give the abstract printed in the article or, where there is none, a summary we wrote from it, each labeled as such.

About the journal

• Publisher: Elsevier
• Published: 1999 to the present, United States
• Language: English
• ISSN: 1525-7304 (print), 1938-0690 (electronic)
• Its record in the NLM Catalog

2020s

• Prognostic Significance of Inflammatory, Cellular, and Tumor-Specific Biomarkers in Patients With Pleural and Peritoneal Mesothelioma. K. Yerigeri, M. Sengupta, J. Zhang, et al. 2026;27(5):77-86.e1. PubMed · Publisher · Free full text

  Abstract

  Background: Mesothelioma is an aggressive malignancy with poor outcomes, particularly when diagnosed at advanced stages. This study evaluated the prognostic value of tumor-specific biomarkers: soluble mesothelin-related peptide (SMRP), megakaryocyte potentiating factor (MPF) and CA125; inflammatory markers: C-reactive protein (CRP) and fibrinogen; cellular markers: platelet count and neutrophil-to-lymphocyte ratio (NLR) in patients with pleural (MPM) and peritoneal mesothelioma (MPeM).

  Methods: A total of 414 patients including 241 MPM, 153 MPeM and 20 with mesothelioma at other body sites were enrolled in the Natural History Protocol (NCT01950572) at the National Cancer Institute. Blood samples collected at enrollment were assessed for biomarker levels and based on their expression levels patients were stratified into quartiles. Kaplan-Meier survival curves were plotted, and median overall survival (mOS) was compared between groups.

  Results: For all the biomarkers evaluated, there was a significant decrease in mOS in the high expression cohorts. The mOS in years in low versus high expression cohorts being: SMRP (3 vs. 0.7), MPF (3.7 vs. 0.7), CA125 (1.6 vs. 0.8), CRP (4.1 vs. 0.4), fibrinogen (4.1 vs. 0.6), platelet count (1.4 vs. 0.8) and NLR (2.1 vs. 0.7). When analyzed separately, the pleural and peritoneal cohorts showed similar trends. Strong correlations existed between SMRP and MPF (r = 0.84), as well as CRP and fibrinogen (r = 0.86).

  Conclusions: Biomarkers such as SMRP, MPF, CA125, CRP, fibrinogen, platelet count and NLR can independently predict overall survival in mesothelioma. These biomarkers can therefore provide prognostic information for these patients and help guide treatment strategies.

  Published by Elsevier Inc.

• Safety of mRNA-COVID-19 Vaccines in Patients With Thoracic Cancers. G. Spitaleri, P. Trillo Aliaga, C. Catania, et al. 2023;24(1):e19-e26. PubMed · Publisher · Free full text

  Abstract

  Background: Pivotal trials of COVID-19 vaccines did not include cancer patients with questions remaining in this population. Particularly in patients with thoracic malignancies receiving anticancer treatments, the safety of these vaccines has so far been little investigated.

  Methods: This is a prospective trial of patients with thoracic cancer receiving anticancer treatments and COVID-19 vaccines at the Division of Thoracic Oncology of European Institute of Oncology between February and September 2021.

  Results: A total 207 patients affected by thoracic cancers (199 lung cancers and 8 mesotheliomas) had received Covid-19 vaccines (206 mRNA vaccines and 1 virus-vectored vaccine). The majority of patients had at least one comorbidity (76.3%). They were concomitantly treating with targeted therapy (TT) (45.9%), immunotherapy (IO) (22.7%), and chemotherapy (CT) (14%). A total of 64 AEs (15.6%) were observed after administration of Sars-Cov-2 vaccine. The majority of AEs were grade 1 [G1] (6.3%) and G2 (8.8%), only two events were G3 (0.5%). The median follow-up was 9 months (range 1-22 months), during this follow-up 21 patients (10.1%) had a positive nasal swab, most of the patients were asymptomatic (67%) and the symptomatic ones (33%) had mild symptoms and fewer complications and hospitalizations.

  Conclusions: COVID-19 m-RNA vaccines appear to be safe in the cohort of patients with thoracic malignances in active treatment, including those receiving immunotherapy. Considering the high morbidity and mortality associated with COVID-19 in patients with lung cancer receiving active treatments, our study supports the current vaccine prioritization, third and/or fourth dose, of all cancer patients with active treatment.

  Copyright © 2022 Elsevier Inc. All rights reserved.

• Short Report of a Phase II Trial of Nintedanib in Recurrent Malignant Pleural Mesothelioma (MPM). A.J. Wozniak, B. Schneider, G.P. Kalemkerian, et al. 2023;24(6):563-567. PubMed · Publisher · Free full text

  Abstract

  Background:: Malignant pleural mesothelioma (MPM) is a disease for which there remains an unmet need for better therapeutic options. Nintedanib is an oral multikinase inhibitor impacting VEGF, FGF, PDGFR, and other kinase activity such as TGFß signaling pathways. We conducted a phase II trial of nintedanib in patients with recurrent MPM.

  Methods:: Patients with MPM previously treated with platinum-based chemotherapy, performance status (PS) 0–1, adequate organ function, and no contraindications to anti-angiogenic therapy were eligible and were treated with nintedanib 200 mg twice per day until disease progression or unacceptable toxicity. The primary endpoint was 4-month progression-free survival (PFS).

  Results:: Twenty patients were enrolled. The median age was 70 years (range 32–81), 90% were male, and 80% were PS 1. The histology was 70% epithelioid, 5% sarcomatoid, 10% biphasic, and 15% unknown. 15% had prior bevacizumab. The median follow-up was 4.1 mo. There were no responses but 40% had stable disease at 8 weeks. The median PFS was 1.8 mo. (95% CI: 1.68, 3.55) and the 4-month PFS rate was 13%. The median OS was 4.2 mo. (95% CI: 2.53, 8.74) and the 4-month OS rate was 55%. Toxicities were primarily grade 1–2 and included diarrhea, fatigue, edema, transaminase elevation, anorexia, nausea, vomiting and dyspnea.

  Conclusions:: The activity of nintedanib in previously treated MPM patients was. modest. The trial did not meet its primary PFS endpoint. Even though 2 patients had prolonged stable disease for >4 months, the efficacy of nintedanib remains unproven.

• Treatment Patterns and Outcomes of Patients With Advanced Pleural Mesothelioma at an Academic Referral Centre. S. Schmid, L. Zhan, K. Dietrich, et al. 2022;23(1):e43-e53. PubMed · Publisher

  Abstract

  Background: Overall survival (OS) for malignant pleural mesothelioma (MPM) in vulnerable subgroups remains poorly understood with scarce data available to guide treatment decisions. The study describes real-world detailed treatment patterns and outcomes of patients with advanced MPM overall and specifically in elderly and poor performance status (PS) patients.

  Methods: Retrospective chart review was performed for all patients with histologically confirmed MPM seen at University Health Network/Princess Margaret Cancer Centre (UHN-PM).

  Results: A total of 667 patients with MPM were identified and 304 advanced-disease MPM (aMPM) patients had continuing care at UHN-PM (UP-cohort). In the UP-cohort, 77% of patients received ≥ one line of systemic treatment. Systemic therapy trial participation was 39%. Patients not treated with systemic therapy (29%) were more likely to be ≥ 75 years and PS ≥ 2. Median OS was 15.3 months (95%CI 13.6-18.3), with longer survival in treated vs. untreated patients (17.4 vs. 10.6 months; P = .01). Longer survival with systemic treatment was seen in patients ≥75 years (12.7 vs. 6.6 months) and patients with poor PS (9.1 vs. 5.9 months). Median progression-free-survival (PFS) and OS for patients treated with second-line therapy was poor (3.0 and 8.9 months, respectively).

  Discussion: In our real-world analysis of patients with aMPM treated at an academic referral centre, systemic treatment was given to the majority of patients and benefit was seen even in the elderly and poor PS patients frequently underrepresented in clinical trials. Trial participation was potentially facilitated by the formation of a dedicated multidisciplinary MPM clinic.

  Copyright © 2021 Elsevier Inc. All rights reserved.

• A Phase II Trial of Nivolumab With Chemotherapy Followed by Maintenance Nivolumab in Patients With Pleural Mesothelioma After Surgery: The NICITA Study Protocol. R. Shah, L.V. Klotz, I. Chung, et al. 2021;22(2):142-146. PubMed · Publisher

  Abstract

  Background: In selected patients with early-stage malignant pleural mesothelioma (MPM), a multimodal therapy that includes surgical cytoreduction, chemotherapy, and/or radiotherapy is recommended. Several clinical trials have demonstrated the beneficial effects of immune checkpoint inhibitors in pretreated MPM patients with advanced disease. Recent clinical data have suggested that the combination of chemotherapy and checkpoint inhibition might improve efficacy.

  Trial Design: The NICITA (nivolumab with chemotherapy in pleural mesothelioma after surgery) trial is a prospective, 1:1 randomized, open-label, multicenter phase II clinical trial (ClinicalTrials.gov identifier, NCT04177953). Ninety-two patients with MPM epithelioid subtype, who had undergone extended pleurectomy and decortication with or without hyperthermic intrathoracic chemoperfusion, will be included to receive adjuvant treatment. All patients will receive ≤ 4 cycles of platinum-based chemotherapy with pemetrexed (arms A and B). Patients in arm B will additionally receive nivolumab, together with the adjuvant chemotherapy, and subsequently for ≤ 12 cycles as maintenance therapy. The primary endpoint of this study is the time-to-next-treatment. The secondary endpoints include progression-free survival, overall survival, proportion of patients with treatment beyond progression, duration of treatment beyond progression in this population, and quality of life.

  Conclusion: This prospective trial will contribute data to assess the efficacy of standard chemotherapy combined with nivolumab in the context of multimodal management of early-stage MPM. The study is currently enrolling patients.

  Copyright © 2020 Elsevier Inc. All rights reserved.

  In plain English

  This article is a study protocol. It describes a planned clinical trial, called NICITA, that was enrolling patients, and it reports no results. The trial was designed as a randomized, open-label phase II trial at twelve sites in Germany. It planned to include 92 patients with epithelioid malignant pleural mesothelioma, stage I to III. All had already had surgery to remove as much tumor as possible (extended pleurectomy and decortication), with or without heated chemotherapy given into the chest during the operation (HITOC). Every patient was to receive up to four cycles of platinum-based chemotherapy with pemetrexed. Patients in one of the two arms (arm B) were also to receive the immunotherapy drug nivolumab together with the chemotherapy, and then nivolumab alone for up to 12 cycles as maintenance. The authors said the trial would contribute data on how well standard chemotherapy combined with nivolumab works within multi-step treatment of early-stage disease. The article does not examine asbestos exposure.

  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.

• A Prospective Phase II Single-arm Study of Niraparib Plus Dostarlimab in Patients With Advanced Non-small-cell Lung Cancer and/or Malignant Pleural Mesothelioma, Positive for PD-L1 Expression and Germline or Somatic Mutations in the DNA Repair Genes: Rationale and Study Design. F. Passiglia, P. Bironzo, L. Righi, et al. 2021;22(1):e63-e66. PubMed · Publisher

  Abstract

  Treatment with poly ADP ribose polymerase (PARP)1/2 inhibitors represents a novel opportunity to selectively kill a subset of cancer cell types by exploiting their deficiencies in DNA repair, thus leading to synthetic lethality. Treatment of homologous recombination deficient (HRD)-tumors with PARP inhibitors generates significant levels of DNA damage, which has the potential to further increasing tumor mutational burden, promoting neoantigen release, and upregulating both interferons and programmed death ligand-1 (PD-L1) expression, suggesting a potential complementary and synergistic role with immune checkpoint inhibitors in cancer treatment. Here we present the design and rationale of a prospective, phase II, single-arm study aiming to investigate the safety and antitumor activity of the combination of niraparib and dostarlimab in patients with HRD-positive and PD-L1 ≥ 1% advanced non-small-cell lung cancer (NSCLC) and/or malignant pleural mesothelioma (MPM). Considering the prevalence of pathogenetic germline mutations in DNA repair genes, reported to be around 5% to 10% in patients with MPM and NSCLC, a total of 700 to 1000 cases will be screened to identify 70 patients who are HRD-positive/PD-L1 ≥ 1% (N = 35 NSCLC; N = 35 MPM) to be included. Patients will receive the combination of niraparib orally once daily and dostarlimab intravenously. The primary endpoint is progression-free survival. Secondary endpoints are objective response, duration of response, overall survival, and safety. The results of this study will provide evidence on the safety and antitumor activity of niraparib and dostarlimab combination in patients with advanced, HRD-positive and PD-L1 ≥ 1% NSCLC and/or MPM.

  Copyright © 2020 Elsevier Inc. All rights reserved.

• Brown-Séquard Syndrome in a Desmoplastic Malignant Mesothelioma Patient: A Rare Complication. M. Ralki, A. Serrien, J. Lambert, et al. 2021;22(4):e552-e554. Case report PubMed · Publisher

• Delayed-Phase Enhancement for Evaluation of Malignant Pleural Mesothelioma on Computed Tomography: A Prospective Cohort Study. A. Patel, L. Roshkovan, S. McNulty, et al. 2021;22(3):210-217.e1. PubMed · Publisher

  Abstract

  Background: Radiologic assessment of malignant pleural mesothelioma (MPM) on computed tomography (CT) imaging can be limited by similar attenuations of MPM and adjacent tissues. This can result in inaccuracies in defining the presence and extent of pleural tumor burden. We hypothesized that increasing the time delay for pleural enhancement will optimize discrimination between MPM and noncancerous tissues on CT. Here we conduct a prospective observational study to determine the optimal time delay for imaging MPM on CT.

  Patients And Methods: Adult MPM patients (n = 15) were enrolled in this prospective exploratory imaging trial. Patients with < 1 cm MPM thickness, prior pleurectomy, pleurodesis, pleural radiotherapy, or antiangiogenic therapy were excluded. All patients underwent a dynamically-enhanced CT with multiple time delays (0 - 10 minutes) after intravenous contrast administration. Tumor tissue attenuation was measured at each phase of enhancement. A qualitative assessment of tumor enhancement kinetics was also performed. The optimal phase of enhancement based on qualitative lesion conspicuity and quantitative tumor enhancement was then compared.

  Results: MPM tumor enhancement was quantitatively and qualitatively increased at time delays beyond the conventional time delay for thoracic CT imaging (40-60 seconds). Patient tumor enhancement kinetics, displayed as the fraction of maximal tumor tissue attenuation as a function of time, revealed an optimal time delay of 230 to 300 seconds after intravenous contrast administration. There was an association between degree of tumor enhancement and subjective lesion conspicuity.

  Conclusion: Optimal MPM contrast enhancement occurs at a later phase than typically acquired with conventional thoracic CT imaging.

  Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

• Mesothelioma Micronodular Metastasis Pattern Confirmed by Transbronchial Cryobiopsy: Case Report. J.W. Kerkhoff, W. Vreuls, L.C. Vermeer. 2021;22(4):e533-e535. Case report PubMed · Publisher

• PD-1/PD-L1 Checkpoint Inhibitor Immunotherapy for Malignant Pleural Mesothelioma: Case Series and Literature Review. M. Zhou, N. Joshi, K.P. Raj, et al. 2021;22(3):e329-e335. Review PubMed · Publisher

  Abstract

  Study design: A retrospective, single-center, case series Introduction: Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm with poor prognosis. The combined cisplatin/pemetrexed regimen is the only regimen currently approved by the FDA. Immunotherapy with checkpoint inhibitors and other therapeutics are quickly becoming the preferred second-line therapy following incorporation into clinical practice guidelines in 2018 as a salvage therapy. Purpose of the study: To describe the use of PD-1/PD-L1 targeted therapy to manage MPM. Methods: Retrospective chart review of patients with MPM treated at a single institution with pembrolizumab or nivolumab was performed. Clinical and pathologic information were extracted and clinical response rate and other outcomes were assessed. Results: Twelve patients received pembrolizumab, and two patients received nivolumab. Patients were 43% male (6 out of 14), 64% non-Hispanic white (9 out of 14), and 93% epithelioid histological subtype (13 out of 14). Prior to immunotherapy, 36% had received surgical resection (5 out of 14), 36% had received radiotherapy (5 out of 14), and 93% received platinum-pemetrexed based chemotherapy (13 out of 14). Objective response rate was 21% (0 CR and 3 PRs), and disease control rate was 43% (3 PRs and 3 SDs). Time to progression ranged from <1 month to 19 months. Conclusion: Based on this small series, real-world PD-1/PD-L1 targeted therapy appears to be a promising treatment for patients with MPM who have disease progression on systemic chemotherapy, consistent with small single arm clinical trials. Further investigation with multicenter, prospective longitudinal cohorts and/or randomized clinical trials may help identify which patients have the largest magnitude of benefit.

  PubMed has no abstract for this study. This is the authors' abstract, copied from the article.

• Three Decades of Malignant Pleural Mesothelioma: An Academic Center Experience. A. Nasser, A. Baird, M.D. Saint-Pierre, et al. 2021;22(5):441-448. PubMed · Publisher

  Abstract

  Background: Malignant pleural mesothelioma (MPM) remains a challenging disease to manage. In the past few decades, extrapleural pneumonectomy (EPP), pemetrexed-based chemotherapy, and indwelling pleural catheters were introduced to MPM care with variable levels of efficacy and evidence.

  Patients And Methods: This was a retrospective review of patients diagnosed with MPM between January 1991 and March 2019. The primary outcome was overall survival (OS). Data were examined by decade to assess trends in MPM demographics, management, and OS. A subgroup analysis was then conducted to examine the impact of EPP, pemetrexed, and indwelling pleural catheters on OS.

  Results: The study included 337 patients; 309 patients had died at last follow-up (91.7%). Median age at diagnosis and the proportion of female patients increased from 65.8 years (interquartile range [IQR], 57.1-73.7) and 11.6% female from 1991 to 1999 to 75 years (IQR, 68.1-80.6) and 20.5% female from 2010 to 2019. Median OS was largely unchanged in the three study periods: 9.0 months (95% confidence interval [CI], 6.9-12.7) in the 1991-1999 cohort, 9.3 months (95% CI, 7.6-13.2) in the 2000-2009 cohort, and 10.1 months (95% CI, 7.9-13.6) in the 2010-2019 cohort. Controlling for a number of demographic and prognostic factors, EPP (hazard ratio [HR] = 0.50; 95% CI, 0.3-0.9; P = .02), pemetrexed-based chemotherapy (HR = 0.59; 95% CI, 0.40-0.87; P = .007), and indwelling pleural catheters (HR = 0.3; 95% CI, 0.13-0.71; P = .006) were each associated with improvements in OS.

  Conclusion: Despite the small incremental improvements in survival shown by the three interventions we examined, prognosis remains guarded for MPM patients. Better modalities of management are needed.

  Copyright © 2021. Published by Elsevier Inc.

• Trabectedin in Malignant Pleural Mesothelioma: Results From the Multicentre, Single Arm, Phase II ATREUS Study. D. Cortinovis, F. Grosso, L. Carlucci, et al. 2021;22(4):361-370.e3. PubMed · Publisher

  Abstract

  Introduction: New therapeutic approaches in unresectable malignant pleural mesothelioma (MPM) are eagerly awaited. Trabectedin is an antitumor agent with an effect on cancer cell proliferation and a modulating action on tumor microenvironment. The ATREUS study explored the activity and safety of trabectedin in patients with unresectable MPM.

  Methods: Epithelioid patients with MPM received trabectedin as second-line while biphasic/sarcomatoid patients with MPM as first- or second-line therapy. Treatment was given intravenously at an initially planned dose of 1.3 mg/m2 every 3 weeks, until progression or unacceptable toxicity. The primary endpoint was progression-free survival rate at 12 weeks (PFS12wks).

  Results: Overall, 78 patients (54%) had epithelioid and 67 (46%) nonepithelioid MPM. PFS12wks in 62 evaluable patients with epithelioid MPM was 43.5% (80% confidence interval 34.9%-52.5%); median progression-free and overall survival were 2.4 and 9.0 months, respectively. PFS12wks in 52 evaluable patients with nonepithelioid MPM was 30.8% (90% confidence interval 20.3%-42.9%); median progression-free and overall survival were 1.7 and 5.4 months. Trabectedin starting dose was amended due to excess of liver toxicity. Eighty-four (64%) and 48 (36%) patients received 1.3 mg/m2 and 1.1. mg/m2, respectively. The most common grade 3-4 toxicities were hepatotoxicity, leukopenia/neutropenia, and fatigue. Grade 3-4 hepatotoxicity was reported in 59 (70%) patients treated at 1.3 mg/m2, and in 19 (40%) treated at 1.1 mg/m2.

  Conclusions: Trabectedin showed modest clinical activity, at the expense of relevant liver toxicity. Further development of this drug in MPM at full doses is not warranted.

  Copyright © 2020 Elsevier Inc. All rights reserved.

• Clinical Features in Patients With Malignant Pleural Mesothelioma With 5-Year Survival and Evaluation of Original Diagnoses. J. Paajanen, S. Laaksonen, I. Ilonen, et al. 2020;21(6):e633-e639. PubMed · Publisher

  Abstract

  Introduction: Malignant pleural mesothelioma (MPM) is a fatal malignancy strongly associated with previous asbestos exposure. Overall survival remains dismal, partly owing to poor response to available treatment. The aims of this study were to evaluate diagnostic accuracy in a group of patients with MPM with an unusually long survival time and to assess the factors related to this prolonged survival.

  Materials And Methods: Forty-three patients with overall survival exceeding 5 years were accepted to the long-term survivor (LTS) group, and these patients were compared with 84 patients with epithelial MPM. Data were collected from various national registries and electronic medical records. In addition, all available histopathologic diagnostic samples and computed tomography studies were re-evaluated by experienced specialists.

  Results: Our study showed a good diagnostic accuracy, with only 1 (0.5%) patient having an incorrect MPM diagnosis. Two (0.9%) localized malignant mesotheliomas and 2 (0.9%) well-differentiated papillary mesotheliomas were also found. LTS patients were younger, more frequently female, had a better performance status at time of diagnosis, and had less evidence of prior asbestos exposure. In multivariate analysis, we showed tumor size, Eastern Cooperative Oncology Group performance status, and first-line treatment (both surgery and chemotherapy) to be associated with survival time.

  Conclusion: We confirmed the diagnosis of MPM in an overwhelming majority of patients in the LTS group. An epithelial subtype of MPM behaving clinically more indolently seems to exist, but further tumor and genetic characterization is needed. The prolonged survival time is most likely explained by a combination of tumor-, patient-, and treatment-related factors.

  Copyright © 2020 Elsevier Inc. All rights reserved.

• Clinical Trials Eligibility of Patients With Malignant Pleural Mesothelioma: Use of Novel Therapies and Outcomes. B. Lau, M. Boyer, J.H. Lee, et al. 2020;21(4):378-383.e1. PubMed · Publisher

  Abstract

  Introduction: Studies of bevacizumab and pembrolizumab in the treatment of malignant pleural mesothelioma suggest anticancer efficacy; clinical trial populations are not reflective of real-world patients. We aimed to determine the proportion of real-world patients who would be eligible for trials, identify patients who participated in clinical trials, and examine treatment and outcome data.

  Patients And Methods: Consecutive patients with unresectable malignant pleural mesothelioma seen at our center from January 2012 to July 2018 were assessed with regards to their eligibility for Mesothelioma Avastin Cisplatin Study (MAPS) and KEYNOTE-028 clinical trials. Prognostic information, treatment use, and overall survival (OS) data were also collected.

  Results: A total of 133 patients were included: 50% and 37%, respectively, did not meet trial eligibility for MAPS or KEYNOTE-028, most commonly owing to age ≥75 (23%), Eastern Cooperative Oncology Group performance status of ≥2 (21%), concomitant medication (21%), or comorbidity (12%). MAPS eligibility did not correlate with use of bevacizumab (P = .30) or improved OS (P = .87). Eligibility for KEYNOTE-028 correlated with pembrolizumab use (P < .001), but not improved OS (P = .21). Patients who received an investigational anticancer therapy on any clinical trial had improved OS: 32.4 (95% CI, 23.9-40.9) months versus 20.5 (95% CI, 15.8-25.3) months (P = .01).

  Conclusion: Only ≤63% of our patients were eligible for these trials, highlighting the differences between real-world patients and the highly select trial population. Our patients who participated in clinical trials had superior OS, further emphasizing the selection bias in the trial population.

  Copyright © 2020 Elsevier Inc. All rights reserved.

• Elevated Circulating Activin A Levels in Patients With Malignant Pleural Mesothelioma Are Related to Cancer Cachexia and Reduced Response to Platinum-based Chemotherapy. J. Paajanen, I. Ilonen, H. Lauri, et al. 2020;21(3):e142-e150. PubMed · Publisher

  Abstract

  Background: Previous preclinical studies have shown that activin A is overexpressed in malignant pleural mesothelioma (MPM), associates with cancer cachexia, and is observed in in vitro resistance to platinum-based chemotherapy. We evaluated circulating activin levels and their endogenous antagonists' follistatin/follistatin-like 3 in intrathoracic tumors.

  Materials And Methods: Patients suspected of thoracic malignancy were recruited prior to surgery. Serum samples were collected from 21 patients with MPM, 59 patients with non-small-cell lung cancer (NSCLC), and 22 patients with benign lung lesions. Circulating activin/follistatin levels were measured using enzyme-linked immunosorbent assay and compared with clinicopathologic parameters.

  Results: Circulating activin A levels were elevated in patients with MPM when compared with patients with NSCLC or benign lung lesion samples (P < .0001). Also, follistatin and follistatin-like 3 levels were the highest in MPM, although with less difference compared with activin A. Receiver operating characteristic analysis for activin A for separating NSCLC from benign lung lesion showed an area under the curve of 0.856 (95% confidence interval, 0.77-0.94). Activin A levels were higher in patients with cachexia (P < .001). In patients with MPM, activin A levels correlated positively with computed tomography-based baseline tumor size (R = 0.549; P = .010) and the change in tumor size after chemotherapy (R = 0.743; P = .0006). Patients with partial response or stable disease had lower circulating activin A levels than the ones with progressive disease (P = .028).

  Conclusion: Activin A serum level could be used as a biomarker in differentiating malignant and benign lung tumors. Circulating activin A levels were elevated in MPM and associates with cancer cachexia and reduced chemotherapy response.

  Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

• Gender-based Disparities in Receipt of Care and Survival in Malignant Pleural Mesothelioma. A.R. Barsky, C.A. Ahern, S. Venigalla, et al. 2020;21(6):e583-e591. PubMed · Publisher

  Abstract

  Background: Despite accounting for a minority of malignant pleural mesothelioma (MPM) diagnoses, females may experience differential survival relative to males. It is unclear if there are gender-based differences in receipt of treatment or disease-related outcomes for patients with MPM. We therefore utilized the National Cancer Database (NCDB) to assess patterns-of-care and overall survival (OS) among patients with MPM by gender.

  Materials And Methods: Patients with histologically confirmed MPM treated from 2004 to 2013 were identified from the NCDB. The association between female gender and OS was assessed using multivariable Cox proportional hazards models with propensity score matching. Patterns-of-care were assessed using multivariable logistic regression. The overall treatment effect was tested in subsets of patients by treatment strategy, histology, and clinical stage.

  Results: A total of 18,799 patients were identified, of whom 14,728 (78%) were male and 4071 (22%) were female. Females were statistically more likely to present at a younger age, with fewer comorbidities, and with epithelioid histology. Despite these favorable prognostic features, women were less likely to receive surgery (P ≤ .001) or chemotherapy (P ≤ .001) compared with males. On multivariable analysis, female gender was associated with improved OS (hazard ratio, 0.83; 95% confidence interval, 0.80-0.86; P ≤ .001). Gender-based survival differences were seen across all stages, but only among patients with epithelioid (P ≤ .001) and not biphasic (P = .17) or sarcomatoid (P = 1.00) histology.

  Conclusions: Surgery and chemotherapy are disproportionately underutilized in female patients with MPM. Despite this concerning disparity, female gender is independently associated with improved survival relative to males. Further research to understand factors that lead to gender disparities in MPM is warranted.

  Copyright © 2020 Elsevier Inc. All rights reserved.

• Impact of Detecting Occult Pathologic Nodal Disease During Resection for Malignant Pleural Mesothelioma. V. Verma, R.E. Wegner, J.M. Stahl, et al. 2020;21(4):e274-e285. PubMed · Publisher

  Abstract

  Background: Lymph node (LN) involvement is a poor prognostic factor for malignant pleural mesothelioma (MPM). However, to our knowledge, postresection outcomes of node-negative (cN0/pN0), occult pathologic nodal disease (cN0/pN+), and clinical node-positive disease (cN+) have not been compared to date.

  Patients And Methods: The National Cancer Data Base was queried for newly diagnosed, resected MPM with known clinical/pathologic LN information. Three cohorts were compared: cN0/pN0, cN+, and cN0/pN+. Multivariable logistic regression examined predictors of pathologic nodal upstaging. Kaplan-Meier analysis with propensity matching assessed overall survival (OS); multivariate Cox proportional hazards modeling examined predictors thereof.

  Results: Of 1369 patients, 687 (50%) had cN0/pN0, 457 (33%) cN+, and 225 (16%) cN0/pN+ disease. Median follow-up was 29 months. In patients with cN0 disease, factors associated with pathologic nodal upstaging were younger age, greater number of examined LNs, and nonsarcomatoid histology (P < .05 for all). Relative to pN0 cases, occult LN involvement (65% being pN2) was associated with 51% higher hazard of mortality on multivariate analysis (P = .005). Following propensity matching, the OS of cN0/pN+ was similar to cN+ cases (P = .281). On multivariate analysis, the number of involved LNs (continuous variable, P = .013), but not nodal tumor, node, metastasis (TNM) classification or LN ratio (P > .05 for both), was associated with OS.

  Conclusion: Detecting occult nodal disease during resection for cN0 MPM is associated with poorer prognosis, with similar survival as cN+ cases, underscoring the importance of routine preoperative pathologic nodal assessment for potentially resectable MPM. The number of involved LNs (rather than current location-based classification) may provide more robust prognostic stratification for future TNM staging.

  Copyright © 2020 Elsevier Inc. All rights reserved.

• Randomized Study of Maintenance Pemetrexed Versus Observation for Treatment of Malignant Pleural Mesothelioma: CALGB 30901. A.Z. Dudek, X. Wang, L. Gu, et al. 2020;21(6):553-561.e1. Randomized trial PubMed · Publisher · Free full text

  Abstract

  Background: The role of maintenance therapy for malignant pleural mesothelioma (MPM) is unknown. We performed a randomized phase II trial to determine if continuation of pemetrexed after first-line pemetrexed and platinum would improve progression-free survival (PFS).

  Patients And Methods: Eligible patients with unresectable MPM, without disease progression following 4 to 6 cycles of pemetrexed and platinum were randomized 1:1 to observation or continuation of pemetrexed until progression, stratified by number of cycles (< 6 or 6), cis- or carboplatin containing regimen, and histology. Study size was calculated based on the assumption that observation would produce a median PFS of 3 months and pemetrexed would yield median PFS of 6 months.

  Results: A total of 72 patients were registered from December 2010 to June 2016. The study closed early after 53 patients were randomized; 49 eligible (22 on the observation arm and 27 on the pemetrexed arm) were included in the analysis. The median PFS was 3 months (95% confidence interval [CI], 2.6-11.9 months) on observation and 3.4 months (95% CI, 2.8-9.8 months) on pemetrexed (hazard ratio [HR], 0.99; 95% CI, 0.51-1.90; P = .9733). The median overall survival (OS) was 11.8 months (95% CI, 9.3-28.7 months) for observation, and 16.3 months (95% CI, 10.5-26.0 months) for pemetrexed (HR, 0.86; 95% CI, 0.44-1.71; P = .6737). Grade 3 or 4 toxicities on the pemetrexed arm included anemia (8%), lymphopenia (8%), neutropenia (4%), and fatigue (4%). A higher baseline level of soluble mesothelin-related peptide was associated with worse PFS (HR, 1.86; 95% CI, 1.00-3.46; P = .049).

  Conclusion: Maintenance pemetrexed following initial pemetrexed and platinum chemotherapy does not improve PFS in patients with MPM.

  Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

2010s

• Moderately Hypofractionated Helical IMRT, FDG-PET/CT-guided, for Progressive Malignant Pleural Mesothelioma in Patients With Intact Lungs. A. Fodor, S. Broggi, E. Incerti, et al. 2019;20(1):e29-e38. PubMed · Publisher

  Abstract

  Introduction: The objective of this study was to present the outcomes of moderately hypofractionated helical intensity-modulated radiation therapy (HT) with/without simultaneous integrated boost (SIB) on fluorodeoxyglucose-positron emission tomography (FDG-PET) positive areas (gross tumor volume [GTV]-PET) for patients with progressive malignant pleural mesothelioma (MPM) after previous treatments.

  Methods And Materials: From May 2006 to April 2014, 51 patients with a median age of 68.8 years (range, 38.6-82 years) were treated. There were 41 men and 10 women; 43 epithelioid MPM and 8 sarcomatoid, involving the left pleura in 25 patients and the right pleura in 26 patients. The initial stage was: I, 11 patients; II, 14 patients; III, 17 patients; and IV, 9 patients. Chemotherapy was prescribed for 46 patients, for 6 cycles (range, 0-18 cycles). Eighteen patients had pleurectomy/decortication, and 33 had talc pleurodesis. FDG-PET was used for target identification. A median dose of 56 Gy/25 fractions was prescribed to the involved pleura, and SIB to 62.5 Gy to GTV-PET was added in 38 patients.

  Results: The median survival from diagnosis was 25.8 months (range, 8.4-99.0 months). One patient, treated with SIB, was alive at the October 2017 follow-up. Two cases of grade 5 radiation pneumonitis were registered. A GTV-PET ≤ 205 cc was predictive of late ≥ grade 2 lung toxicity, but also of better survival in stage III and IV disease: 5.9 versus 11.7 months (P = .04). A GTV-PET ≥ 473 cc was predictive of early death (P = .001).

  Conclusions: Moderately hypofractionated, FDG-PET guided salvage HT in patients with progressive MPM after previous treatments showed acceptable toxicity and outcome results similar to adjuvant radiotherapy after pleurectomy/decortication, suggesting that the delay of radiotherapy is not detrimental to survival, and has the associated benefit of postponing inherent toxicity.

  Copyright © 2018 Elsevier Inc. All rights reserved.

• Shorter Survival in Malignant Pleural Mesothelioma Patients With High PD-L1 Expression Associated With Sarcomatoid or Biphasic Histology Subtype: A Series of 214 Cases From the Bio-MAPS Cohort. S. Brosseau, C. Danel, A. Scherpereel, et al. 2019;20(5):e564-e575. Randomized trial PubMed · Publisher

  Abstract

  Background: Anticancer immune responses are negatively regulated by programmed cell death 1 (PD-1) T-cell membrane protein interaction with its ligand, programmed death ligand 1 (PD-L1), on cancer cells. We sought to assess the prognostic role of PD-L1 expression in tumor samples from patients enrolled onto the IFCT-0701 MAPS randomized phase 3 trial (NCT00651456).

  Patients And Methods: Tumor samples were analyzed by immunohistochemistry for percentages of PD-L1 membrane-stained tumor cells using the E1L3N clone, and data were correlated to survival by multivariate Cox models including stratification variables.

  Results: PD-L1 staining was assessed in 214 (47.75%) of 448 patients. Epithelioid subtype represented 83.7% (179/214). Absence of PD-L1 staining occurred in 137 (64.1%) of 214 malignant pleural mesothelioma (MPM) samples, while 77 (35.9%) of 214 were PD-L1 positive, with 50 (64.9%) of 77 showing < 50% PD-L1-expressing tumor cells. Sarcomatoid/biphasic subtypes were more commonly PD-L1 positive than epithelioid subtype (P < .001). In patients with 1% or more PD-L1-stained tumor cells, median overall survival (OS) was 12.3 months versus 22.2 months for other patients (hazard ratio [HR] = 1.25; 95% confidence interval [CI], 0.93-1.67; P = .14). OS did not differ according to PD-L1 positivity in multivariate analyses (adjusted HR = 1.10; 95% CI, 0.81-1.49; P = .55). With a 50% cutoff, PD-L1-positive patients displayed a 10.5 months median OS versus 19.3 months for patients with lower PD-L1 expression (HR = 1.93; 95% CI, 1.27-2.93; P = .002). OS did not significantly differ in adjusted Cox models (adjusted HR = 1.20; 95% CI, 0.74-1.94; P = .47). In the 179 epithelioid MPM patients, high PD-L1 staining (≥ 50% of tumor cells) negatively affected OS, although not significantly, showing a 12.3-month median OS (95% CI, 4.3-21.6) versus 23-month (95% CI, 18.5-25.2) for patients with tumor PD-L1 staining in < 50% cells (P = .071). The progression-free survival (PFS) differences were statistically significant, with a longer 9.9-month median PFS in patients with low PD-L1 staining (< 50% cells) compared to 6.7 months of median PFS in patients with high PD-L1 expression (≥ 50% cells) (P = .0047).

  Conclusion: Although high PD-L1 tumor cell expression was associated with poorer OS in MPM patients from the MAPS trial, its prognostic influence was lost in multivariate analyses in the whole cohort, while PD-L1 expression was strongly associated with the sarcomatoid/biphasic subtypes. In the epithelioid MPM subset of patients, high PD-L1 tumor expression (≥ 50%) negatively affected OS and PFS, with this prognostic influence remaining statistically significant for PFS after adjustment in multivariate Cox model.

  Copyright © 2019 Elsevier Inc. All rights reserved.

• The Prognostic Role of TNM Staging Compared With Tumor Volume and Number of Pleural Sites in Malignant Pleural Mesothelioma. C. Proto, D. Signorelli, S. Mallone, et al. 2019;20(6):e652-e660. PubMed · Publisher

  Abstract

  Background: Age, sex, stage, histotype, and surgery are the most recognized prognostic factors for malignant pleural mesothelioma (MPM). Tumor volume (TV) was suggested as an alternative prognostic evaluation. We aimed to assess the prognostic role of Tumor, Node, Metastases (TNM) versus TV and number of pleural sites (NPS).

  Patients And Methods: Information on stage, TV, and NPS was collected for 52 MPM patients (pts) at our institution from 2009 to 2012. Baseline computed tomography imaging was performed to define TNM, TV, and NPS. Pts were divided in 3 stage groups: early (I-II), III, and IV. A dedicated computer system calculated TV. Pts were divided in 2 groups according to mean baseline TV (483 cm3). NPS was defined on the basis of the NPS macroscopically involved by disease (1-3). The association between TNM, tumor size (T), TV, NPS, TV and NPS, and overall survival was assessed using Cox models adjusted for age, sex, histology, and treatment.

  Results: Most pts were male; mean age was 62 years. We showed an association between TV, TNM, and T. Stage III (hazard ratio [HR], 4.71; P = .02) and IV (HR, 7.40; P < .01), T3 (HR, 5.07; P < .01) and T4 (HR, 5.09; P < .01), TV > 483 cm3 (HR, 3.47; P < .01) and NPS 2 (HR, 3.00; P = .08) and 3 (HR, 6.05; P < .01) were predictive of worse survival. However, the TV and NPS combination performed better than TV, NPS, and TNM alone as a prognostic classifier.

  Conclusion: We showed that TV is related to TNM staging and T, in particular. Improved prognostic performance might be achievable using quantitative clinical staging combining TV and NPS.

  Copyright © 2019 Elsevier Inc. All rights reserved.

• Treatment and Outcomes of Primary Pericardial Mesothelioma: A Contemporary Review of 103 Published Cases. E. McGehee, D.E. Gerber, J. Reisch, et al. 2019;20(2):e152-e157. Systematic review PubMed · Publisher

  Abstract

  Primary pericardial mesothelioma (PPM) is a rare cancer for which there is no consensus on treatment. We evaluated and summarized a large contemporary population of published PPM cases to characterize risk factors, treatment patterns, and clinical outcomes. Using Ovid and PubMed, literature published from 2000 through 2016 was searched using the terms "primary pericardial mesothelioma," "pericardial mesothelioma," and "malignant pericardial mesothelioma." We identified 6 case series and 84 case reports for a total of 103 PPM cases published from 2000 through 2016. The median age at diagnosis was 55 years, and the median overall survival was 6 months. In univariate analyses of clinical characteristics including gender, asbestos exposure, tobacco use, prior radiation exposure, histologic subtype, and metastasis and/or mediastinal spread, only the presence of metastasis and/or mediastinal spread was a significant predictor of decreased survival (P = .015). Surgery did not provide a statistically significant survival benefit (P = .12). A survival benefit was noted in those who received chemotherapy (median survival, 13 months vs. 0.5 months, P = .002), specifically chemotherapy with a platinum agent with or without pemetrexed. In multivariate analysis, only the receipt of chemotherapy was associated with improved survival. PPM remains a rare and poorly understood malignancy with unclear etiology and a poor prognosis. In this retrospective systematic review, a survival benefit was seen in patients who received chemotherapy.

  Copyright © 2018 Elsevier Inc. All rights reserved.

• A Phase II Trial of First-Line Combination Chemotherapy With Cisplatin, Pemetrexed, and Nivolumab for Unresectable Malignant Pleural Mesothelioma: A Study Protocol. N. Fujimoto, K. Aoe, T. Kozuki, et al. 2018;19(5):e705-e707. PubMed · Publisher

  Abstract

  Background: The purpose of this study is to assess the efficacy and safety of combination chemotherapy with cisplatin, pemetrexed, and nivolumab for unresectable malignant pleural mesothelioma (MPM).

  Patients And Methods: Patients with untreated, advanced, or metastatic MPM who meet the inclusion and exclusion criteria will be included. A total of 18 patients will be enrolled from 4 Japanese institutions within 1 year. Combination chemotherapy with cisplatin (75 mg/m2), pemetrexed (500 mg/m2), and nivolumab (360 mg/person) is administered every 3 weeks for a total of 4 to 6 cycles. Then, maintenance therapy with nivolumab will be administered until disease progression, unacceptable toxicities, or the patient's condition meets the withdrawal criteria. The primary end point is the centrally reviewed overall response rate. The secondary end points include the disease control rate, overall survival, progression-free survival, and adverse events.

  Conclusion: This phase II trial evaluating first-line combination chemotherapy for unresectable MPM commenced in January 2018. This is the first prospective trial to evaluate the effect of an anti-programmed death-1 antibody combined with cisplatin and pemetrexed for unresectable MPM.

  Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

• Safety of Same-Day Vitamin B12 Supplementation in Patients Receiving Pemetrexed for the Treatment of Non-Small-Cell Lung Cancer or Pleural Mesothelioma: A Retrospective Analysis. Z. Schlei, W. Tan, M.G. Faber, et al. 2018;19(6):467-475. PubMed · Publisher

  Abstract

  Background: Pemetrexed is a folate analog inhibitor for the treatment of non-small-cell lung cancer (NSCLC) and malignant pleural mesothelioma. Folic acid and vitamin B12 supplementation before initiating pemetrexed is necessary because of high rates of cytopenias without supplementation. However, the timing of supplementation has not been thoroughly investigated.

  Patients And Methods: This was a single-center, retrospective study investigating patients receiving pemetrexed from January 1, 2012, to June 30, 2015, who received same-day vitamin B12 supplementation versus ≥ 1 day before pemetrexed. The objective was to evaluate safety outcomes in patients who received vitamin B12 on the same day as pemetrexed (group A) versus vitamin B12 ≥ 1 day (group B) before pemetrexed.

  Results: Two hundred eighty-one patients met the inclusion criteria: 137 patients in group A (same-day administration of vitamin B12) and 144 patients in group B (median time of vitamin B12 administration before pemetrexed, 7 days; range, 1-42 days). Mean changes in hematologic indices from cycle (C) 1 to C2 or C2 to C3 did not differ significantly between groups. There were no significant differences in clinical events between C1 and C2 or C2 and C3 requiring supportive care. There was a significant difference noted in treatment delay in C3 [28/114 (24.6%) group A vs. 14/118 (11.9%) group B, P = .0164]. In group A, significant predictors of delay in C3 were baseline hemoglobin (mean 13.3 g/dL vs. 12.4 g/dL, P = .0137) and ANC (mean 6 × 109/L vs. 5 × 109/L, P = .0003).

  Conclusion: Same-day vitamin B12 and pemetrexed administration is a safe practice in NSCLC and malignant pleural mesothelioma patients.

  Copyright © 2018 Elsevier Inc. All rights reserved.

• Survival by Histologic Subtype of Malignant Pleural Mesothelioma and the Impact of Surgical Resection on Overall Survival. V. Verma, C.A. Ahern, C.G. Berlind, et al. 2018;19(6):e901-e912. PubMed · Publisher

  Abstract

  Introduction: For the 3 histologic subtypes of malignant pleural mesothelioma (MPM)-epithelioid, sarcomatoid, and biphasic-the magnitude of benefit with surgical management remains underdefined.

  Materials And Methods: The National Cancer Data Base was queried for newly diagnosed nonmetastatic MPM with known histology. Patients in each histologic group were dichotomized into those receiving gross macroscopic resection versus lack thereof/no surgery. Kaplan-Meier analysis evaluated overall survival (OS) between cohorts; multivariable Cox proportional hazards modeling assessed factors associated with OS. After propensity matching, survival was evaluated for each histologic subtype with and without surgery.

  Results: Overall, 4207 patients (68% epithelioid, 18% sarcomatoid, 13% biphasic) met the study criteria. Before propensity matching, patients with epithelioid disease experienced the highest median OS (14.4 months), followed by biphasic (9.5 months) and sarcomatoid (5.3 months) disease; this also persisted after propensity matching (P < .001). After propensity matching, surgery was associated with significantly improved OS for epithelioid (20.9 vs. 14.7 months, P < .001) and biphasic (14.5 vs. 8.8 months, P = .013) but not sarcomatoid (11.2 vs. 6.5 months, P = .140) disease. On multivariable analysis, factors predictive of poorer OS included advanced age, male gender, uninsured status, urban residence, treatment at community centers, and T4/N2 disease (all P < .05). Chemotherapy and surgery were independently associated with improved OS, as was histology (all P < .001).

  Conclusion: This large investigation evaluated surgical practice patterns and survival by histology for MPM and found that histology independently affects survival. Gross macroscopic resection is associated with significantly increased survival in epithelioid and biphasic, but not sarcomatoid, disease. However, the decision to perform surgery should continue to be individualized in light of available randomized data.

  Copyright © 2018 Elsevier Inc. All rights reserved.

• Utilization of Intensity-Modulated Radiation Therapy for Malignant Pleural Mesothelioma in the United States. S.G. Shaaban, V. Verma, J.I. Choi, et al. 2018;19(5):e685-e692. PubMed · Publisher

  Abstract

  Background: Although postoperative radiotherapy (RT) for malignant pleural mesothelioma (MPM) has historically been delivered using 3-dimensional conformal RT (3DCRT) techniques, multiple reports show noteworthy safety and efficacy of the more advanced intensity-modulated RT (IMRT). To our knowledge, this is the only known study to evaluate national practice patterns of IMRT utilization for MPM.

  Materials And Methods: The National Cancer Data Base was queried for newly-diagnosed MPM patients who underwent definitive surgery (extrapleural pneumonectomy [EPP] or extended pleurectomy/decortication [P/D]) followed by adjuvant RT. Patients with metastatic disease, non-EPP or P/D surgical techniques, and lack of RT receipt (or without specified RT technique) were excluded. Statistics included multivariable logistic regression, Kaplan-Meier overall survival (OS) analysis, and Cox proportional hazards modeling.

  Results: Overall, 286 patients met criteria (181 [63%] IMRT and 105 [37%] 3DCRT). Temporal trends revealed that although 3DCRT was more common at initial time periods, IMRT utilization rose from 2004 to 2007 and stayed as a relatively constant majority thereafter. This was also present when substratifying the cohort according to EPP versus P/D approaches. IMRT was more often delivered at academic centers, along with institutions in the Southern United States, whereas 3DCRT was more frequently utilized in community facilities and in the Northeast (P ≤ .05 for all). RT technique did not affect OS (P > .05 for all comparisons).

  Conclusion: In the United States, IMRT is now the most commonly utilized adjuvant RT technique for MPM. Facility and regional differences might associate with IMRT delivery. The findings of this investigation have implications for insurance coverage, clinical referral patterns, and ongoing and future prospective trial design.

  Copyright © 2018 Elsevier Inc. All rights reserved.

• LUME-Meso: Design and Rationale of the Phase III Part of a Placebo-Controlled Study of Nintedanib and Pemetrexed/Cisplatin Followed by Maintenance Nintedanib in Patients With Unresectable Malignant Pleural Mesothelioma. G.V. Scagliotti, R. Gaafar, A.K. Nowak, et al. 2017;18(5):589-593. Randomized trial PubMed · Publisher

  Abstract

  Malignant pleural mesothelioma (MPM) is a rare but aggressive disease: median survival is 6 to 9 months if untreated. Standard first-line treatment for patients with unresectable MPM is cisplatin/pemetrexed, with a median overall survival (OS) of approximately 1 year. Improvements in first-line treatment options are needed. With the benefit of combining bevacizumab with standard therapy shown in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS), vascular endothelial growth factor (VEGF) pathway inhibition has gained renewed interest as a treatment approach. Nintedanib is an oral angiokinase inhibitor targeting multiple signaling pathways implicated in the pathogenesis of MPM, including the VEGF receptor. The phase III part of the international, phase II/III LUME-Meso study is evaluating the efficacy and safety of nintedanib plus pemetrexed/cisplatin in patients with unresectable epithelioid MPM. Originally, this was a double-blind, randomized, phase II exploratory study and was amended to include a confirmatory phase III part following the recommendation of an internal Data Monitoring Committee and review of phase II data. The phase III part plans to enroll 450 chemotherapy-naive patients, who will be randomized to receive pemetrexed/cisplatin on day 1 and nintedanib or placebo on days 2 to 21, for a maximum of 6 cycles. Patients without disease progression who are eligible to continue study treatment will receive maintenance treatment with nintedanib or placebo until disease progression or undue toxicity. The primary end point is progression-free survival; OS is the key secondary end point. The study will use an adaptive design, including an interim analysis to reassess the number of OS events required to ensure sufficient power for OS analysis. The study is currently enrolling patients.

  Copyright © 2017 Elsevier Inc. All rights reserved.

• The Controlling Nutritional Status Score Is a Significant Independent Predictor of Poor Prognosis in Patients With Malignant Pleural Mesothelioma. S. Takamori, G. Toyokawa, K. Taguchi, et al. 2017;18(4):e303-e313. PubMed · Publisher

  Abstract

  Introduction: Malignant pleural mesothelioma (MPM) is a devastating neoplasm; however, some patients exhibit a good response to chemotherapy or multidisciplinary therapy, including surgery and chemotherapy. It is therefore important to discover the factors that can be used to select patients who will benefit from such treatment. Although the Controlling Nutritional Status (CONUT) score has been used to predict the prognosis in other types of malignancy, its utility in patients with MPM is unknown. The aim of this study was to clarify the clinical significance of the CONUT in patients with MPM.

  Methods: The data of 83 patients, who were treated with surgery, chemotherapy, or multidisciplinary therapy, were analyzed in the present study. A cut-off CONUT score of 2 was used to classify all of the patients into low or high CONUT groups.

  Results: Fifty-two of the 83 patients were classified into the low CONUT group. A high CONUT score was significantly correlated with chemotherapy alone (P = .011). The high CONUT group had significantly poorer overall survival (OS) (P < .001) and disease- or progression-free survival (DFS/PFS) (P < .001). The clinical stage and the CONUT score were found to be independent predictive factors for the OS: clinical stage, I/II and III/IV; P = .001 and CONUT score, ≥ 3 and ≤ 2; P = .011, respectively. The clinical stage and the CONUT score were also independent predictive factors for DFS/PFS: clinical stage, I/II and III/IV; P = .006 and CONUT score, ≥ 3 and ≤ 2; P = .013, respectively.

  Conclusions: The CONUT score was an independent predictor of a poor prognosis in the patients with MPM. This score provides useful information for selecting patients who will benefit from the treatment.

  Copyright © 2017 Elsevier Inc. All rights reserved.

• Impact of Age on Long-Term Outcomes of Surgery for Malignant Pleural Mesothelioma. C.J. Yang, B.W. Yan, R.R. Meyerhoff, et al. 2016;17(5):419-426. PubMed · Publisher · Free full text

  Abstract

  Background: Although malignant pleural mesothelioma (MPM) is generally a disease associated with more advanced age, the association of age, treatment, and outcomes has not been well-characterized. We evaluated the impact of age on outcomes in patients with MPM to provide data for use in the treatment selection process for elderly patients with potentially resectable disease.

  Patients And Methods: Overall survival (OS) of patients younger than 70 and 70 years or older with Stage I to III MPM who underwent cancer-directed surgery or nonoperative management in the Surveillance, Epidemiology, and End Results database (2004-2010) was evaluated using multivariable Cox proportional hazard models and propensity score-matched analysis.

  Results: Cancer-directed surgery was used in 284 of 879 (32%) patients who met inclusion criteria, and was associated with improved OS in multivariable analysis (hazard ratio, 0.71; P = .001). Cancer-directed surgery was used much less commonly in patients 70 years and older compared with patients younger than 70 years (22% [109/497] vs. 46% [175/382]; P < .001), but patients 70 years and older had improved 1-year (59.4% vs. 37.9%) and 3-year (15.4% vs. 8.0%) OS compared with nonoperative management. The benefit of surgery in patients 70 years and older was observed even after propensity score-matched analysis was used to control for selection bias.

  Conclusion: Surgical treatment is associated with improved survival compared with nonoperative management for both patients younger than 70 years and patients aged 70 years or older.

  Copyright © 2016 Elsevier Inc. All rights reserved.

• Correlation between TS, MTHFR, and ERCC1 gene polymorphisms and the efficacy of platinum in combination with pemetrexed first-line chemotherapy in mesothelioma patients. T. Powrózek, D.M. Kowalski, P. Krawczyk, et al. 2014;15(6):455-65. PubMed · Publisher

  Abstract

  Introduction: The combination of pemetrexed and platinum compound represents the standard regimen for first-line chemotherapy in malignant pleural mesothelioma patients. Pemetrexed is a multitarget antifolate agent that inhibits folate-dependent enzymes (eg, thymidylate synthase [TS]) and thus synthesis of nucleotides and DNA. Expression of TS and folate availability, regulated by gene polymorphisms, have implications for effectiveness of chemotherapy and the outcome of mesothelioma patients. The aim of this retrospective multicenter study was to assess the correlation between TS, 5,10-methylenetetrahydrofolate reductase (MTHFR) and excision repair cross-complementing group 1 (ERCC1) gene polymorphisms and the efficacy of pemetrexed-based first-line chemotherapy of mesothelioma patients.

  Patients And Methods: Fifty-nine mesothelioma patients (31 men with a median age of 62 years) treated in first-line chemotherapy with platinum in combination with pemetrexed or pemetrexed monotherapy were enrolled. Genomic DNA was isolated from peripheral blood. Using polymerase chain reaction and high resolution melt methods, the variable number of tandem repeat, the G>C single nucleotide polymorphism (SNP) in these repeats, and 6-base pair (bp) insertion/deletion polymorphism of the TS gene, the SNP of 677C>T in MTHFR, and 19007C>T in the ERCC1 gene were analyzed and correlated with disease control rate, progression-free survival (PFS), and overall survival (OS) of mesothelioma patients.

  Results: Greater risk of early disease progression (PD), and shortening of PFS and OS were associated with several clinical factors (eg, anemia for early PD and OS), weight loss (for PFS and OS), and previous surgical treatment (for early PD, PFS, and OS). Insertion of 6-bp in both alleles of the TS gene (1494del6) was the only genetic factor that increased the incidence of early progression (P = .028) and shortening of median PFS (P = .06) in patients treated with pemetrexed-based chemotherapy. In multivariate analysis, the 1494del6 in the 3' untranslated region (UTR) of the TS gene also had a predictive role for PFS (P = .0185; hazard ratio, 2.3258 for +6/+6 homozygotes) in analyzed mesothelioma patients.

  Conclusion: Most analyzed polymorphisms in TS, MTHFR, and ERCC1 genes failed to predict outcome in mesothelioma patients treated with pemetrexed-based chemotherapy. However, different variants of 1494del6 in the 3' UTR of the TS gene were associated with differences in disease control rate and PFS of our patients.

  Copyright © 2014 Elsevier Inc. All rights reserved.

• Phase I trial of cisplatin, pemetrexed, and imatinib mesylate in chemonaive patients with unresectable malignant pleural mesothelioma. A.S. Tsao, N. Harun, J.J. Lee, et al. 2014;15(3):197-201. PubMed · Publisher · Free full text

  Abstract

  Background: We conducted a phase I trial of cisplatin/pemetrexed/imatinib mesylate, an oral platelet-derived growth factor receptor (PDGFR) inhibitor, in chemonaive patients with malignant pleural mesothelioma (MPM).

  Methods: A standard 3 + 3 dose-escalating trial was used with the end points of maximum tolerated dose (MTD), response rate, survival, safety/toxicity, and tumor PDGFR levels.

  Results: Seventeen patients with MPM were enrolled. The most common (any grade) side effects were nausea, fatigue, hypomagnesemia, and anemia. The MTD was established at dose level 3 (imatinib 600 mg) with a dose-limiting toxicity (DLT) of nausea and vomiting. The median progression-free survival (PFS) was 7.9 months and the median overall survival (OS) was 8.8 months. Patients with a sarcomatoid subtype had worse PFS (P = .01) and OS (P = .009), whereas they had a better Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 predicted for improved OS (P = .001) and PFS (P = .013). The 6 patients who completed all 6 treatment cycles had better OS (P = .006); the median PFS was 9.6 months and the OS was 22.4 months. In the translational studies, 14 patients had adequate tumor tissue that could be assessed for immunohistochemical (IHC) analysis and fluorescence in situ hybridization (FISH). Patients with higher than median p-PDGFRα IHC expression had a better OS (P = .013). When assessed as a continuous variable, higher p-PDGFRα in tumor cells correlated with an improved OS (P = .045). None of the other 4 IHC biomarkers were predictive or prognostic for survival. Twelve patients had successful PDGFRB FISH results, but none met the criteria of ≥ 4 copies of the PDGFRB gene; thus a correlation with clinical outcomes could not be done.

  Conclusion: The cisplatin/pemetrexed/imatinib mesylate combination had clinical benefit in some patients with MPM but was not well tolerated. Further investigation into alternative antiangiogenic agents, including PDGFRα inhibitors, is warranted.

  Copyright © 2014 Elsevier Inc. All rights reserved.

• ERCC1, MLH1, MSH2, MSH6, and βIII-tubulin: resistance proteins associated with response and outcome to platinum-based chemotherapy in malignant pleural mesothelioma. S. Ting, F.D. Mairinger, T. Hager, et al. 2013;14(5):558-567.e3. PubMed · Publisher

  Abstract

  Introduction: Platinum-based chemotherapy is besides the standard antifolate therapy with pemetrexed, the cornerstone for treatment of patients with malignant pleural mesothelioma (MPM), and its efficacy depends on several DNA repair enzymes. Therefore, these enzymes could be biomarkers for "tailoring" chemotherapy. This study evaluated enzymes involved in repair of platinum-caused DNA damage, potentially resulting in a biomarker panel associated with patient response and outcome to platinum-based chemotherapy.

  Material And Methods: Pre- or posttreatment specimens from a total of 103 patients with MPM who were undergoing first-line chemotherapy were tested separately. Immunohistochemistry for ERCC1 (endonuclease excision repair cross-complementing 1), MLH1 (MutL homologue 1), MutS homologue (MSH) 2, MSH6, and βIII-tubulin protein expression, and pyrosequencing for ERCC1 codon 118 and C8092A polymorphisms were performed, and their results were correlated to clinicopathologic data.

  Results: ERCC1, MLH1, MSH2, MSH6, and βIII-tubulin were expressed in human MPM specimens at different intensities. When considering only pretreatment specimens, MSH6 protein levels were correlated to progression during chemotherapy (P = .0281). MLH1 protein levels (P = .0205), and ERCC1 codon 118 polymorphisms (P ≤ .0001) were significantly associated with progression-free survival. A significant association between ERCC1 protein levels and overall survival was noted (P = .032). Analyses of posttreatment specimens revealed significant associations between βIII-tubulin protein levels and progression-free survival (P = .0066). ERCC1 C8092A polymorphisms were significantly associated with progression-free survival and overall survival (P = .0463 and P = .0080, respectively) in this group.

  Conclusions: Enzymes involved in DNA repair mechanisms are associated with patient response and outcome to platinum-based chemotherapy. Their assessment may be a helpful tool to tailor platinum-based chemotherapy of MPM patients who might expect the largest clinical benefit. Prospective validation of this biomarker panel is warranted.

  Copyright © 2013 Elsevier Inc. All rights reserved.

• Excision repair cross complementation group 1 and thymidylate synthase expression in patients with mesothelioma. S.C. Kao, K. Lee, S. Klebe, et al. 2013;14(2):164-71. PubMed · Publisher

  Abstract

  Background: We hypothesized that in patients with malignant pleural mesothelioma (MPM) undergoing extrapleural pneumonectomy (EPP), high expression of excision repair cross complementation group 1 (ERCC1) and low expression of thymidylate synthase (TS) are associated with prolonged survival.

  Patients And Methods: Consecutive patients undergoing EPP at our institutions were reviewed. Tissue microarrays were constructed using five 1-mm cores per patient. TS and ERCC1 protein expression was evaluated by immunohistochemical techniques. The average percentage scores from evaluable cores were assessed and the median score was used to divide the group. Overall survival (OS) from the time of surgery was determined by the Kaplan-Meier method and results were compared by the log-rank test.

  Results: Eighty patients were included: median age, 58 years; 79% men; 76% epithelial and 24% biphasic subtypes; 25% and pathologic stage I/II and 73% stage III/IV. The median OS was 18.2 months (80% deceased at the censor date). Nineteen patients received neoadjuvant chemotherapy; 2 patients received chemotherapy with adjuvant intent and 28 patients received palliative chemotherapy. The median score was 10.2% for TS and 35% for ERCC1. There was no correlation between TS expression and OS (13.7 vs. 21.6 months for low and high levels, respectively; P = .32). There was a trend between high ERCC1 expression and longer OS (27.6 vs. 10.3 months; P = .06).

  Conclusion: In this series of patients with MPM undergoing EPP, TS expression was not associated with prolonged survival, but there was a trend for longer survival in patients with high ERCC1 expression.

  Copyright © 2013 Elsevier Inc. All rights reserved.

• Validation of prognostic factors in malignant pleural mesothelioma: a retrospective analysis of data from patients seeking compensation from the New South Wales Dust Diseases Board. S.C. Kao, J. Vardy, M. Chatfield, et al. 2013;14(1):70-7. PubMed · Publisher

  Abstract

  Introduction: We aimed to examine the prognostic values of established risk factors and to validate the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in an independent series of patients with malignant pleural mesothelioma (MPM).

  Patients And Methods: A total of 148 patients who applied for compensation at the Dust Diseases Board from 2007 to 2009 were included in this study. Overall survival was determined by the Kaplan-Meier method, and NLR was defined as the absolute neutrophil divided by the lymphocyte count. The prognostic value of the variables was examined by using Cox regression analysis, and all factors were entered into a multivariate model to determine their independent effect.

  Results: The patient characteristics were median age of 73 years; 93% men; 59% epithelial subtype; median NLR of 3.5 at diagnosis (n = 79); median overall survival of 10.6 months. The following variables were predictive of longer overall survival in univariate analysis: younger age, epithelial subtype, lower tumor stage, low white cell count, low platelet count, low hemoglobin level, and low NLR. Multivariate analysis confirmed that nonepithelial vs. epithelial subtype (hazard ratio [HR], 3.0; P < .001), tumor stage (HR, 1.6; P < .001), hemoglobin level difference ≥10 vs. <10 (HR, 2.0; P = .03), no chemotherapy vs. use of chemotherapy (HR, 2.4; P < .001), and NLR ≥3 vs. <3 (HR, 2.2; P < .01) were independently associated with prognosis.

  Conclusions: Apart from previously recognized factors, such as histosubtype, tumor stage, and hemoglobin level difference, NLR, an index of systemic inflammation bears prognostic significance that shows that a snapshot of immune status is able to convey important prognostic information.

  Copyright © 2013 Elsevier Inc. All rights reserved.

• Mesothelin levels in urine are affected by glomerular leakage and tubular reabsorption. K. Hollevoet, M.M. Speeckaert, A.S. Decavele, et al. 2012;13(6):470-4. PubMed · Publisher

  Abstract

  Background: Mesothelin is a soluble biomarker of malignant mesothelioma. Levels in serum, however, are also influenced by other factors, including age and glomerular filtration rate (GFR). The measurement of mesothelin in urine has recently gained interest, but the renal handling of this protein has not been sufficiently examined.

  Patients And Methods: A total of 75 patients with benign kidney disease were prospectively included in the study. Mesothelin levels were measured in the serum and in the urine of all the participants by using enzyme-linked immunosorbent assay. Urinary albumin and alpha 1-microglobulin (A1M) levels, which are markers of glomerular leakage and of decreased tubular reabsorption, respectively, and the estimated GFR (eGFR) of each participant were obtained. All urine analyte levels were standardized (std) against urinary creatinine levels.

  Results: Absolute mesothelin levels in urine (median, 0.58 nmol/L; interquartile range [IQR], 0.25-1.03 nmol/L) were significantly lower than those in serum (median, 1.74 nmol/L; IQR, 1.35-2.43 nmol/L; P < .001). Urinary mesothelin(std) levels positively correlated with serum mesothelin (r = 0.35, P < .01), albumin(std) (r = 0.51, P < .001), and A1M(std) levels (r = 0.71, P < .001). Neither age nor eGFR were associated with urinary mesothelin(std) levels. Similarly, multiple linear regression analysis indicated that only albumin(std) and A1M(std) levels were significantly positively associated with the urinary mesothelin(std) levels (adjusted R(2) = 0.49).

  Conclusion: Mesothelin levels in urine are affected by impaired glomerular and tubular function, which can influence the interpretation of mesothelin measurements and might cause false-positive results. These effects need to be accounted for to improve the further validation and possible clinical use of urinary mesothelin.

  Copyright © 2012 Elsevier Inc. All rights reserved.

• Carboplatin plus pemetrexed as first-line treatment of patients with malignant pleural mesothelioma: a phase II study. N. Katirtzoglou, I. Gkiozos, N. Makrilia, et al. 2010;11(1):30-5. PubMed · Publisher

  Abstract

  Introduction: Malignant pleural mesothelioma (MPM) is a rapidly progressive tumor that is increasing in frequency worldwide. Treatment options are limited, and response to chemotherapy is poor. The aim of this phase II study was to evaluate the activity of the carboplatin/pemetrexed combination as first-line chemotherapy in patients with unresectable MPM.

  Patients And Methods: Chemotherapy-naive patients with histologically confirmed MPM and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled. Treatment consisted of pemetrexed 500 mg/m2 and carboplatin area under the concentration-time curve of 5 mg/mL/min, both administered on day 1 of a 21-day cycle. The treatment continued until 6 cycles were completed or until unacceptable toxicity or disease progression were observed.

  Results: A total of 62 patients were enrolled. Of these patients, 18 (29%) had a confirmed partial response, whereas the disease remained stable in 34 patients (54.9%) and progressed in 10 patients (16.1%). The median overall survival (OS) was estimated at 14 months (95% CI, 11.8-16.2 months), and the median time to progression was 7 months (95% CI, 5.8-8.2 months). The difference in median OS between the epithelial histologic subtype (16 months) and the sarcomatoid subtype (11 months) was statistically significant.

  Conclusion: This study confirmed the activity of the carboplatin/ pemetrexed combination in the first-line treatment of patients with MPM. It is a viable option, especially in cases in which side effects are generally anticipated.

2000s

• Pathogenesis of malignant mesothelioma. M. Carbone, M.A. Rdzanek. 2004;5 Suppl 2:S46-50. Review PubMed · Publisher

  Abstract

  Malignant mesothelioma (MM) is a very aggressive tumor that is caused by environmental, biologic, and genetic factors. Among these factors, asbestos plays a major role. The link between asbestos and MM has been firmly established through numerous epidemiologic studies conducted during the past 40 years. However, the causal role of chrysotile asbestos compared with crocidolite asbestos in MM, the method of correctly establishing asbestos exposure, the amount of asbestos necessary to cause MM, and the mechanisms of asbestos tumorigenicity are still being debated. Along with asbestos, Simian virus 40 (SV40), a DNA monkey virus, has recently been implicated in the etiology of MM. Simian virus 40 large T antigen (Tag) and small t antigen (tag) are largely responsible for the carcinogenicity of the virus, and it is possible that SV40 and asbestos are cocarcinogens. Finally, a genetic factor identified in 3 villages in Cappadocia, Turkey, where 50% of individuals die of MM, appears to be the cause of a high incidence of the disease. In these villages, genetic predisposition for MM works together with erionite, a nonasbestos fiber found in the stones used in construction of houses. The diagnosis of MM is made histologically and confirmed through electron microscopy and immunohistochemistry. Currently available therapies for MM prolong survival by a few months at most. An SV40 vaccine is being developed for human use and it is hoped that it may reduce the incidence of MM in asbestos workers.

• Molecular pathogenesis of malignant mesothelioma and its relationship to simian virus 40. A.F. Gazdar, M. Carbone. 2003;5(3):177-81. Review PubMed · Publisher

  Abstract

  Malignant mesothelioma is a relatively rare tumor, but the incidence of the disease appears to be increasing. Unique molecular changes are associated with the disease that distinguish it from lung cancers. Smoking is not an etiologic factor; the major causative agent is asbestos exposure, usually many years or decades before the development of the tumor. Recently, a simian virus, SV40, has been associated with malignant mesotheliomas and is a probable cofactor in tumor development. The molecular changes caused by each of these major etiologic factors and their interrelationships are the focus of this review.

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