Malignant Pleural Mesothelioma Outcomes in the Era of Combined Platinum and Folate Antimetabolite Chemotherapy

Introduction. Malignant pleural mesothelioma (MPM) is associated with a poor prognosis. Palliative platinum-based chemotherapy may help to improve symptoms and prolong life. Since 2004, the platinum is commonly partnered with a folate antimetabolite. We performed a review investigating if survival had significantly changed before and after the arrival of folate antimetabolites in clinical practice. Methods. All MPM patients from January 1991 to June 2012 were identified. Data collected included age, gender, asbestos exposure, presenting signs/symptoms, performance status, histology, stage, bloodwork, treatment modalities including chemotherapy, and date of death or last follow-up. The primary endpoint was overall survival. Cox models were applied to determine variables associated with survival. Results. There were 245 patients identified. Median overall survival for all patients was 9.4 months. After multivariate analysis, performance status, stage, histology, leucocytosis, and thrombophilia remained independently associated with survival. Among all patients who received chemotherapy, there was no difference in overall survival between the periods before and after folate antimetabolite approval: 14.2 versus 13.2 months (P=0.35). Specifically receiving combined platinum-based/folate antimetabolite chemotherapy did not improve overall survival compared to all other chemotherapy regimens: 14.1 versus 13.6 months (P=0.97). Conclusions. In this review, we did not observe an incremental improvement in overall survival after folate antimetabolites became available.

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Multimodality treatment of malignant pleural mesothelioma

F1000Research ◽

10.12688/f1000research.15796.1 ◽

2018 ◽

Vol 7 ◽

pp. 1681 ◽

Cited By ~ 6

Author(s):

Lawek Berzenji ◽

Paul Van Schil

Keyword(s):

Malignant Pleural Mesothelioma ◽

Asbestos Exposure ◽

Multimodality Treatment ◽

Treatment Modalities ◽

Surgical Approaches ◽

Extrapleural Pneumonectomy ◽

Pleural Mesothelioma ◽

Treatment Approaches ◽

Definitive Answer ◽

Platinum Based Chemotherapy

Malignant pleural mesothelioma (MPM) is a rare disease of the pleura and is largely related to asbestos exposure. Despite recent advancements in technologies and a greater understanding of the disease, the prognosis of MPM remains poor; the median overall survival rate is about 6 to 9 months in untreated patients. The main therapeutic strategies for MPM are surgery, chemotherapy, and radiation therapy (RT). The two main surgical approaches for MPM are extrapleural pneumonectomy (EPP), in which the lung is removed en bloc, and pleurectomy/decortication, in which the lung stays in situ. Chemotherapy usually consists of a platinum-based chemotherapy, such as cisplatin, often combined with a folate antimetabolite, such as pemetrexed. More recently, immunotherapy has emerged as a possible therapeutic strategy for MPM. Evidence suggests that single-modality treatments are not an effective therapeutic approach for MPM. Therefore, researchers have started to explore different multimodality treatment approaches, in which often combinations of surgery, chemotherapy, immunotherapy, and RT are investigated. There is still no definitive answer to the question of which multimodality treatment combinations are most effective in improving the poor prognosis of MPM. Research into the effects of trimodality treatment approaches have found that radical approaches such as EPP and hemithoracic RT post-EPP are less effective than was previously assumed. In general, there are still a great number of unanswered questions and unknown factors regarding the ideal treatment approach for MPM. Hopefully, more research into multimodality therapy will provide insight into which combination of treatment modalities is most effective.

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Nintedanib Plus Pemetrexed/Cisplatin in Patients With Malignant Pleural Mesothelioma: Phase II Results From the Randomized, Placebo-Controlled LUME-Meso Trial

Journal of Clinical Oncology ◽

10.1200/jco.2017.72.9012 ◽

2017 ◽

Vol 35 (31) ◽

pp. 3591-3600 ◽

Cited By ~ 59

Author(s):

Federica Grosso ◽

Nicola Steele ◽

Silvia Novello ◽

Anna K. Nowak ◽

Sanjay Popat ◽

...

Keyword(s):

Overall Survival ◽

Placebo Group ◽

Phase Ii ◽

Malignant Pleural Mesothelioma ◽

Group Performance ◽

Performance Status ◽

Eastern Cooperative Oncology Group ◽

Phase Iii ◽

Pleural Mesothelioma ◽

Double Blind

Purpose LUME-Meso is a phase II/III randomized, double-blind trial designed to assess efficacy and safety of nintedanib plus chemotherapy as first-line treatment of malignant pleural mesothelioma (MPM). Phase II results are reported here. Patients and Methods Chemotherapy-naïve patients with unresectable, nonsarcomatoid MPM (Eastern Cooperative Oncology Group performance status 0 to 1), stratified by histology (epithelioid or biphasic), were randomly assigned in a 1:1 ratio to up to six cycles of pemetrexed and cisplatin plus nintedanib (200 mg twice daily) or placebo followed by nintedanib plus placebo monotherapy until progression. The primary end point was progression-free survival (PFS). Results Eighty-seven patients were randomly assigned. The median number of pemetrexed and cisplatin cycles was six; the median treatment duration for nintedanib was 7.8 months and 5.3 months for placebo. Primary PFS favored nintedanib (hazard ratio [HR], 0.56; 95% CI, 0.34 to 0.91; P = .017), which was confirmed in updated PFS analyses (HR, 0.54; 95% CI, 0.33 to 0.87; P = .010). A trend toward improved overall survival also favored nintedanib (HR, 0.77; 95% CI, 0.46 to 1.29; P = .319). Benefit was evident in epithelioid histology, with a median overall survival gain of 5.4 months (HR, 0.70; 95% CI, 0.40 to 1.21; P = .197; median [nintedanib v placebo], 20.6 months v 15.2 months) and median PFS gain of 4.0 months (HR, 0.49; 95% CI, 0.30 to 0.82; P = .006; median [nintedanib v placebo], 9.7 v 5.7 months). Neutropenia was the most frequent grade ≥ 3 adverse event (AE; nintedanib 43.2% v placebo 12.2%); rates of febrile neutropenia were low (4.5% in nintedanib group v 0% in placebo group). AEs leading to discontinuation were reported in 6.8% of those receiving nintedanib versus 17.1% of those in the placebo group. Conclusion Addition of nintedanib to pemetrexed plus cisplatin resulted in PFS improvement. AEs were manageable. The clinical benefit was evident in patients with epithelioid histology. The confirmatory phase III part of the study is ongoing.

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A phase II trial of nintedanib in recurrent malignant pleural mesothelioma (MPM).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e20061 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e20061-e20061

Author(s):

Antoinette J. Wozniak ◽

Bryan J. Schneider ◽

Gregory Peter Kalemkerian ◽

Robert Michael Daly ◽

Wei Chen ◽

...

Keyword(s):

Phase Ii ◽

Malignant Pleural Mesothelioma ◽

Stable Disease ◽

Phase Ii Trial ◽

Performance Status ◽

Unmet Need ◽

Small Subset ◽

Pleural Mesothelioma ◽

Platinum Based Chemotherapy ◽

Previously Treated

e20061 Background: Malignant pleural mesothelioma (MPM) is a disease that is resistant to chemotherapy and there remains an unmet need for better therapeutic options. Nintedanib (BIBF 1120) is an oral multikinase inhibitor impacting VEGFR, FGFR, PDGFR, and other kinase activity such as TGFß signaling pathways. VEGF, FGF, and TGFβ are commonly expressed in MPM. We conducted a phase II trial in patients with recurrent MPM after platinum-based chemotherapy. Methods: Patients (pts) 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 for treatment. Nintedanib 200 mg twice per day was administered until disease progression or unacceptable toxicity. The primary endpoint was the 4-month progression-free survival (PFS). A two-stage design was used and > 4 pts had to have a PFS of ≥4 months to proceed to the second stage. Results: Twenty pts. were enrolled. The median age was 70 yrs. (32-81), 90% were male, and 80% were PS = 1. The histology was 70% epithelioidal, 5% sarcomatoid, 10% biphasic, and 15% unknown. 15% had prior bevacizumab. The median follow-up is 16.4 mo. A median of 2 treatment cycles (range 1-18) were delivered. There were no responses but 40% had stable disease. The median PFS was 1.8 mo. (95% CI: 1.68, 3.55) and the PFS rate at 4 mo. was 13%. The median OS was 4.2 mo. (95% CI: 2.53, 8.74) and the OS rate at 4 mo. was 55%. Toxicities were usually grade 1-2 and included diarrhea, fatigue, edema, transaminase elevation, anorexia, nausea, vomiting and dyspnea. Conclusions: The activity of nintedanib in previously treated MPM pts. was modest. The trial did not meet the primary PFS endpoint. However, there was a small subset of pts. that had prolonged stable disease for > 4 months thus potentially deriving some clinical benefit from treatment. Supported by Boehringer Ingelheim. Clinical trial information: NCT02568449.

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Clinical characteristics, treatment, and survival outcomes in malignant pleural mesothelioma: A institution experience in Turkey.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e18544 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e18544-e18544 ◽

Cited By ~ 1

Author(s):

Mehmet Kucukoner ◽

Muhammed Ali Kaplan ◽

Ali Inal ◽

Zuhat Urakcı ◽

Ozlem Abakay ◽

...

Keyword(s):

Prognostic Factors ◽

Malignant Pleural Mesothelioma ◽

Performance Status ◽

Survival Rates ◽

Treatment Modalities ◽

Pleural Mesothelioma ◽

Ecog Performance Status ◽

Clinicopathologic Characteristics ◽

Rank Analysis ◽

Significant Difference

e18544 Background: Malignant pleural mesothelioma (MPM) is a aggressive tumor that causes high mortality. Treatment of MPM remains disappointing, even new approaches are present today. Methods: The present study retrospectively examined the data related to 150 patients with MPM who were examined and treated in our center in Turkey from 2005 to 2012. The aims of this study were; to investigate clinicopathologic characteristics, treatment modalities and potential prognostic factors. Results: There were 87 males (58%) and 63 females (42%), 92 of the patients (61.3%) had an asbestos contact and this contact was generally environmental. Surgical resection (EPP or P/D) was used in 32 patients, 87 patients (58%) received only chemotherapy. The median progression free and overall survival (PFS and OS) for all patients were 10.6 and 14.8 months. There was no statistically significant difference between the patients who received pemetrexed/cisplatin (54 patients) and gemcitabine/cisplatin (28 patients) regimens in terms of the PFS and OS (p=0.145, p=0.244). The comparison between patients who were operated on and those who were not did not reveal any statistical difference in PFS and OS (p=0.416, p=0.095). There was no difference in both PFS and OS rates in comparison of patients who had P/D or EPP (p=0.87, p=0.652). Log rank analysis, ECOG performance status (p=0.018), histology (p<0.001), stage (p<0.001) and leukocytosis (p=0.005) were found to be significant prognostic factors in OS. At multivariate analysis, ECOG performance status (p=0.016), and stage (p<0.001) remained independently associated with OS. Conclusions: In survival analysis revealed significant differences in terms of both the PFS and OS, performance status, histology, stage and leukocytosis. EPP or P / D surgical options did not provide difference in term of survival. Survival rates in patients who received combining platinum analogues with pemetrexed or gemcitabine as front-line chemotherapy were found similar.

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Malignant pleural mesothelioma: a disease unaffected by current therapeutic maneuvers.

Journal of Clinical Oncology ◽

10.1200/jco.1988.6.3.527 ◽

1988 ◽

Vol 6 (3) ◽

pp. 527-535 ◽

Cited By ~ 181

Author(s):

A S Alberts ◽

G Falkson ◽

L Goedhals ◽

D A Vorobiof ◽

C A Van der Merwe

Keyword(s):

Malignant Pleural Mesothelioma ◽

Early Stage ◽

Performance Status ◽

Univariate Analysis ◽

Treatment Modalities ◽

Pleural Mesothelioma ◽

Phase Ii Trials ◽

Duration Of Symptoms ◽

Histologic Subtype ◽

Treatment Groups

From 1965 to 1985, 262 patients with malignant pleural mesothelioma were treated with cytostatics only; radiotherapy (RT); RT and cytostatics; or decortication plus RT plus cytostatics. The median survival (MS) from diagnosis was 9.6 months. This was similar for all comparable treatment groups. In a univariate analysis, significant favorable prognostic factors were good performance status (PS), duration of symptoms greater than 6 months at the time of diagnosis, early stage of disease, white race, and female sex. In a multivariate analysis, PS, race, duration of symptoms, and stage were of significance for a favorable prognosis. Age, pain as first symptom, histologic subtype, and RT dose were not of prognosis significance in this study. The stepwise addition of treatment modalities did not increase survival, which remained the same as that reported for untreated patients. Therefore, phase II trials of new agents offer the only hope for advance in the treatment of this disease.

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Survival of Korean Patients with Malignant Pleural Mesothelioma Compensated for the Asbestos Injury Relief

Applied Sciences ◽

10.3390/app11209713 ◽

2021 ◽

Vol 11 (20) ◽

pp. 9713

Author(s):

Min-Sung Kang ◽

Sung-Soo Lee ◽

Soon-Chan Kwon ◽

Da-An Huh ◽

Yong-Jin Lee

Keyword(s):

Prognostic Factors ◽

Occupational Exposure ◽

Malignant Pleural Mesothelioma ◽

Malignant Mesothelioma ◽

Asbestos Exposure ◽

Performance Status ◽

Smoking History ◽

Pleural Mesothelioma ◽

Histological Subtype ◽

Epidemiologic Characteristics

Background: The purpose of this study was to identify the epidemiologic characteristics and prognostic factors for malignant pleural mesothelioma in Korea, which are currently insufficient. The data were derived from malignant mesothelioma patients who registered under the Asbestos Injury Relief Act; Methods: A total of 728 patients received compensation from the Asbestos Injury Relief Act due to malignant mesothelioma between 2011 and 2015. Of these, 313 patients (43.0%) with malignant pleural mesothelioma were included in the study. The study variables were sex (male, female), age at diagnosis (<59, 60–69, ≥70), smoking history (yes, no), surgery (yes, no), chemotherapy (yes, no), occupational exposure to asbestos (yes, no), and histological subtype (epithelioid, nonepithelioid); Results: Median survival of mesothelioma was 8.0 months (95% confidence interval: 6.2 to 9.8). The 1-year, 2-year, and 5-year survival rates (%) were 43.5%, 23.6%, and 12.5%, respectively. In multivariate analysis of Cox’s proportional hazards model; sex, age, smoking history, occupational asbestos exposure, and histological subtype were not significant prognostic factors, but surgery and chemotherapy combined was a significant predictor; Conclusions: Although the representativeness of these data is limited, our study estimates the epidemiologic characteristics of malignant pleural mesothelioma. Non-occupational exposure had a similar prognosis to occupational asbestos exposure, and there was no sex difference. In addition, it was found that receiving a combination of surgery and chemotherapy affects the survival rate, but there is a limitation in that factors such as performance status, comorbidities, and stage that contribute to survival are not considered.

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

Cancers ◽

10.3390/cancers13030508 ◽

2021 ◽

Vol 13 (3) ◽

pp. 508

Author(s):

Emanuela Di Gregorio ◽

Gianmaria Miolo ◽

Asia Saorin ◽

Elena Muraro ◽

Michela Cangemi ◽

...

Keyword(s):

Amino Acids ◽

Overall Survival ◽

Clinical Outcome ◽

Malignant Pleural Mesothelioma ◽

Therapeutic Option ◽

Enrichment Analysis ◽

Metabolic Effects ◽

Pleural Mesothelioma ◽

Polyamine Biosynthesis ◽

The Individual

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.

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Identification of Redox-Sensitive Transcription Factors as Markers of Malignant Pleural Mesothelioma

Cancers ◽

10.3390/cancers13051138 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1138

Author(s):

Martina Schiavello ◽

Elena Gazzano ◽

Loredana Bergandi ◽

Francesca Silvagno ◽

Roberta Libener ◽

...

Keyword(s):

Oxidative Stress ◽

Transcription Factors ◽

Malignant Pleural Mesothelioma ◽

Antioxidant Defense ◽

Asbestos Exposure ◽

Predictive Biomarkers ◽

Antioxidant Systems ◽

Pleural Mesothelioma ◽

Related Factor ◽

Aggressive Cancer

Although asbestos has been banned in most countries around the world, malignant pleural mesothelioma (MPM) is a current problem. MPM is an aggressive tumor with a poor prognosis, so it is crucial to identify new markers in the preventive field. Asbestos exposure induces oxidative stress and its carcinogenesis has been linked to a strong oxidative damage, event counteracted by antioxidant systems at the pulmonary level. The present study has been focused on some redox-sensitive transcription factors that regulate cellular antioxidant defense and are overexpressed in many tumors, such as Nrf2 (Nuclear factor erythroid 2-related factor 2), Ref-1 (Redox effector factor 1), and FOXM1 (Forkhead box protein M1). The research was performed in human mesothelial and MPM cells. Our results have clearly demonstrated an overexpression of Nrf2, Ref-1, and FOXM1 in mesothelioma towards mesothelium, and a consequent activation of downstream genes controlled by these factors, which in turn regulates antioxidant defense. This event is mediated by oxidative free radicals produced when mesothelial cells are exposed to asbestos fibers. We observed an increased expression of Nrf2, Ref-1, and FOXM1 towards untreated cells, confirming asbestos as the mediator of oxidative stress evoked at the mesothelium level. These factors can therefore be considered predictive biomarkers of MPM and potential pharmacological targets in the treatment of this aggressive cancer.

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Increased Standardised Incidence Ratio of Malignant Pleural Mesothelioma in Taiwanese Asbestos Workers: A 29-Year Retrospective Cohort Study

BioMed Research International ◽

10.1155/2015/678598 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Cheng-Kuan Lin ◽

Yu-Ying Chang ◽

Jung-Der Wang ◽

Lukas Jyuhn-Hsiarn Lee

Keyword(s):

Cohort Study ◽

General Population ◽

Incidence Rate ◽

Malignant Pleural Mesothelioma ◽

Retrospective Cohort Study ◽

Retrospective Cohort ◽

Asbestos Exposure ◽

Pleural Mesothelioma ◽

Calendar Period ◽

Incident Cases

Objective. This paper aimed to determine the standardised incidence ratio (SIR) of malignant pleural mesothelioma (MPM) in workers exposed to asbestos in Taiwan.Methods. All workers employed in asbestos-related factories and registered by the Bureau of Labour Insurance between 1 March, 1950, and 31 December, 1989, were included in the study and were followed from 1 January, 1980, through 31 December, 2009. Incident cases of all cancers, including MPM (ICD-9 code: 163), were obtained from the Taiwan Cancer Registry. SIRs were calculated based on comparison with the incidence rate of the general population of Taiwan and adjusted for age, calendar period, sex, and duration of employment.Results. The highest SIR of MPM was found for male workers first employed before 1979, with a time since first employment more than 30 years (SIR 4.52, 95% CI: 2.25–8.09). After consideration of duration of employment, the SIR for male MPM was 5.78 (95% CI: 1.19–16.89) for the workers employed for more than 20 years in asbestos-related factories.Conclusions. This study corroborates the association between occupational asbestos exposure and MPM. The highest risk of MPM was found among male asbestos workers employed before 1979 and working for more than 20 years in asbestos-related factories.

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Induction Chemotherapy Followed by Pleurectomy Decortication and Hyperthermic Intraoperative Chemotherapy (HITHOC) for Early-Stage Epitheliod Malignant Pleural Mesothelioma—A Prospective Report

Journal of Clinical Medicine ◽

10.3390/jcm10235542 ◽

2021 ◽

Vol 10 (23) ◽

pp. 5542

Author(s):

Stefano Bongiolatti ◽

Francesca Mazzoni ◽

Ottavia Salimbene ◽

Enrico Caliman ◽

Carlo Ammatuna ◽

...

Keyword(s):

Induction Chemotherapy ◽

Malignant Pleural Mesothelioma ◽

Early Stage ◽

Disease Free Survival ◽

Stage I ◽

Long Term Results ◽

Pleural Mesothelioma ◽

Free Survival ◽

Therapy Regimen ◽

Platinum Based Chemotherapy

Malignant pleural mesothelioma (MPM) is an aggressive disease with poor prognosis and the current treatment for early-stage MPM is based on a multimodality therapy regimen involving platinum-based chemotherapy preceding or following surgery. To enhance the cytoreductive role of surgery, some peri- or intra-operative intracavitary treatments have been developed, such as hyperthermic chemotherapy, but long-term results are weak. The aim of this study was to report the post-operative results and mid-term outcomes of our multimodal intention-to-treat pathway, including induction chemotherapy, followed by surgery and Hyperthermic Intraoperative THOracic Chemotherapy (HITHOC) in the treatment of early-stage epithelioid MPM. Since 2017, stage I or II epithelioid MPM patients have been inserted in a surgery-based multimodal approach comprising platinum-based induction chemotherapy, followed by pleurectomy and decortication (P/D) and HITHOC with cisplatin. The Kaplan–Meier method was used to estimate overall survival (OS), disease-free survival (DFS) and progression-free survival (PFS). During the study period, n = 65 patients affected by MPM were evaluated by our institutional Multidisciplinary Tumour Board; n = 12 patients with stage I-II who had no progression after induction chemotherapy underwent P/D and HITHOC. Post-operative mortality was 0, and complications developed in n = 7 (58.3%) patients. The median estimated OS was 31 months with a 1-year and 3-year OS of 100% and 55%, respectively. The median PFS was 26 months with 92% of a 1-year PFS, whereas DFS was 19 months with a 1-year DFS rate of 83%. The multimodal treatment of early-stage epithelioid MPM, including induction chemotherapy followed by P/D and HITHOC, was well tolerated and feasible with promising mid-term oncological results.

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