Malignant pleural mesothelioma: an update on investigation, diagnosis and treatment

Malignant pleural mesothelioma is an aggressive malignancy of the pleural surface, predominantly caused by prior asbestos exposure. There is a global epidemic of malignant pleural mesothelioma underway, and incidence rates are predicted to peak in the next few years.

This article summarises the epidemiology and pathogenesis of malignant pleural mesothelioma, before describing some key factors in the patient experience and outlining common symptoms. Diagnostic approaches are reviewed, including imaging techniques and the role of various biomarkers. Treatment options are summarised, including the importance of palliative care and methods of controlling pleural effusions. The evidence for chemotherapy, radiotherapy and surgery is reviewed, both in the palliative setting and in the context of trimodality treatment. An algorithm for managing malignant pleural effusion in malignant pleural mesothelioma patients is presented. Finally new treatment developments and novel therapeutic approaches are summarised.

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Source: Malignant pleural mesothelioma: an update on investigation, diagnosis and treatment


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FTY720 inhibits mesothelioma growth in vitro and in a syngeneic mouse model

Background  Malignant mesothelioma (MM) is a very aggressive type of cancer, with a dismal prognosis and inherent resistance to chemotherapeutics. Development and evaluation of new therapeutic approaches is highly needed. Immunosuppressant FTY720, approved for multiple sclerosis treatment, has recently raised attention for its anti-tumor activity in a variety of cancers. However, its therapeutic potential in MM has not been evaluated yet.

Methods  Cell viability and anchorage–independent growth were evaluated in a panel of MM cell lines and human mesothelial cells (HM) upon FTY720 treatment to assess in vitro anti-tumor efficacy. The mechanism of action of FTY720 in MM was assessed by measuring the activity of phosphatase protein 2A (PP2A)—a major target of FTY720….

Conclusions  Our preclinical data indicate that FTY720 is a potentially promising therapeutic agent for MM treatment.

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Source: FTY720 inhibits mesothelioma growth in vitro and in a syngeneic mouse model


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Clinical Safety and Activity of Pembrolizumab in Patients With Malignant Pleural Mesothelioma

BACKGROUND  Malignant pleural mesothelioma is a highly aggressive cancer with poor prognosis and few treatment options following progression on platinum-containing chemotherapy. We assessed the safety and efficacy of pembrolizumab (an anti-programmed cell death receptor 1 [PD-1] antibody) in advanced solid tumours expressing programmed cell death ligand 1 (PD-L1) and report here on the interim analysis of the malignant pleural mesothelioma cohort.

METHODS  Previously treated patients with PD-L1-positive malignant pleural mesothelioma were enrolled from 13 centres in six countries. Patients received pembrolizumab (10 mg/kg every 2 weeks) for up to 2 years or until confirmed progression or unacceptable toxicity….

FINDINGS  As of June 20, 2016, 25 patients received pembrolizumab. 16 (64%) patients reported a treatment-related adverse event; the most common adverse event were fatigue (six [24%]), nausea (six [24%]), and arthralgia (five [20%])….

INTERPRETATION  Pembrolizumab appears to be well tolerated and might confer anti-tumour activity in patients with PD-L1-positive malignant pleural mesothelioma. Response durability and efficacy in this patient population warrants further investigation.

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Source: Clinical Safety and Activity of Pembrolizumab in Patients With Malignant Pleural Mesothelioma


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Patient-Derived Xenograft Establishment from Human Malignant Pleural Mesothelioma

Purpose: Malignant pleural mesothelioma (MPM) is a rare but aggressive disease with few therapeutic options. The tumor–stromal interface is important in MPM, but this is lost in cell lines, the main model used for preclinical studies. We sought to characterize MPM patient-derived xenografts (PDX) to determine their suitability as preclinical models and whether tumors that engraft reflect a more aggressive biological phenotype.

Experimental Design: Fresh tumors were harvested from extrapleural pneumonectomy, decortication, or biopsy samples of 50 MPM patients and implanted subcutaneously into immunodeficient mice and serially passaged for up to five generations. We correlated selected mesothelioma biomarkers between PDX and patient tumors, and PDX establishment with the clinical pathologic features of the patients, including their survival. DNA of nine PDXs was profiled using the OncoScan FFPE Express platform. Ten PDXs were treated with cisplatin and pemetrexed.

Results: A PDX was formed in 20 of 50 (40%) tumors implanted. Histologically, PDX models closely resembled the parent tumor. PDX models formed despite preoperative chemotherapy and radiotherapy. In multivariable analysis, patients whose tumors formed a PDX had significantly poorer survival when the model was adjusted for preoperative treatment (HR, 2.46; 95% confidence interval, 1.1–5.52; P = 0.028). Among 10 models treated with cisplatin, seven demonstrated growth inhibition. Genomic abnormalities seen in nine PDX models were similar to that previously reported.

Conclusions: Patients whose tumors form PDX models have poorer clinical outcomes. MPM PDX tumors closely resemble the genotype and phenotype of parent tumors, making them valuable models for preclinical studies.

Source: Patient-Derived Xenograft Establishment from Human Malignant Pleural Mesothelioma


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Diagnostic and Prognostic Biomarkers in the Rational Assessment of Mesothelioma (DIAPHRAGM) study: protocol of a prospective, multicentre, observational study

Malignant pleural mesothelioma (MPM) is an asbestos-related cancer, which is difficult to diagnose. Thoracoscopy is frequently required but is not widely available. An accurate, non-invasive diagnostic biomarker would allow early specialist referral, limit diagnostic delays and maximise clinical trial access. Current markers offer insufficient sensitivity and are not routinely used. The SOMAmer proteomic classifier and fibulin-3 have recently demonstrated sensitivity and specificity exceeding 90% in retrospective studies. DIAPHRAGM (Diagnostic and Prognostic Biomarkers in the Rational Assessment of Mesothelioma) is a suitably powered, multicentre, prospective observational study designed to determine whether these markers provide clinically useful diagnostic and prognostic information.

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Source: Diagnostic and Prognostic Biomarkers in the Rational Assessment of Mesothelioma (DIAPHRAGM) study: protocol of a prospective, multicentre, observational study


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Lung-sparing surgery may boost mesothelioma survival

Surgery that preserves the lung, when combined with other therapies, appears to extend the lives of people with a subtype of the rare and deadly cancer mesothelioma, a new study suggests.

Tracking 73 patients with advanced malignant pleural mesothelioma—which affects the lungs’ protective lining in the chest cavity—researchers found that those treated with lung-sparing had an average survival of nearly three years. A subset of those patients survived longer than seven years.

Mesothelioma patients treated with chemotherapy alone, which is standard care, live an average of 12 to 18 months, the researchers said.

Study participants received lung-sparing surgeries and another treatment called photodynamic therapy that uses light to kill cancer cells. Ninety-two percent of the group also received chemotherapy.

The study volunteers achieved far longer survival times, said study author Dr. Joseph Friedberg.

“When you take the [entire] lung out, it’s a significant compromise in quality of life,” said Friedberg. He’s director of the University of Maryland Medical Center’s Mesothelioma and Thoracic Oncology Treatment and Research Center in Baltimore.

“For all intents and purposes, this [lung-sparing surgical approach] is the largest palliative operation known to man, since chances of curing mesothelioma are vanishingly small,” said Friedberg. He completed the research while at his previous post at the University of Pennsylvania.

“Plus, most of these patients are elderly, so preserving quality of life was really the goal,” he added.

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Source: Lung-sparing surgery may boost mesothelioma survival


 

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Asbestos-related cancer won’t be overcome anytime soon, doctors say

New methods are giving doctors a better handle on diagnosing and treating asbestos-related cancers, but no cures are on the horizon.

“I think it would be overly optimistic to say it’s going to be cured. I mean we can always dream,” said oncologist Dr. Christopher Lee, an expert on mesothelioma.

Paul Demers, a senior scientist in prevention at the Occupational Cancer Research Centre in Toronto, said one of the difficulties in diagnosing mesothelioma is the long latency period — the period between exposure and the development of symptoms — which can sometimes be up to 40 years.

When asbestos fibres are inhaled or ingested, they become trapped in the pleural lining of the lungs. Over time, thousands of tiny fibres cause scarring in the tissue.

New equipment like the CyTOF instrument allows doctors to detect asbestos earlier and with more precision, which could facilitate more effective treatments for asbestos victims.

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Source: Asbestos-related cancer won’t be overcome anytime soon, doctors say


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Treatments to prolong life for mesothelioma patients closer

Researchers have uncovered a strange way that asbestos-related tumours grow, which could pave the way towards better treatments.

The scientists at Adelaide’s Flinders University have found that malignant mesothelioma tumours are able to transform into blood vessels, promoting their own growth.

Associate Professor Sonja Klebe said the behaviour was unusual.

“Instead of waiting for the outside of the tissue to grow blood vessels in, the tumour cells themselves branch out, growing blood vessels that reach out into surrounding tissues, tapping into the native vasculature,” she said.

Existing tumour treatments target blood vessels that grow into the cancer, and not the other way around.

“So I think a future approach would involve treating both of these types of vessels to more or less starve the tumour of blood supply,” Associate Professor Klebe said.

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Source: Treatments to prolong life for mesothelioma patients closer


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New Paradigms in the Treatment of Mesothelioma and NSCLC: An Overview by Fred Hirsch

Dr. Haffizulla: Welcome to PracticeUpdate. I’m Dr. Farzanna Haffizulla. Joining me today is Dr. Fred Hirsch, CEO of the International Association for the Study of Lung Cancer, and Professor of Medicine at the University of Colorado in Denver. Dr. Hirsch, thank you, so much, for joining me.

Dr. Hirsch: Thank you, so much, for the invitation.

Dr. Haffizulla: You’re very welcome. Well, I want to first start off with talking about mesothelioma. Any latest advances or current treatments that have come to the forefront that have precipitated based on clinical trials recently?

Dr. Hirsch: Mesothelioma is an interesting disease where we unfortunately haven’t seen much progress, either, over a long time. Pemetrexed-platinum is a standard of care for mesothelioma, but what we have seen most recently is the introduction of immunotherapy also in this disease, and with very encouraging data. It is still very preliminary data, and certainly we need much more matured clinical trials, but already by now we can see a very clear encouraging signal with the PD-L1, PD-1 antibodies.

Dr. Haffizulla: Okay. Absolutely. Well, switching gears a little bit. I want to talk a little bit further on immunologic biomarkers, talking about neoantigen signatures and mutational load of tumors. Other than assessing or using this information to assess the severity of the disease, perhaps, or the risk of relapse and choice of agents that you would like to use in this particular patient, anything else you’d like to share on that home front?

Dr. Hirsch: Yeah, so that will probably be most related to non-small cell lung cancer. We have recently seen data in mesothelioma for follow-up on the mesothelioma stuff that mesothelioma has much less mutation burden than we see in small cell and non-small cell lung cancer, and that might be important when we are talking immunotherapy and promises, but we don’t know. We see encouraging results currently in mesothelioma with the new immune checkpoints. In non-small cell lung cancer there seems to be a relation between mutation burden and sensitivity to some of the checkpoint inhibitors, and that is interesting. On a personal level, I think we need to learn more about it because I don’t think all mutations are equal, and all mutations are not equally immunogenic, so we need to learn more about the mutation load, mutation types. Are we talking tumor heterogeneity? Are we talking trunk mutations? Are we talking branch mutations, so mutation load might be too broad in term in the future, but currently we actually see an association between mutation load and sensitivity to some of those immune checkpoints.

Source: New Paradigms in the Treatment of Mesothelioma and NSCLC: An Overview by Fred Hirsch


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Systemically administered RNAi molecule sensitizes malignant pleural mesothelioma cells to pemetrexed therapy

Pemetrexed (PMX) is a key drug for the treatment of malignant pleural mesothelioma (MPM). However, its therapeutic efficacy is cruelly restricted in many clinical settings by the over-expression of thymidylate synthase (TS) gene. Recently, we emphasized the efficacy of locally administered shRNA designed against TS gene in enhancing the cytotoxic effect of PMX against orthotopically implanted MPM cells in tumor xenograft tumor model. In the present study, we investigated the efficacy of systemic, rather than local, delivery of TS RNAi molecule in sensitizing MPM cells to the cytotoxic effect of PMX. We here designed a PEG-coated TS shRNA lipoplex (PEG-coated TS shRNA-lipoplex) for systemic injection. PEG modifiaction efficiently delivered TS shRNA in the lipoplex to tumor tissue following intravenous administration as indicated by a significant suppression of TS expression level in tumor tissue. In addition, the combined treatment of PMX with systemic injection of PEG-coated TS shRNA-lipoplex exerted a potent antitumor activity against MSTO-211H xenograft mouse model, compared to a single treatment with either PMX or PEG-coated TS shRNA-lipoplex. Metastasis, or the spread, of mesothelioma plays an important role in the effectiveness of treatment options. The systemic, in addition to local, delivery of tumor targeted anti-TS RNAi system we propose in this study might be an effective option to extend the clinical utility of PMX in treating malignant mesothelioma.

Source: Systemically administered RNAi molecule sensitizes malignant pleural mesothelioma cells to pemetrexed therapy.


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