THE EPIDEMIOLOGY OF MALIGNANT PLEURAL MESOTHELIOMA (MPM): AN EXPERT ANALYSIS OF CURRENT LITERATURE

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1 THE EPIDEMIOLOGY OF MALIGNANT PLEURAL MESOTHELIOMA (MPM): AN EXPERT ANALYSIS OF CURRENT LITERATURE Participants: Dr. Paolo Bironzo (University of Torino, Italy), Liz Darlison (University Hospitals of Leicester NHS Trust, UK, Director of Services Mesothelioma UK), Dr. Takashi Kijima (Hyogo College of Medicine, Japan), Prof. Martin Schuler (University Hospital Essen, Germany), Dr. Anne Tsao (University of Texas MD Anderson Cancer Centre, USA). Copyright Boehringer Ingelheim International GmbH. All rights reserved. April Procedure ID: xxxx

2 Creative representation of the roundtable discussion - created by Lauren from Scriberia

3 BACKGROUND Malignant pleural mesothelioma (MPM) is a rare, aggressive and difficult-to-treat malignancy. MPM represents fewer than 1% of all malignancies and is often related to prolonged asbestos exposure. 1 Prognosis is often poor, with diagnosis often occurring at an advanced stage. Median survival across all patients is reported to be as little as 7 months and many patients are unfit for active treatment. Additional determinants of prognosis include MPM subtype and comorbidities. 2 There are three different histological MPM subtypes: epithelioid, the most common and most treatable; sarcomatoid, the most aggressive and resistant to treatment, and biphasic, which is a combination of the epithelioid and sarcomatoid histologies. Each different type is characterised by difference in treatment response and prognosis. 3 No biomarker stratified targeted therapies are currently approved to treat MPM and patients continue to have a poor prognosis, with fewer than 10% surviving for five years following diagnosis. 4 On Friday 13th April 2018, an expert committee met to review the existing literature* on the epidemiology of MPM. The committee included: Dr. Paolo Bironzo (University of Torino, Italy) Liz Darlison (University Hospitals of Leicester NHS Trust, UK, Director of Services Mesothelioma UK) Dr. Takashi Kijima (Hyogo College of Medicine, Japan) Prof. Martin Schuler (University Hospital Essen, Germany) Dr. Anne Tsao (University of Texas MD Anderson Cancer Centre, USA). The material reviewed was based on a literature review* compiled by Boehringer Ingelheim which covered data: On incidence, prevalence, mortality and demographic profiles; From original English language population-based studies published since 2000, where Malignant Pleural Mesothelioma (MPM) was distinguishable separately from Malignant Mesothelioma (MM); PubMed and EMBASE databases were searched in September and October of 2017; Studies of fewer than 50 cases were excluded. The objective of the roundtable discussion was to bring together experts in the field, to analyse the existing literature* around the epidemiology of this disease, and chart a path forward for the community as a whole. The output of the meeting is a clear and coherent expert statement which outlines the expert s opinion on the future of MPM management. References: 1. Moore A. et al. Malignant mesothelioma. Orphanet J Rare Dis (34). 2. Opitz I. Management of malignant pleural mesothelioma -The European experience. J Thorac Dis Suppl 2: S Shavelle R et al. Life expectancy in pleural and peritoneal mesothelioma. Lung Cancer Int

4 DEMOGRAPHICS AND DIAGNOSIS Demographics Demographic variances play a vital role in refining and personalising the management of MPM. Factors such as incidence, gender, histology and overall survival rate are defining factors in MPM. Key statistics: Estimated general population incidences ranged from per 100,000 with huge differences between locations (e.g. Ireland 0.5, Leeds, UK 4.7) 1 The incidence in men is approximately four times the incidence in women, largely due to occupational exposure. Male to female ratios range from 1.5 in Turkey to 6.1 in the US 2,3 Epithelioid type was most common, occurring in 45-93% (median: 66%) of patients 4,5 Observed median overall survival in most studies in the literature review* was less than one year. Epithelioid subtypes are associated with longer survival compared to other subtypes 6 Women routinely have better survival outcomes than men. 7 In my clinic, there has been a slight increase in female incidence due to asbestos exposure in textile factories. Also, as a general trend, women live longer, so we may see more cases of old age female patients. Dr. Paolo Bironzo 4

5 Diagnosis Diagnosis for MPM is complex and prognosis is generally poor. The diagnostic process, misdiagnosis and screening are all central elements that impact on the epidemiology of MPM. Key statistic/points: Most patients with MPM present with advanced disease and their symptoms are often categorised as general including cough, dyspnoea, chest pain, and constitutional symptoms such as fatigue, insomnia, weight loss and anorexia. Pleural effusions are also common upon clinical examination 8 Without immunohistochemistry testing, MPM can be misdiagnosed as lung adenocarcinoma. 9 There is no rigorous screening in the UK. In the past, legal issues have driven us to pursue diagnosis, but more recently as there are more clinical trials available, there has been an increase in diagnosis. Liz Darlison In Germany, when people have been exposed to asbestos due to their occupation, systematic surveillance including regular chest X-rays is provided by the Berufsgenossenschaften. However, in reality this is not particularly helpful. Clinically MPM can be misdiagnosed as adenocarcinoma of the lung and conversely, adenocarcinoma can be misdiagnosed as malignant pleural mesothelioma. We have to push for proper screening. Prof. Martin Schuler References: 1. Chapman et al. Population based epidemiology and prognosis of mesothelioma in Leeds, UK. Thorax : Carkanat et al. The incidence of mesothelioma has not decreased for the last twenty years in Southeast region of Anatolia. Afr Health Sci : Strickler HD et al. Trends in U.S. pleural mesothelioma incidence rates following simian virus 4 contamination of early poliovirus vaccines. J Natl Cancer Inst : Jung SH et al. A decade of malignant mesothelioma surveillance in Korea. Am J Ind Med : Flores-Franco RA et al. Malignant mesothelioma trends in Chihuahua, Mexico. Salud Publica Mex : Ettinger DS et al. Malignant pleural mesothelioma. J Natl Compr Canc Netw : Taioli E et al. Women with malignant pleural mesothelioma have a threefold better survival rate than men. Ann Thorac Surg : NCCN Guidelines Version : Malignant Pleural Mesothelioma. Available at: Mesothelioma.pdf Last accessed April Delgermaa V et al. Global mesothelioma deaths reported to the World Health Organization between 1994 and Bull World Health Organ : , c. 5

6 EXPOSURE, TREATMENT AND GUIDELINES Asbestos exposure Asbestos exposure and associated issues should be considered in the diagnosis of MPM. Occupational exposure is the primary risk factor for developing MPM, however the latency period for development is between 20 and 60 years meaning that identification can be difficult. 1 The plateauing incidence rates of MPM in countries that have eradicated asbestos via regulation (over the past years) suggest that the push to eradicate occupational exposure has a direct impact on MPM incidence. However, environmental exposure and identification of germline mutations, such as BAP1 continue to lead to persistence in MPM. 2,3,4,5 Treatment The management of MPM is complex and there is a great unmet need of treatment options. As a rare disease, with a rapid course and poor prognosis, MPM is difficult to study. This prevents the accumulation of large volumes of valuable knowledge particularly regarding second and third line treatments in patients with unresectable disease. Furthermore, existing multimodal therapy is complex and is the optimal treatment plan for a minority of patients with MPM. However, treatment patterns are not fully established. Key statistics/points: The rarity of MPM adversely affects study accrual. Identifying the best potential therapy for each patient in a timely manner is crucial Identification of biomarkers that could improve either diagnosis or potential response to treatment is an important and highly active area of study Patients with the best prognosis (e.g. those with early, epithelioid-type disease who are otherwise healthy) endure roughly 6 months of intense effort to complete trimodal therapy; although this can be effective, the quality of life trade-offs of this intense treatment are not certain Up to 50% of patients present with advanced disease or non-epithelioid types of MPM and are therefore not candidates for aggressive treatment. The disease course in the population of patients treated with supportive care alone is not well described in the literature. There is a definite need for patient portals on National Registries, with work history captured. Lack of this slows down legal proceedings to find witnesses of work history. Liz Darlison I am very interested in the data from lowincome countries, where governments are not doing so much to help the situation. Epidemics will soon touch other countries a statement is important to raise awareness on something which is often underreported. Some people are still working with asbestos every day of their lives and are dying because of this. Dr. Paolo Bironzo The most important thing is trying to put patients into trials, even non-randomized ones, exploring viable treatment options in localised disease. Otherwise in 20 years, we will still be discussing trimodality therapy. Trials may lead us to an answer. Dr. Paolo Bironzo In Japan, MPM specialists always check for several potential markers such as BAP-1, CDKs, p16 and NF-2. Dr. Takashi Kijima 6

7 Guidelines Several treatment guidelines exist for MPM both in the US and Europe, including those set out by ASCO, ESMO and NCCN, which recommend cis/pem in first-line unresectable MPM. It is still not clear what approaches yield the best clinical outcomes due to paucity of data with highest level evidence. This may be a result of the poor prognosis of this patient population. The optimal treatment sequence has yet to be demonstrated and prognostic studies that utilise patients clinical and other characteristics have yet to move beyond histologic subtype, age and stage at presentation as predictors of successful therapy. The group hopes that treatment according to histology will be implemented in the near future. We need to raise awareness of malignant pleural mesothelioma and its treatment. Patients need to be referred to oncologists. Large numbers of patients don t reach an oncologist. There are drugs being developed to target specific pathways. There will be a shift in the next couple of years. Dr. Anne Tsao Longer-term data on the outcomes of therapy are needed to assess the risk/benefit of interventions for MPM. References: 1. Zandwijk N et al. Guidelines for the diagnosis and treatment of malignant pleural mesothelioma. J Thorac Dis (6): E254 E Baumann F et al. Asbestos is not just asbestos: an unrecognised health hazard. Lancet Oncol : Carbone M et al. Erionite exposure in North Dakota and Turkish villages with mesothelioma. Proc Natl Acad Sci U S A : Baumann F et al. The Presence of Asbestos in the Natural Environment is Likely Related to Mesothelioma in Young Individuals and Women from Southern Nevada. J Thorac Oncol : Testa JR et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet :

8 EXPERT STATEMENT** Every patient should know there is hope; we have a better understanding of mesothelioma biology and better tools than ever before. Today, we can be justified in feeling optimistic about the future as there is so much left to come. We must now empower all patients support them with their treatment choices, ensure access to specialists and facilities, and provide them with the care and community they deserve. As members of this community, we need to provide greater transparency and access for patients and work to actively connect our patients to all that they need. We must deepen our connections and expand the network of clinicians working collaboratively towards a cure. We owe it to all future generations to ban asbestos globally, to stem the tide of this disease. Until then, we must give mesothelioma the funding and attention it deserves. * Searches were conducted by a medical librarian using PubMed and EMBASE databases between September 26th and October 17, Englishlanguage publications from 2000 onward were sought. The search terms included were intended to capture publications that addressed MPM and any aspects of it required to address all sections of the document. Title and abstract review excluded all studies of less than 50 cases of MPM. Throughout, studies that included patients with malignant mesothelioma that did not differentiate by site (e.g. pleural, peritoneal, testicular) were also excluded. ** This statement was developed by the experts in a workshop session during the meeting and represents their call-to-action for the wider community, to address the unmet needs in MPM management. 8

9 Boehringer Ingelheim would like to thank all the experts who attended the expert committee roundtable meeting for their invaluable insights into malignant pleural mesothelioma. Disclaimer: Boehringer Ingelheim sponsored the Epidemiology of Malignant Pleural Mesothelioma (MPM) roundtable referenced in this report as well as the development of this report. 9

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