Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer arising from the mesothelial cells lining the pleura. Asbestos exposure is the major risk factor for mesothelioma with a very prolonged latency period between exposure to asbestos and the development of mesothelioma (20–50 years)1. The incidence rates of mesothelioma in the United States are 0.9 for men and 0.3 for women and in Europe 1.7 for males and 0.4 for females per 100,000 habitants2. The annual incidence of mesothelioma is increasing in Great Britain and Australia and it is predicted to increase in countries with poor regulation of asbestos mining.
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Malignant mesothelioma is often refractory to standard chemotherapy regimens and exhibit poor prognosis, with overall survival being on the order of 9–18 months after diagnosis3,4. ECOG performance status, stage and histology are the strongest prognostic factors among patients with mesothelioma. The World Health Organization (WHO) classification includes three main histological subtypes (epithelioid, sarcomatoid and biphasic) with a different prognosis. Epithelioid histology is associated with a more favorable prognosis.
Treatment options for MPM patients who are not eligible for surgery are very limited. Platinum-based chemotherapy combined with an antifolate lead to a median survival of about 12–16 months3,4. The addition of bevacizumab or Tumor-Treating fields (TTF) to chemotherapy increases survival (18.8 and 18.2 months respectively)5,6. Carboplatin in association with pemetrexed is an accepted alternative option for patients who may not tolerate cisplatin7,8.
There remains an unmet clinical need for new, effective therapies that can improve outcomes in the first line. In recent years a dramatic improvement in advanced cancers therapy has been achieved with immune checkpoint blockade. However, results of early studies with immunotherapy in mesothelioma are contradictory, and currently Japan has approved nivolumab in second line setting and US and EU the combination of nivolumab plus ipilimumab in first line setting. Initial studies using single drug checkpoint inhibitors in previously treated patients demonstrated some efficacy with a median progression free survival (PFS) between 2 and 6 months with nivolumab and about 5 months with pembrolizumab9,10,11.
However, the results of randomized trial are controversial12,13,14. Pembrolizumab and tremelimumab failed to show improvement in PFS and overall survival (OS) in second-third line versus chemotherapy or placebo, but recently the CONFIRM trial demonstrated that nivolumab improved PFS and OS versus placebo in relapsed MPM14. The combination of immune checkpoint inhibition with ipilimumab and nivolumab in previously treated patients demonstrated similar results for the combination and monotherapy in the MAPS2 trial, and in first line the combination demonstrated being superior to chemotherapy in the pivotal CheckMate 743 in terms of survival (OS 18.1 months) leading to the approval of this combination by FDA and EMA15,16. In a preplanned subanalysis considering histology, improvements in efficacy of immunotherapy over chemotherapy were statistically significant among those with non-epithelioid histology but not for epithelioid histology. Authors suggested that the differences were due to reduced efficacy of chemotherapy in non-epithelioid MPM.
However, the pivotal trial which led to the approval of cisplatin plus pemetrexed in MPM did not evaluate the efficacy of chemotherapy by histology3. Moreover, ASCO guidelines published in 2018 did not recommend different systemic treatment according to histology and EURACAN/IASLC classification published in 2020 concluded that there is no clear evidence that chemotherapy provides less proportional benefit to patients with biphasic or sarcomatoid disease17,18. After the publication of CheckMate 743 we have review the clinical trials that had led to approval or recommendation of therapies in MPM (pemetrexed, raltitrexed, bevacizumab and TTFields). We found that the studies of pemetrexed and raltitrexed did not report the results by histology and in the trial with bevacizumab no differences were detected for histology. Finally, in a posthoc analysis in the study of TTFields patients with epithelioid tumors presented longer PFS. Only the combination of carboplatin plus pemetrexed reported no responses in sarcomatoid mesothelioma in a phase 2 trial. The aim of our study is to evaluate the efficacy of chemotherapy by histological subgroups in a real-world series of MPM patients
Study design
This retrospective cohort study used real-world data from the electronic medical records from the Vall d’Hebron Hospital Universitari to identify patients with MPM who had initiated systemic therapy under routine clinical practice between February 2002 to February 2020. The study selection period encompasses the dates when immunotherapy was been evaluated in MPM, but not approved. Patients were followed longitudinally until death or their last visit prior to data cutoff. Demographic information, asbestos exposure, stage at initial diagnosis, sites of metastases, cancer treatment, medical history, disease characteristics and data on tumor evaluation (including progression of the disease and response to treatment), were considered as appropriate. Tissue specimens were obtained from the primary mesothelioma at the time of diagnosis by surgery or core biopsy. Each sample was assessed histologically for tumor tissue by two pathologists and cases were classified as epithelioid, sarcomatoid and biphasic subtypes of malignant mesothelioma. This study was approved by local ethical committee (Ethical Committee at Vall d’Hebron Hospital Universitary). Informed consent form was waived due to the retrospective nature of the study and permission for data usage was obtained from the local ethic committee (Ethical Committee at Vall d’Hebron Hospital Universitary). All methods were performed in accordance with the relevant guidelines and regulations.
Patients
The study cohort included patients with confirmed MPM who had received at least one line of therapy for their disease between February 2002 to February 2020, had clinical record available and were 18 years or older. To allow for sufficient follow-up for clinical outcomes, patients entered the cohort no later than 10 months prior to data cutoff (March 2021). One hundred eighty-nine consecutive cases of MPM were retrospectively collected. Clinicopathologic information gathered included complete history, age, sex, performance status (PS), asbestos exposure, tumor stage and histological subtype. Neutrophil-to-lymphocyte ratio was calculated as the ratio between neutrophils and lymphocyte in the blood analysis obtained at the time of diagnosis. The tumor stage was defined according to the International Union Against Cancer´s tumor-node metastasis 8th classification and sub-classified histologically according to the WHO guidelines18,19. All cases were reviewed by the local pathologists with expertise in the diagnosis of MPM. We evaluated a single tumor biopsy for each patient. All tumor biopsies analyzed were obtained by surgery (147 patients) or core needle biopsy (42 patients) and local pathologists confirmed the adequation of the sample to provide a diagnosis of MPM, histological subclassification and perform the needle immunohistochemical staining.
Study outcomes
The primary objective of this study was to describe the association of the histology with overall survival (OS) and progression-free survival (PFS) in MPM who received systemic chemotherapy. Secondary analyses included assessment of the outcomes in patients treated with immunotherapy and a study of prognostic factors in a real-world series of MPM. OS for each patient was defined as the time to death from diagnosis of malignancy. Progression of the disease was determined by physician assessment based on radiographic evidence. PFS was defined as the time until the earliest record of actual disease progression or death from any cause from initiation of line therapy. PFS was analyzed by therapy type.
Statistical analysis
Data were censored at last follow up for patients without relapse or death. Median follow-up time was calculated with reverse Kaplan–Meier estimator20. Median follow-up time was calculated with reverse Kaplan–Meier estimator. OS was calculated from diagnosis of malignancy until death due to any cause or until the date of last follow-up visit for still alive patients. Survival analysis that compared efficacy of chemotherapy by histology was carried out using the Kaplan–Meier curves and the significance was verified by a log-rank test. All p values were determined by two-sided tests and p values < 0.05 were considered significant. Multivariable analysis was done using the Cox regression model including only the clinical variables that showed significance in univariable analysis. A model with interaction between histology and platinum agent was constructed to determine whether the predictive value of chemotherapy agent is dependent on histology. Data analysis was produced by the R statistical software version 4.0.
Results
Patient population
We studied 189 patients with MPM whose clinicopathologic characteristics are summarized in Table 1. The median age was 68 years (range 45–88). Patients were predominantly male (70%), smokers (50%), had previous asbestos exposure (75%) and stage III (45%). The median neutrophil–lymphocyte ratio (NLR) was 5.2 and 58% have NLR less than 5. The total cohort comprised 145 epithelioid tumors, 17 sarcomatoid, 14 biphasic, and 13 cases with histological type not specified (10 of them obtained by thoracoscopy and 3 by an image-guided biopsy).
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