Extended pleurectomy decortication and chemotherapy versus chemotherapy alone for pleural mesothelioma (MARS 2): a phase 3 randomised controlled trial.

BACKGROUND: Extended pleurectomy decortication for complete macroscopic resection for pleural mesothelioma has never been evaluated in a randomised trial. The aim of this study was to compare outcomes after extended pleurectomy decortication plus chemotherapy versus chemotherapy alone. METHODS: MARS 2 was a phase 3, national, multicentre, open-label, parallel two-group, pragmatic, superiority randomised controlled trial conducted in the UK. The trial took place across 26 hospitals (21 recruiting only, one surgical only, and four recruiting and surgical). Following two cycles of chemotherapy, eligible participants with pleural mesothelioma were randomly assigned (1:1) to surgery and chemotherapy or chemotherapy alone using a secure web-based system. Individuals aged 16 years or older with resectable pleural mesothelioma and adequate organ and lung function were eligible for inclusion. Participants in the chemotherapy only group received two to four further cycles of chemotherapy, and participants in the surgery and chemotherapy group received pleurectomy decortication or extended pleurectomy decortication, followed by two to four further cycles of chemotherapy. It was not possible to mask allocation because the intervention was a major surgical procedure. The primary outcome was overall survival, defined as time from randomisation to death from any cause. Analyses were done on the intention-to-treat population for all outcomes, unless specified. This study is registered with ClinicalTrials.gov, NCT02040272, and is closed to new participants. FINDINGS: Between June 19, 2015, and Jan 21, 2021, of 1030 assessed for eligibility, 335 participants were randomly assigned (169 to surgery and chemotherapy, and 166 to chemotherapy alone). 291 (87%) participants were men and 44 (13%) women, and 288 (86%) were diagnosed with epithelioid mesothelioma. At a median follow-up of 22·4 months (IQR 11·3-30·8), median survival was shorter in the surgery and chemotherapy group (19·3 months [IQR 10·0-33·7]) than in the chemotherapy alone group (24·8 months [IQR 12·6-37·4]), and the difference in restricted mean survival time at 2 years was -1·9 months (95% CI -3·4 to -0·3, p=0·019). There were 318 serious adverse events (grade ≥3) in the surgery group and 169 in the chemotherapy group (incidence rate ratio 3·6 [95% CI 2·3 to 5·5], p<0·0001), with increased incidence of cardiac (30 vs 12; 3·01 [1·13 to 8·02]) and respiratory (84 vs 34; 2·62 [1·58 to 4·33]) disorders, infection (124 vs 53; 2·13 [1·36 to 3·33]), and additional surgical or medical procedures (15 vs eight; 2·41 [1·04 to 5·57]) in the surgery group. INTERPRETATION: Extended pleurectomy decortication was associated with worse survival to 2 years, and more serious adverse events for individuals with resectable pleural mesothelioma, compared with chemotherapy alone. FUNDING: National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (15/188/31), Cancer Research UK Feasibility Studies Project Grant (A15895).

Repurposing clofazimine for malignant pleural mesothelioma treatment - In-vitro assessment of efficacy and mechanism of action.

AIMS: Malignant pleural mesothelioma (MPM) is a rare cancer of lungs' pleural cavity, with minimally effective therapies available. Thus, there exists a necessity for drug repurposing which is an attractive strategy for drug development in MPM. Repurposing of an old FDA-approved anti-leprotic drug, Clofazimine (CFZ), presents an outstanding opportunity to explore its efficacy in treating MPM. MAIN METHODS: Cytotoxicity, scratch assay, and clonogenic assays were employed to determine CFZ's ability to inhibit cell viability, cell migration, and colony growth. 3D Spheroid cell culture studies were performed to identify tumor growth inhibition potential of CFZ in MSTO-211H cell line. Gene expression analysis was performed using RT-qPCR assays to determine the CFZ's effect of key genes. Western blot studies were performed to determine CFZ's ability to induce apoptosis its effect to induce autophagy marker. KEY FINDINGS: CFZ showed significant cytotoxicity against both immortalized and primary patient-derived cell lines with IC50 values ranging from 3.4 µM (MSTO-211H) to 7.1 µM (HAY). CFZ significantly impaired MPM cell cloning efficiency, migration, and tumor spheroid formation. 3D Spheroid model showed that CFZ resulted in reduction in spheroid volume. RT-qPCR data showed downregulation of genes ß-catenin, BCL-9, and PRDX1; and upregulation of apoptosis markers such as PARP, Cleaved caspase 3, and AXIN2. Additionally, immunoblot analysis showed that CFZ down-regulates the expression of ß-catenin (apoptosis induction) and up-regulates p62, LC3B protein II (autophagy inhibition). SIGNIFICANCE: It can be concluded that CFZ could be a promising molecule to repurpose for MPM treatment which needs numerous efforts from further studies.

Malignant pleural mesothelioma: treatment patterns and humanistic burden of disease in Europe.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive and rare tumour with poor prognosis. Most patients are diagnosed with advanced disease and there is a paucity of data on the humanistic burden of MPM in terms of impact on health-related quality of life (HRQoL) and activity. This study examined real-world treatment patterns and humanistic disease burden of MPM in Europe. METHODS: Physicians abstracted demographic/clinical characteristics and treatment data from MPM-patient medical records; MPM patients self-completed a questionnaire including symptoms, 3-level-EQ-5D questionnaire and Visual Analogue Scale (VAS), Lung Cancer Symptom Scale for Mesothelioma (LCSS-Meso), and Work Productivity and Activity Impairment (WPAI) questionnaire. RESULTS: Physicians (n = 171) abstracted data of 1390 patients; 767/1390 patients self-completed questionnaires. Patients were elderly with advanced, unresectable MPM. Treatment patterns followed guidelines with most (81%) patients receiving platinum+antifolate chemotherapy at first line (1 L). Maintenance treatment use was high (51.1%) despite no recommended maintenance therapies. Symptom burden was high and health states and HRQoL were poor at 1; declining further with progression. Overall mean (SD): LCSS-Average Symptom Burden Index score was 48.8 (19.3; n = 758); EQ-5D Utility Index score was 0.510 (0.349; n = 763); EQ-5D VAS score was 54.2 (20.3;n = 766); LCSS-3-Item Global Index score was 143.2 (64.5; n = 762); LCSS-normal activities score was 51.9 (24.6;n = 765); WPAI-activity impairment was 56.0% (23.2%; n = 737). CONCLUSION: The humanistic burden of MPM is high, despite treatments being prescribed as per available guidance. Treatments that delay progression and provide palliation of symptoms are most likely to improve/maintain HRQoL.

Treatment patterns and outcomes in older patients with advanced malignant pleural mesothelioma: Analyses of Surveillance, Epidemiology, and End Results-Medicare data.

BACKGROUND: Malignant mesothelioma is a rare neoplasm associated with asbestos exposure. Characterizing treatment patterns and outcomes of older patients with advanced malignant pleural mesothelioma (MPM) is important to understand the unmet needs of this population. AIM: To evaluate the demographic and clinical characteristics, treatment patterns, and outcomes among older patients diagnosed with advanced MPM in the United States between 2007 and 2013. METHODS: This was a retrospective cohort study using Surveillance, Epidemiology, and End Results (SEER) data linked with Medicare claims. We included patients who were age 66 or older at the time of their primary MPM diagnosis between 2007 and 2013 and followed them through 2014. Treated patients who received first-line chemotherapy with pemetrexed and platinum within 90 days of diagnosis, second-line, or third-line therapy were identified for evaluation of outcomes. RESULTS: There were 666 older patients with advanced MPM, of whom 82% were male, 87% White, 78% stage IV, and 70% had no mobility limitation indicators at diagnosis. There were 262 patients who received first-line chemotherapy for advanced MPM, most of whom (80%; n = 209) received pemetrexed-platinum. Of these 209 patients, 41% (n = 86) initiated second-line therapy, and 26% (n = 22) initiated third-line therapy. Median overall survival for the cohort of 209 patients was 7.2 months. Patients with epithelioid histology had better median overall survival (12.2 months) compared with other histologies (4.4-5.6 months). Within 90 days of diagnosis of advanced MPM, 78% of patients were hospitalized, 52% visited an emergency department, and 21% had hospice care. The 2-year cost of care was over $100 000 for all patients with advanced MPM treated with first-line pemetrexed-platinum. CONCLUSIONS: Although first-line systemic anticancer treatment was generally consistent with guidelines (e.g., pemetrexed-platinum), poor patient outcomes highlight the need for effective treatment options for older patients with advanced MPM.

Dynamic contrast-enhanced CT for the assessment of tumour response in malignant pleural mesothelioma: a pilot study.

OBJECTIVES: The aim of this pilot study was to investigate the utility of haemodynamic parameters derived from dynamic contrast-enhanced computed tomography (DCE-CT) scans in the assessment of tumour response to treatment in malignant pleural mesothelioma (MPM) patients. METHODS: The patient cohort included nine patients undergoing chemotherapy and five patients on observation. Each patient underwent two DCE-CT scans separated by approximately 2 months. The DCE-CT parameters of tissue blood flow (BF) and tissue blood volume (BV) were obtained within the dynamically imaged tumour. Mean relative changes in tumour DCE-CT parameters between scans were compared between the on-treatment and on-observation cohorts. DCE-CT parameter changes were correlated with relative change in tumour bulk evaluated according to the modified RECIST protocol. RESULTS: Differing trends in relative change in BF and BV between scans were found between the two patient groups (p = 0.19 and p = 0.06 for BF and BV, respectively). No significant rank correlations were found when comparing relative changes in DCE-CT parameters with relative change in tumour bulk. CONCLUSIONS: Differing trends in the relative change of BF and BV between patients on treatment and on observation indicate the potential of DCE-CT for the assessment of pharmacodynamic endpoints with respect to treatment in MPM. A future study with a larger patient cohort and unified treatment regimens should be undertaken to confirm the results of this pilot study. KEY POINTS: • CT-derived haemodynamic parameters show differing trends between malignant pleural mesothelioma patients on treatment and patients off treatment • Changes in haemodynamic parameters do not correlate with changes in tumour bulk as measured according to the modified RECIST protocol • Differing trends across the two patient groups indicate the potential sensitivity of DCE-CT to assess pharmacodynamic endpoints in the treatment of MPM.

Real-life treatment practice for malignant pleural mesothelioma in Belgium.

OBJECTIVES: Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer, for which treatment is often limited to palliative combination chemotherapy. Multimodality-therapy, including radical surgery, is largely restricted to clinical trials, leaving its benefit currently unclear. This study aimed to get a comprehensive view on real-world MPM treatment at the Belgian population level, to assess survival and to identify prognostic factors. MATERIALS AND METHODS: The study period covered the incidence years 2004-2012 (N = 1453). Starting from the Belgian Cancer Registry, additional information regarding patient characteristics, diagnosis and treatment was retrieved from multiple data sources. Adjusted cox proportional-hazard regression models using time-dependent covariates were performed to assess survival in relation to treatment patterns and centre volume. RESULTS: Sixty-nine percent of patients underwent tumour-directed treatment, mostly cisplatin-pemetrexed chemotherapy. Radical surgery was mainly performed in younger patients with epithelioid subtype. Centre volume, surgery and chemotherapy showed a positive relation with survival in univariable analyses, but only chemotherapy remained significantly relevant in multivariable analyses. Younger patients, females, and epithelioid subtypes also independently had a better survival. CONCLUSION: This large population-based study provides insights in MPM treatment practice in Belgium. Centre volume and surgery being related to survival in univariable analyses, only chemotherapy remained prognostic after adjustment.

Assessment of new HDAC inhibitors for immunotherapy of malignant pleural mesothelioma.

Background: Malignant pleural mesothelioma (MPM) is a very rare and highly aggressive cancer of the pleura associated in most cases with asbestos exposure. To date, no really efficient treatments are available for this pathology. Recently, it has been shown that epigenetic drugs, particularly DNA methylation or histone acetylation modulating agents, could be very efficient in terms of cytotoxicity for several types of cancer cells. We previously showed that a hypomethylating agent (decitabine) and a histone deacetylase inhibitor (HDACi) (valproic acid (VPA)) combination was immunogenic and led to the induction of an anti-tumor immune response in a mice model of mesothelioma. However, VPA is not very specific, is active at millimolar concentrations and is responsible for side effects in clinic. To improve this approach, we studied four newly synthetized HDACi, two hydroxamates (ODH and NODH) and two benzamides (ODB and NODB), in comparison with VPA and SAHA. We evaluated their toxicity on immune cells and their immunogenicity on MPM cells in combination with decitabine. Results: All the tested HDACi were toxic for immune cells at high concentrations. Combination with decitabine increased toxicity of HDACi only towards T-cell clone. A decrease in the proportion of regulatory T cells and natural killer cells was observed in particular with VPA and ODH. In MPM cells, all HDACi combinations induced NY-ESO-1 cancer testis antigen (CTA) expression and the recognition of the treated cells by a NY-ESO-1 specific T-CD8 clone. However, for MAGE-A1, MAGE-A3 and XAGE-1b mRNA expression, the results obtained depended on the HDACi used and on the CTA studied. Depending on the MPM cell line studied, molecules alone increased moderately PD-L1 expression. When combined, a higher stimulation of this immune check point inhibitor expression was observed. Decitabine-induced anti-viral response seemed to be inhibited in the presence of HDACi. Conclusions: This work shows that the combination of decitabine and HDACi could be of interest for MPM immunotherapy. However, this combination induced PD-L1 expression which suggests that an association with anti-PD-L1 therapy should be performed to induce an efficient anti-tumor immune response.

Revised Modified Response Evaluation Criteria in Solid Tumors for Assessment of Response in Malignant Pleural Mesothelioma (Version 1.1).

INTRODUCTION: Malignant pleural mesothelioma poses unique difficulties in tumor measurement and response assessment; however, robust and reproducible assessment of response is critically important in the conduct, interpretation, and reporting of clinical trials. METHODS: The current de facto standard for the assessment of mesothelioma tumor response, "modified RECIST" (Response Evaluation Criteria in Solid Tumors), was published in 2004 as a research paper. Practical application of the modified RECIST guidelines has suffered from varied interpretations, resulting in inaccuracies and inconsistencies in tumor response assessment across and within mesothelioma clinical trials. The presented "modified RECIST 1.1 for mesothelioma" response assessment guidelines provide a much-needed update that incorporates recommendations from RECIST 1.1 and approaches to other practical issues, including: (1) definition of minimally measurable disease; (2) definition of measurable lesions; (3) acceptable measurement location; (4) non-pleural disease considerations; (5) characterization of non-measurable pleural disease; (6) assessment of pathological lymph nodes; (7) establishing progressive disease; and (8) accommodations for bilateral pleural disease. RESULTS: These modified RECIST 1.1 guidelines for mesothelioma tumor response collate and apply research published since the development of modified RECIST, align modified RECIST with RECIST 1.1, address those aspects of tumor measurement that were neglected or not well characterized in the modified RECIST paper, and clarify ambiguous or difficult measurement issues that have been highlighted through the subsequent decade of clinical trials research. CONCLUSION: Adoption of the modified RECIST 1.1 guidelines for mesothelioma is recommended to harmonize the application of tumor measurement and response assessment across the next generation of clinical trials in this disease.

Possible repurposing of pyrvinium pamoate for the treatment of mesothelioma: A pre-clinical assessment.

Malignant mesothelioma (MM) is a very aggressive asbestos-related cancer, whose incidence is increasing worldwide. Unfortunately, no effective therapies are currently available and the prognosis is extremely poor. Recently, the anti-helminthic drug pyrvinium pamoate has attracted a strong interest for its anti-cancer activity, which has been demonstrated in many cancer models. Considering the previously established inhibitory effect of pyrvinium pamoate on the Wnt/ß-catenin pathway and given the important role of this pathway in MM, we investigated the potential anti-tumor activity of this drug in MM cell lines. We observed that pyrvinium pamoate significantly impairs MM cell proliferation, cloning efficiency, migration, and tumor spheroid formation. At the molecular level, our data show that pyrvinium pamoate down-regulates the expression of ß-catenin and Wnt-regulates genes. Overall, our study suggests that the repurposing of pyrvinium pamoate for MM treatment could represent a new promising therapeutic approach.

CONFIRM: a double-blind, placebo-controlled phase III clinical trial investigating the effect of nivolumab in patients with relapsed mesothelioma: study protocol for a randomised controlled trial.

BACKGROUND: Mesothelioma is an incurable, apoptosis-resistant cancer caused in most cases by previous exposure to asbestos and is increasing in incidence. It represents a growing health burden but remains under-researched, with limited treatment options. Early promising signals of activity relating to both PD-L1- and PD-1-targeted treatment in mesothelioma implicate a dependency of mesothelioma on this immune checkpoint. There is a need to evaluate checkpoint inhibitors in patients with relapsed mesothelioma where treatment options are limited. METHODS: The addition of 12 months of nivolumab (anti-PD1 antibody) to standard practice will be conducted in the UK using a randomised, placebo-controlled phase III trial (the Cancer Research UK CONFIRM trial). A total of 336 patients with pleural or peritoneal mesothelioma who have received at least two prior lines of therapy will be recruited from UK secondary care sites. Patients will be randomised 2:1 (nivolumab:placebo), stratified according to epithelioid/non-epithelioid, to receive either 240 mg nivolumab monotherapy or saline placebo as a 30-min intravenous infusion. Treatment will be for up to 12 months. We will determine whether the use of nivolumab increases overall survival (the primary efficacy endpoint). Secondary endpoints will include progression-free survival, objective response rate, toxicity, quality of life and cost-effectiveness. Analysis will be performed according to the intention-to-treat principle using a Cox regression analysis for the primary endpoint (and for other time-to-event endpoints). DISCUSSION: The outcome of this trial will provide evidence of the potential benefit of the use of nivolumab in the treatment of relapsed mesothelioma. If found to be clinically effective, safe and cost-effective it is likely to become the new standard of care in the UK. TRIAL REGISTRATION: EudraCT Number: 2016-003111-35 (entered on 21 July 2016); ClinicalTrials.gov, ID: NCT03063450 . Registered on 24 February 2017.

Mesothelioma in Australia: a review.

The incidence of malignant mesothelioma in Australia is among the highest in the world as a result of widespread use of asbestos by industry and in construction throughout the 20th century. The risk of developing malignant mesothelioma after asbestos exposure is dose-related; a transient, low dose exposure confers a correspondingly very low risk of disease. Malignant mesothelioma is a heterogeneous disease, partly explaining the limited role of biomarkers in screening and diagnosis. The prognosis remains poor, and early advice on medico-legal compensation and a collaborative team approach to managing malignant mesothelioma are both essential. Chemotherapy can have a modest treatment effect in some people. New therapies, such as immunotherapy, do not yet have a defined role in the treatment of malignant mesothelioma. As treatment options for malignant mesothelioma are limited and no cure is available, there is no established role for early detection or screening of at risk populations. A multidisciplinary approach to caring for patients with malignant mesothelioma and their carers is vital.

PDT dose dosimetry for Photofrin-mediated pleural photodynamic therapy (pPDT).

Photosensitizer fluorescence excited by photodynamic therapy (PDT) treatment light can be used to monitor the in vivo concentration of the photosensitizer and its photobleaching. The temporal integral of the product of in vivo photosensitizer concentration and light fluence is called PDT dose, which is an important dosimetry quantity for PDT. However, the detected photosensitizer fluorescence may be distorted by variations in the absorption and scattering of both excitation and fluorescence light in tissue. Therefore, correction of the measured fluorescence for distortion due to variable optical properties is required for absolute quantification of photosensitizer concentration. In this study, we have developed a four-channel PDT dose dosimetry system to simultaneously acquire light dosimetry and photosensitizer fluorescence data. We measured PDT dose at four sites in the pleural cavity during pleural PDT. We have determined an empirical optical property correction function using Monte Carlo simulations of fluorescence for a range of physiologically relevant tissue optical properties. Parameters of the optical property correction function for Photofrin fluorescence were determined experimentally using tissue-simulating phantoms. In vivo measurements of photosensitizer fluorescence showed negligible photobleaching of Photofrin during the PDT treatment, but large intra- and inter-patient heterogeneities of in vivo Photofrin concentration are observed. PDT doses delivered to 22 sites in the pleural cavity of 8 patients were different by 2.9 times intra-patient and 8.3 times inter-patient.

Cost-effectiveness analysis of additional bevacizumab to pemetrexed plus cisplatin for malignant pleural mesothelioma based on the MAPS trial.

PURPOSE: Malignant pleural mesothelioma (MPM) is a rare malignancy, and pemetrexed/cisplatin (PC) is the gold standard first-line regime. This study evaluated the cost-effectiveness of the addition of bevacizumab to PC (with maintenance bevacizumab) for unresectable MPM based on a phase III trial that showed a survival benefit compared with chemotherapy alone. METHODS: To estimate the incremental cost-effectiveness ratio (ICER) of the incorporation of bevacizumab, a Markov model based on the MAPS trial, including the disease states of progression-free survival, progressive disease and death, was used. Total costs were calculated from a Chinese payer perspective, and health outcomes were converted into quality-adjusted life year (QALY). Model robustness was explored in sensitivity analyses. RESULTS: The addition of bevacizumab to PC was estimated to increase the cost by $81446.69, with a gain of 0.112 QALYs, resulting in an ICER of $727202.589 per QALY. In both one-way sensitivity and probabilistic sensitivity analyses, the ICER exceeded the commonly accepted willingness-to-pay threshold of 3 times the gross domestic product per capita of China ($23970.00 per QALY). The cost of bevacizumab had the most important impact on the ICER. CONCLUSIONS: The combination of bevacizumab with PC chemotherapy is not a cost-effective treatment option for MPM in China. Given its positive clinical value and extremely low incidence of MPM, an appropriate price discount, assistance programs and medical insurance should be considered to make bevacizumab more affordable for this rare patient population.

Immune Checkpoints Aberrations and Malignant Mesothelioma: Assessment of Prognostic Value and Evaluation of Therapeutic Potentials.

Malignant pleural mesothelioma (MPM) is a hard to treat malignancy arising from the mesothelial surface of the pleura. Immune checkpoint inhibitors are considered a promising therapeutic strategy in many hardto- treat malignancies. In this review, we are trying to provide an in depth coverage of the prognostic value of immune checkpoints aberrations as well as discuss the different novel therapeutic strategies implementing these agents in the management of MPM.

Metabolic response assessment with 18F-FDG-PET/CT is superior to modified RECIST for the evaluation of response to platinum-based doublet chemotherapy in malignant pleural mesothelioma.

PURPOSE: Efficient monitoring of tumor responsiveness to chemotherapy is essential to mitigate high mortality risks and cytotoxic effects of chemotherapeutics. However, there is no consensus on the most suitable diagnostic technique/parameters for assessing response to chemotherapy in malignant pleural mesothelioma (MPM). We compared the tumor responsiveness of MPM patients as assessed using modified RECIST (mRECIST) criteria and integrated 18F-FDG-PET/CT. METHODS: Histologically confirmed MPM patients (N=82) who were treated with three cycles of cisplatin and pemetrexed, or carboplatin and pemetrexed, were included. mRECIST and integrated 18F-FDG-PET/CT were used to evaluate MPM tumor response to chemotherapy. Metabolic non-responders were defined as those with a 25% or greater increase in SUVmax compared with the previous value. Time to progression (TTP) and overall survival (OS) were compared between metabolic-responders and non-responders. RESULTS: After three cycles of chemotherapy, 62(75.6%) of the patients were classified as having SD, 15 (18%) with partial remission (PR), and 5 (6%) with progressive disease (PD), based on mRECIST criteria. The cumulative median OS was 728.0days (95% confidence interval [CI]: 545.9-910.1) and cumulative median TTP was 365.0days (95% CI: 296.9-433.1). For the 82 patients, the disease control rate was 93.9%, whereas the metabolic response rate was only 71.9% (p<0.001). All PD and PR patients were found to be metabolic responders on 18F-FDG-PET/CT; however, among the 62mRECIST SD patients, 18 (29%) were classified as metabolic non-responders. The median TTP for metabolic responders was 13.7 months, while it was 10.0 months for non-responders(p<0.001). Metabolic responders had a trend toward longer OS, although the difference did not reach statistical significance (metabolic responders:33.9 months; non-responders: 21.6 months; p>0.05). CONCLUSION: Several mRECIST-confirmed SD MPM patients may be classified as metabolic non-responders on18F-FDGPET/CT. Metabolic response is significantly correlated with the median TTP, suggesting it should be included in the evaluation of the response to chemotherapy in MPM patients classified as mRECIST SD, to identify non-responders.

Eficacia y seguridad de pemetrexed en el tratamiento de primera línea del mesotelioma maligno pleural estadio clínico IV, y III no operable / Efficacy and safety of pemetrexed in the first-line treatment of malignant pleural mesothelioma clinical stage IV, and III not operable

INTRODUCCIÓN: El presente informe expone la evaluación de la combinación de pemetrexed con quimioterapia como tratamiento de primera línea en los casos de mesotelioma maligno pleural (MMP) estadio clínico IV (metastásico), y III no operable. El mesotelioma maligno pleural (MMP) es un raro tipo de neoplasia que se origina en las células mesoteliales que recubren la cavidad pleural. Más del 80% de los casos están relacionados con la exposición ocupacional a los asbestos; esta condición es significativamente más común en hombres, con una razón de hombre-mujer de 5:1. Con frecuencia la manifestación clínica y el diagnóstico aparecen en estadios avanzados, siendo muy pobre el pronóstico para la mayoría de los afectados. OBJETIVO: Comparar el efecto de la combinación de pemetrexed + cisplatino en la sobrevida global (SG) de los pacientes, respecto al uso de cisplatino solo. TECNOLOGÍA SANITARIA DE INTERÉS: Pemetrexed es un agente anti-folato que ejerce su acción antineoplásica por medio de la alteración de varios procesos metabólicos, dependientes de folato, esenciales de la división celular. Suprime la síntesis de purinas y pirimidinas, las cuales son claves en la formación de bloques de ADN y ARN. METODOLOGÍA: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de la combinación de pemetrexed con platino como tratamiento de primera línea de los casos de mesotelioma maligno pleural (MMP) estadio clínico IV (metastásico), y III no operable. Esta búsqueda se realizó utilizando los meta-buscadores: Translating Research into Practice (TRIPDATABASE), National Library of Medicine (Pubmed-Medline) y Health Systems Evidence. Adicionalmente, se amplió la búsqueda revisando la evidencia generada por grupos internacionales que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), tales como la Cochrane Group, The National Institute for Health and Care Excellence (NICE), the Agency for Health care Research and Quality (AHRQ), The Canadian Agency for Drugs and Technologies in Health (CADTH) y The Scottish Medicines Consortium (SMC). Esta búsqueda se completó ingresando a la página web www.clinicaltrials.gov, para así poder identificar ensayos clínicos en elaboración o que no hayan sido publicados aún, y así disminuir el riesgo de sesgo de publicación. RESULTADOS: Se realizó la búsqueda bibliográfica y de evidencia científica para el sustento del uso de la combinación de pemetrexed con cisplatino como tratamiento de primera línea de los casos de mesotelioma maligno pleural (MMP) estadio clínico IV (metastásico), y III no operable. La evidencia de mayor calidad disponible es el estudio EMPHACIS. Este estúdio fue un ECA de fase III, ciego simple, cuyo objetivo principal fue comparar el efecto de la combinación de pemetrexed + cisplatino en la sobrevida global (SG) de los pacientes, respecto al uso de cisplatino solo. El estudio EMPHACIS sugiere que pemetrexed + cisplatino puede ofrecer mayor beneficio comparado con cisplatino solo, en pacientes con enfermedad avanzada en términos de ganancia de aproximadamente 2.8 meses en la sobrevida. Se observó una diferencia significativa en la sobrevida a favor de la combinación de pemetrexed + cisplatino, respecto al uso de cisplatino solo. Al considerarse la población por intención a tratar, la mediana de SG fue 12.1 meses (IC 95% 10.0-14.4) en el brazo de pemetrexed + cisplatino, comparado con los 9.3 meses (IC 95% 7.8-10.7) en el brazo de cisplatino (HR=0.77; IC 95%, 0.61 - 0.96; p=0.02). El uso de pemetrexed suplementado con ácido fólico y vitamina B12 puede mejorar la sobrevida cuando es usada en combinación con cisplatino, pero en pacientes con buen funcionamiento general (ECOG 0-1). No obstante, aun seleccionando al paciente según este criterio, la decisión de tratar a un paciente con la combinación de pemetrexed con cisplatino debe también tomar em consideración la toxicidad asociada. En EsSalud, están disponibles vinorelbina y el régimen MVP (mitomicina C, vinblastina y cisplatino), que son los agentes que se han venido usando en el tratamiento del MMP, pero han mostrado ofrecer solo algún alivio de los sintomas con aceptable toxicidad y sin ninguna mejora en la tasa de respuesta ni en la sobrevida global. Actualmente, no hay evidencia de otro agente que haya logrado más allá de respuestas parciales sin ningún efecto en la sobrevida. La única combinación que mostró algún beneficio en la SG es la de pemetrexed con cisplatino. A pesar de las limitantes del estudio, el MMP es una enfermedad con una mediana de sobrevida de alrededor de 12 meses, por lo que, una ganancia en la sobrevida de 2.8 meses en pacientes seleccionados es de utilidad clínica. Por lo tanto, la combinación de pemetrexed con cisplatino puede ser recomendado como una opción para el tratamiento de MMP solamente si los pacientes tienen enfermedad avanzada y con puntuación ECOG 0-1, en quienes la cirugía no está recomendada. CONCLUSIÓN: el Instituto de Evaluación de Tecnologías en Salud e Investigación IETSI, aprueba el uso de pemetrexed + cisplatino con suplementación de ácido fólico y vitamina B12, en pacientes con diagnóstico de MMP estadio avanzado inoperable, estado de funcionamiento de ECOG 0-1, y para quienes la cirugía no está recomendada, según lo establecido en el Anexo N° 1 del presente Dictamen Preliminar, el que tiene una vigencia de dos años a partir de su fecha de publicación.

Sarcomatoid mesothelioma: future advances in diagnosis, biomolecular assessment, and therapeutic options in a poor-outcome disease.

Malignant pleural mesothelioma (MPM) is the most frequent pleural neoplasm, with asbestos exposure as one of the recognized carcinogen agents, causative in 80% of cases. The prognosis is poor; median survival of untreated cases is 6-9 months, with fewer than 5% of patients surviving 5 years. Sarcomatoid mesothelioma (SM) represents the subtype with the worst outcome and median survival ranging from 3.5 to 8 months. In the last few years, an accurate differentiation between the subtypes of MPM has become a crucial issue, due to differences in chemosensitivity and clinical outcome, and several studies have evaluated different immunohistochemical markers to better define the diagnosis. The different and worse outcome of patients with SM and, in general, nonepithelioid subtypes makes it intriguing to select these cases to better study the biomolecular profile in order to find factors linked to prognosis and/or predictive of therapeutic response. Considering recent studies on miRNA and genetic mapping, further investigation of this rare subtype might represent a field for basic and clinical-translational research providing for more tailored therapies.

Tratamento quimioterápico do mesotelioma pleural maligno: uma revisão sistemática / Chemotherapy treatment of malignant pleural mesothelioma: a systematic review

Contexto - O mesotelioma pleural maligno é um tipo de câncer raro, agressivo e com uma expectativa de aumento na incidência até 2030. As melhores formas de diagnosticar,estadiar e tratar essa neoplasia continuam em debate. Objetivos - Estabelecer a evidência de eficácia e segurança dos diferentes esquemas quimioterápicos disponíveis para o tratamento do mesotelioma pleural maligno.Fontes de Dados - As bases bibliográficas utilizadas para a busca de artigos indexados foram Cochrane Controlled Trials Register, Lilacs, Medline (via Pubmed), Scopus e Webof Science. Além disso, foram buscados estudos na literatura cinzenta.Critérios de Elegibilidade – Participantes: pacientes com mesotelioma pleural maligno virgens de tratamento quimioterápico; Intervenção: tratamento quimioterápico; Controle:tratamento quimioterápico ou controle ativo de sintomas; Desfechos: Tempo de sobrevida,tempo livre de progressão, resposta tumoral e toxicidade; Estudos: ensaios clínicos randomizados de fase II ou III.Resultados - Um total de nove estudos envolvendo treze esquemas terapêuticos preencheram os critérios para inclusão nesta revisão. Em relação à eficácia, o único esquema quimioterápico que se apresenta superior ao seu comparador com significância estatística nos três desfechos é cisplatina mais pemetrexede. Os outros esquemas que demonstraram superioridade, mas sem a significância estatística foram: cisplatina mais raltitrexede, vinorelbina e carboplatina mais pemetrexede. Em relação à toxicidade, cisplatinamais pemetrexede, cisplatina mais raltitrexede se destacaram negativamente...

Background - Malignant pleural mesothelioma is a rare and aggressive cancer with anexpected increase in the incidence by 2030. The best ways to diagnose, staging and treat this disease still under discussion.Objectives - To establish the evidence of efficacy and safety of different chemotherapy regimens available for the treatment of malignant pleural mesothelioma. Data Sources - The bibliographic databases used for the search of indexed articles were Cochrane Controlled Trials Register, Lilacs, Medline (via Pubmed), Scopus and Web of Science. In addition, studies were sought in the gray literature. Study Eligibility Criteria - Participants: chemotherapy naïve patients with malignant pleural mesothelioma; Intervention: chemotherapy; Control: chemotherapy or active symptom control; Outcomes: survival time, progression-free time, tumor response and toxicity; Studies: phase II or III randomized clinical trials. Data Synthesis - A total of nine studies involving thirteen regimens met the criteria for inclusion in this review. Regarding efficacy, the only chemotherapy regimen that appears superior to their control group with statistical significance in the three outcomes is cisplatinplus pemetrexed. The other schemes that have shown superiority but without statistical significance were: cisplatin plus raltitrexed, vinorelbine and carboplatin plus pemetrexed. Regarding toxicity, cisplatin plus pemetrexed, cisplatin plus raltitrexed stood out negatively. Conclusions - The use of platinum more antifolate combination as first line chemotherapy ofmalignant pleural mesothelioma is in accordance with therapeutic guidelines and other systematic reviews published. Cisplatin and pemetrexed have preference over carboplatinand raltitrexed. Economic evaluations and a clinical study in Brazil are required to give foundation incorporating decision of antifolates in the routine treatment of this cancer...

Estimating treatment effects from a randomized clinical trial in the presence of a secondary treatment.

In randomized clinical trials involving survival time, a challenge that arises frequently, for example, in cancer studies (Manegold, Symanowski, Gatzemeier, Reck, von Pawel, Kortsik, Nackaerts, Lianes and Vogelzang, 2005. Second-line (post-study) chemotherapy received by patients treated in the phase III trial of pemetrexed plus cisplatin versus cisplatin alone in malignant pleural mesothelioma. Annals of Oncology 16, 923--927), is that subjects may initiate secondary treatments during the follow-up. The marginal structural Cox model and the method of inverse probability of treatment weighting (IPTW) have been proposed, originally for observational studies, to make causal inference on time-dependent treatments. In this paper, we adopt the marginal structural Cox model and propose an inferential method that improves the efficiency of the usual IPTW method by tailoring it to the setting of randomized clinical trials. The improvement in efficiency does not depend on any additional assumptions other than those required by the IPTW method, which is achieved by exploiting the knowledge that the study treatment is independent of baseline covariates due to randomization. The finite-sample performance of the proposed method is demonstrated via simulations and by application to data from a cancer clinical trial.