Annals of Oncology

About the journal

Publisher: Elsevier
Published: 1990 to the present, England
Language: English
ISSN: 0923-7534 (print), 1569-8041 (electronic)
Its record in the NLM Catalog

2020s

Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up☆. S. Popat, P. Baas, C. Faivre-Finn, et al. 2022;33(2):129-142. Guideline PubMed · Publisher
A multicentre randomised phase III trial comparing pembrolizumab versus single-agent chemotherapy for advanced pre-treated malignant pleural mesothelioma: the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial. S. Popat, A. Curioni-Fontecedro, U. Dafni, et al. 2020;31(12):1734-1745. PubMed · Publisher

Abstract

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy characterised by limited treatment options and a poor prognosis. At relapse after platinum-based chemotherapy, single-agent chemotherapy is commonly used and single-arm trials of immune-checkpoint inhibitors have demonstrated encouraging activity.

Patients And Methods: PROMISE-meso is an open-label 1:1 randomised phase III trial investigating the efficacy of pembrolizumab (200 mg/Q3W) versus institutional choice single-agent chemotherapy (gemcitabine or vinorelbine) in relapsed MPM patients with progression after/on previous platinum-based chemotherapy. Patients were performance status 0-1 and unselected for programmed cell death ligand 1 (PD-L1) status. At progression, patients randomly assigned to receive chemotherapy were allowed to crossover to pembrolizumab. The primary end point was progression-free survival (PFS), assessed by blinded independent central review (BICR). Secondary end points were overall survival (OS), investigator-assessed PFS, objective response rate (ORR), and safety. Efficacy by PD-L1 status was investigated in exploratory analyses.

Results: Between September 2017 and August 2018, 144 patients were randomly allocated (pembrolizumab: 73; chemotherapy: 71). At data cut-off [20 February 2019, median follow-up of 11.8 months (interquartile range: 9.9-14.5)], 118 BICR-PFS events were observed. No difference in BICR-PFS was detected [hazard ratio = 1.06, 95% confidence interval (CI): 0.73-1.53; P = 0.76], and median BICR-PFS (95% CI) for pembrolizumab was 2.5 (2.1-4.2), compared with 3.4 (2.2-4.3) months for chemotherapy. A difference in ORR for pembrolizumab was identified (22%, 95% CI: 13% to 33%), over chemotherapy (6%, 95% CI: 2% to 14%; P = 0.004). Forty-five patients (63%) assigned to chemotherapy received pembrolizumab at progression. With follow-up to 21 August 2019 [17.5 months: (14.8-19.7)], no difference in OS was detected between groups (HR = 1.12, 95% CI: 0.74-1.69; P = 0.59), even after adjusting for crossover. Pembrolizumab safety was consistent with previous observations. Exploratory efficacy analyses by PD-L1 status demonstrated no improvements in ORR/PFS/OS.

Conclusion: This is the first randomised trial evaluating the efficacy of pembrolizumab in MPM patients progressing after/on previous platinum-based chemotherapy. In biologically unselected patients, although associated with an improved ORR, pembrolizumab improves neither PFS nor OS over single-agent chemotherapy.

Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.
Lurbinectedin as second- or third-line palliative therapy in malignant pleural mesothelioma: an international, multi-centre, single-arm, phase II trial (SAKK 17/16). Y. Metaxas, M. Früh, E.I. Eboulet, et al. 2020;31(4):495-500. PubMed · Publisher

Abstract

Background: Systemic second- and third-line therapies for malignant pleural mesothelioma (MPM) result in a median progression-free survival (mPFS) of <2 months and median overall survival (mOS) of 6-9 months. Lurbinectedin binds to the DNA of the regulatory region while inhibiting tumour-associated macrophage transcription. In early trials, encouraging outcomes occurred in patients (pts) with MPM treated with lurbinectedin. We aimed to generate lurbinectedin efficacy and safety data among pts with progressive MPM.

Patients And Methods: Pts with progressing MPM treated with first-line platinum-pemetrexed chemotherapy with or without immunotherapy received lurbinectedin monotherapy. Treatment was given intravenously at 3.2 mg/m2 dose every 3 weeks until progression or unacceptable toxicity. Using Simon's two-stage design, the primary endpoint, progression-free survival (PFS) at 12 weeks (PFS12wks), was met if achieved by ≥21 pts (p0 ≤35% versus p1 ≥55%).

Results: Forty-two pts from nine centres across Switzerland and Italy were recruited. Histology was epithelioid in 33 cases, sarcomatoid in 5, and biphasic in 4. Overall 10/42 (23.8%) underwent prior immunotherapy and 14/42 (33.3%) had progressed ≤6 months after first-line chemotherapy. At data cut-off PFS12wks was met by 22/42 pts (52.4%; 90% confidence interval (CI): 38.7% to 63.5%; P = 0.015) with an mPFS of 4.1 months and mOS of 11.1 months. The best response was complete and partial remission observed in one patient each and stable disease in 20 pts. The duration of disease control was 6.6 months (95% CI: 5.2-7.4). No significant difference in PFS12wks, mPFS, and mOS was recorded in epithelioid versus non-epithelioid cases and pts with prior immunotherapy versus those without. Similar mPFS but shorter mOS were observed among pts who progressed within ≤6 months after first-line chemotherapy. Lurbinectedin-related grade 3-4 toxicity was seen in 21 pts, mostly being neutropenia (23.8%) and fatigue (16.7%).

Conclusions: The primary efficacy endpoint was reached with acceptable toxicity. Lurbinectedin showed promising activity regardless of histology, prior immunotherapy, or outcome on prior treatment. CLINICALTRIALS.

Gov Identifier: NCT03213301.

Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.

2010s

Comment on the paper 'Boffetta et al. Validation of the diagnosis of mesothelioma and BAP1 protein expression in a cohort of asbestos textile workers from Northern Italy. Ann Oncol 2018; 29(2): 484-489'. D. Consonni, C. Mensi. 2019;30(2):340-341. Letter · Comment PubMed · Publisher
Reply to letters to the editor by Brentisci et al. and Consonni and Mensi. P. Boffetta, L. Righi, C. Ciocan, et al. 2019;30(2):341. Letter · Comment PubMed · Publisher
Validation of the diagnosis of mesothelioma and BAP1 protein expression in a cohort of asbestos textile workers from Northern Italy. P. Boffetta, L. Righi, C. Ciocan, et al. 2019;30(11):1844. PubMed · Publisher
Comment on 'Validation of the diagnosis of mesothelioma and BAP1 protein expression in a cohort of asbestos textile workers from Northern Italy'. C. Brentisci, M. Gangemi, E. Migliore, et al. 2018;29(12):2395-2396. Letter · Comment PubMed · Publisher
Validation of the diagnosis of mesothelioma and BAP1 protein expression in a cohort of asbestos textile workers from Northern Italy. P. Boffetta, L. Righi, C. Ciocan, et al. 2018;29(2):484-489. PubMed · Publisher

Abstract

Background: Diagnosis of mesothelioma based on death certificate is subject to misclassification, which may bias the results of epidemiology studies. A high proportion of mesothelioma harbor mutations in the BRCA1-associated protein 1 (BAP1) gene.

Methods: We searched medical and pathology records and specimens for 127 workers from a textile-asbestos factory in Italy who died during 1963-2013 with a diagnosis of pleural or peritoneal neoplasm or mesothelioma on death certificate, to confirm the diagnosis with immunohistochemistry markers. We calculated the odds ratio of confirmation by selected characteristics and asbestos exposure variables. When sufficient pathology material was available, we analyzed BAP1 protein expression.

Results: The diagnosis of mesothelioma was histologically confirmed for 35 cases (27.6%); 5 cases were classified as non-mesothelioma (3.9%), for 33 cases a mention of mesothelioma was found on record but no sufficient material was available for revision (26.0%); no records were available for 54 cases (death-certificate-only 42.5%). Diagnostic confirmation was not associated with sex, location of the neoplasm, age, or duration of employment; however, there was a significant association with time since first employment (P for linear trend 0.04). An association between duration of employment and time since first employment was observed for confirmed cases but not for death-certificate-only cases. BAP1 protein was lost in 18/35 cases (51.4%), without an association with sex, location, age, indices of asbestos exposure, or survival.

Conclusions: We were able to confirm by immunohistochemistry a small proportion of mesothelioma diagnoses on certificates of deceased asbestos workers, and confirmation correlated with latency of asbestos exposure but not other characteristics. BAP1 protein loss is a frequent event in mesothelioma of asbestos-exposed workers, but does not correlate with exposure.

© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
A phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal adhesion kinase inhibitor, in patients with advanced solid tumors. J.C. Soria, H.K. Gan, S.P. Blagden, et al. 2016;27(12):2268-2274. PubMed · Publisher

Abstract

Background: Focal adhesion kinase (FAK) is important in cancer growth, survival, invasion, and migration. The purpose of this study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the FAK inhibitor, GSK2256098, in cancer patients.

Patients And Methods: The dose of GSK2256098 was escalated, in cohorts of patients with advanced cancer, from 80 to 1500 mg, oral twice daily (BID), until the MTD was determined. Serial blood samples were obtained from all patients, and the PK was determined. Paired tumor biopsies were obtained in select patients, and the level of phospho-FAK (pFAK) was determined.

Results: Sixty-two patients (39 males, 23 females; median age 61 y.o., range 21-84) received GSK2256098. Dose-limiting toxicities of grade 2 proteinuria (1000 mg BID), grade 2 fatigue, nausea, vomiting (1250 mg BID), and grade 3 asthenia and grade 2 fatigue (1500 mg BID) were reported with the MTD identified as 1000 mg BID. The most frequent adverse events (AEs) were nausea (76%), diarrhea (65%), vomiting (58%), and decreased appetite (47%) with the majority of AEs being grades 1-2. The PK was generally dose proportional with a geometric mean elimination half-life range of 4-9 h. At the 750, 1000, and 1500 mg BID dose levels evaluated, the pFAK, Y397 autophosphorylation site, was reduced by ∼80% from baseline. Minor responses were observed in a patient with melanoma (-26%) and three patients with mesothelioma (-13%, -15%, and -17%). In the 29 patients with recurrent mesothelioma, the median progression-free survival was 12 weeks with 95% CI 9.1, 23.4 weeks (23.4 weeks merlin negative, n = 14; 11.4 weeks merlin positive, n = 9; 10.9 weeks merlin status unknown, n = 6).

Conclusions: GSK2256098 has an acceptable safety profile, has evidence of target engagement at doses at or below the MTD, and has clinical activity in patients with mesothelioma, particularly those with merlin loss.

© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma. A.K. Nowak, A.M. Cook, A.M. McDonnell, et al. 2015;26(12):2483-90. PubMed · Publisher

Abstract

Background: Data from murine models suggest that CD40 activation may synergize with cytotoxic chemotherapy. We aimed to determine the maximum tolerated dose (MTD) and toxicity profile and to explore immunological biomarkers of the CD40-activating antibody CP-870,893 with cisplatin and pemetrexed in patients with malignant pleural mesothelioma (MPM).

Patients And Methods: Eligible patients had confirmed MPM, ECOG performance status 0-1, and measurable disease. Patients received cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 and CP-870,893 on day 8 of a 21-day cycle for maximum 6 cycles with up to 6 subsequent cycles single-agent CP-870,893. Immune cell subset changes were examined weekly by flow cytometry.

Results: Fifteen patients were treated at three dose levels. The MTD of CP-870,893 was 0.15 mg/kg, and was exceeded at 0.2 mg/kg with one grade 4 splenic infarction and one grade 3 confusion and hyponatraemia. Cytokine release syndrome (CRS) occurred in most patients (80%) following CP-870,893. Haematological toxicities were consistent with cisplatin and pemetrexed chemotherapy. Six partial responses (40%) and 9 stable disease (53%) as best response were observed. The median overall survival was 16.5 months; the median progression-free survival was 6.3 months. Three patients survived beyond 30 months. CD19+ B cells decreased over 6 cycles of chemoimmunotherapy (P < 0.001) with a concomitant increase in the proportion of CD27+ memory B cells (P < 0.001) and activated CD86+CD27+ memory B cells (P < 0.001), as an immunopharmacodynamic marker of CD40 activation.

Conclusions: CP-870,893 with cisplatin and pemetrexed is safe and tolerable at 0.15 mg/kg, although most patients experience CRS. While objective response rates are similar to chemotherapy alone, three patients achieved long-term survival.

Australia New Zealand Clinical Trials Registry Number: ACTRN12609000294257.

© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. P. Baas, D. Fennell, K.M. Kerr, et al. 2015;26 Suppl 5:v31-9. Guideline PubMed · Publisher

Summary

This article presented the European Society for Medical Oncology (ESMO) clinical practice guidelines for the diagnosis, treatment and follow-up of malignant pleural mesothelioma (MPM), last updated in July 2015 and replacing the 2010 version. The expert authors selected the relevant literature and graded their recommendations using levels of evidence and grades of recommendation adapted from the Infectious Diseases Society of America-United States Public Health Service system. The authors reported incidence rates in males of 3.4/100 000 in Great Britain, 2.3/100 000 in France and 3.2/100 000 in the Netherlands, and stated that occupational asbestos exposure accounts for more than 80% of cases. They recommended taking an occupational history with emphasis on asbestos exposure, CT scanning of the thorax, and obtaining a pathological specimen in patients with unilateral pleural thickening. They stated that there is no place for screening of persons exposed to asbestos and that tumour markers cannot distinguish MPM. Definitive diagnosis required tissue biopsy showing invasion, with immunohistochemistry using at least two mesothelial and two (adeno)carcinoma markers. They advised staging with the TNM-based IMIG/UICC classification. An anti-folate/platinum doublet was the only approved first-line standard of care. There was no second-line standard, and patients were recommended to join trials. Radiotherapy could be considered for pain palliation, while prophylactic drain-tract irradiation was not proven useful. Surgery was indicated for effusion palliation, diagnosis and staging, multimodality treatment preferably within a study, and macroscopic complete resection.

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Searching for targets for the systemic therapy of mesothelioma. R.A. Stahel, W. Weder, E. Felley-Bosco, et al. 2015;26(8):1649-60. Review PubMed · Publisher

Abstract

Malignant mesothelioma is an incurable disease associated with asbestos exposure arising in the pleural cavity and less frequently in the peritoneal cavity. Platinum-based combination chemotherapy with pemetrexed is the established standard of care. Multimodality approaches including surgery and radiotherapy are being investigated. Increasing knowledge about the molecular characteristics of mesothelioma had led to the identification of novel potential targets for systemic therapy. Current evidence suggests pathways activated in response to merlin deficiency, including Pi3K/mTOR and the focal adhesion kinase, as well as immunotherapeutic approaches to be most promising. This review elaborates on the rationale behind targeted approaches that have been and are undergoing exploration in mesothelioma and summarizes available clinical results and ongoing efforts to improve the systemic therapy of mesothelioma.

© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Expression profiling stratifies mesothelioma tumors and signifies deregulation of spindle checkpoint pathway and microtubule network with therapeutic implications. M.B. Suraokar, M.I. Nunez, L. Diao, et al. 2014;25(6):1184-92. PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a lethal neoplasm exhibiting resistance to most treatment regimens and requires effective therapeutic options. Though an effective strategy in many cancer, targeted therapy is relatively unexplored in MPM because the therapeutically important oncogenic pathways and networks in MPM are largely unknown.

Materials And Methods: We carried out gene expression microarray profiling of 53 surgically resected MPMs tumors along with paired normal tissue. We also carried out whole transcriptomic sequence (RNA-seq) analysis on eight tumor specimens. Taqman-based quantitative Reverse-transcription polymerase chain reaction (qRT-PCR), western analysis and immunohistochemistry (IHC) analysis of mitotic arrest deficient-like 1 (MAD2L1) was carried out on tissue specimens. Cell viability assays of MPM cell lines were carried out to assess sensitivity to specific small molecule inhibitors.

Results: Bioinformatics analysis of the microarray data followed by pathway analysis revealed that the mitotic spindle assembly checkpoint (MSAC) pathway was most significantly altered in MPM tumors with upregulation of 18 component genes, including MAD2L1 gene. We validated the microarray data for MAD2L1 expression using quantitative qRT-PCR and western blot analysis on tissue lysates. Additionally, we analyzed expression of the MAD2L1 protein by IHC using an independent tissue microarray set of 80 MPM tissue samples. Robust clustering of gene expression data revealed three novel subgroups of tumors, with unique expression profiles, and showed differential expression of MSAC pathway genes. Network analysis of the microarray data showed the cytoskeleton/spindle microtubules network was the second-most significantly affected network. We also demonstrate that a nontaxane small molecule inhibitor, epothilone B, targeting the microtubules have great efficacy in decreasing viability of 14 MPM cell lines.

Conclusions: Overall, our findings show that MPM tumors have significant deregulation of the MSAC pathway and the microtubule network, it can be classified into three novel molecular subgroups of potential therapeutic importance and epothilone B is a promising therapeutic agent for MPM.

© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Disease volumes as a marker for patient response in malignant pleural mesothelioma. Z.E. Labby, A.K. Nowak, J.J. Dignam, et al. 2013;24(4):999-1005. PubMed · Publisher · Free full text

Abstract

Background: The goal of this study was to create a comprehensive model for malignant pleural mesothelioma patient survival utilizing continuous, time-varying estimates of disease volume from computed tomography (CT) imaging in conjunction with clinical covariates.

Patients And Methods: Serial CT scans were obtained during the course of clinically standard chemotherapy for 81 patients. The pleural disease volume was segmented for each of the 281 CT scans, and relative changes in disease volume from the baseline scan were tracked over the course of serial follow-up imaging. A prognostic model was built using time-varying disease volume measurements in conjunction with clinical covariates.

Results: Over the course of treatment, disease volume decreased by an average of 19%, and median patient survival was 12.6 months from baseline. In a multivariate survival model, changes in disease volume were significantly associated with patient survival along with disease histology, Eastern Cooperative Oncology Group performance status, and presence of dyspnea.

Conclusions: Analysis of the trajectories of disease volumes during chemotherapy for patients with mesothelioma indicates that increasing disease volume was significantly and independently associated with poor patient prognosis in both univariate and multivariate survival models.
Prognostic significance of metabolic response by positron emission tomography after neoadjuvant chemotherapy for resectable malignant pleural mesothelioma. Y. Tsutani, T. Takuwa, Y. Miyata, et al. 2013;24(4):1005-10. PubMed · Publisher

Abstract

Background: To select optimal candidates for extrapleural pneumonectomy (EPP), we retrospectively evaluated the usefulness of metabolic response by fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) after neoadjuvant chemotherapy to predict prognosis for patients with resectable malignant pleural mesothelioma (MPM) who underwent EPP in a multicenter study.

Patients And Methods: We carried out high-resolution CT (HRCT) and FDG-PET/CT before and after neoadjuvant platinum-based chemotherapy on 50 patients with clinical T1-3 N0-2 M0 MPM who underwent EPP ± postoperative hemithoracic radiotherapy. A decrease of ≥30% in the tumor maximum standardized uptake value (SUVmax) was defined as a metabolic responder. The radiologic response using the modified RECIST or metabolic response and surgical results were analyzed.

Results: The median overall survival (OS) from diagnosis was 20.5 months. Metabolic responders significantly correlated to OS with median OS for metabolic responders not reached versus 18.7 months for non-responders. No correlation was observed between OS and radiologic response with median OS for radiologic responders and non-responders. Based on the multivariate Cox analyses, decreased SUVmax and epithelioid subtype were significantly independent factors for OS.

Conclusions: The metabolic response after neoadjuvant chemotherapy is an independent prognostic factor for patients with resectable MPM. Patients with metabolic responder or epithelioid subtype may be good candidates for EPP.
Restoring expression of miR-16: a novel approach to therapy for malignant pleural mesothelioma. G. Reid, M.E. Pel, M.B. Kirschner, et al. 2013;24(12):3128-35. PubMed · Publisher

Abstract

Background: Malignant pleural mesothelioma (MPM) is recalcitrant to treatment and new approaches to therapy are needed. Reduced expression of miR-15/16 in a range of cancer types has suggested a tumour suppressor function for these microRNAs, and re-expression has been shown to inhibit tumour cell proliferation. The miR-15/16 status in MPM is largely unknown.

Materials And Methods: MicroRNA expression was analysed by TaqMan-based RT-qPCR in MPM tumour specimens and cell lines. MicroRNA expression was restored in vitro using microRNA mimics, and effects on proliferation, drug sensitivity and target gene expression were assessed. Xenograft-bearing mice were treated with miR-16 mimic packaged in minicells targeted with epidermal growth factor receptor (EGFR)-specific antibodies.

Results: Expression of the miR-15 family was consistently downregulated in MPM tumour specimens and cell lines. A decrease of 4- to 22-fold was found when tumour specimens were compared with normal pleura. When MPM cell lines were compared with the normal mesothelial cell line MeT-5A, the downregulation of miR-15/16 was 2- to 10-fold. Using synthetic mimics to restore miR-15/16 expression led to growth inhibition in MPM cell lines but not in MeT-5A cells. Growth inhibition caused by miR-16 correlated with downregulation of target genes including Bcl-2 and CCND1, and miR-16 re-expression sensitised MPM cells to pemetrexed and gemcitabine. In xenograft-bearing nude mice, intravenous administration of miR-16 mimics packaged in minicells led to consistent and dose-dependent inhibition of MPM tumour growth.

Conclusions: The miR-15/16 family is downregulated and has tumour suppressor function in MPM. Restoring miR-16 expression represents a novel therapeutic approach for MPM.
Well-differentiated papillary mesothelioma: clustering in a Portuguese family with a germline BAP1 mutation. C. Ribeiro, S. Campelos, C.S. Moura, et al. 2013;24(8):2147-50. Case report PubMed · Publisher

Abstract

Background: Well-differentiated papillary mesothelioma (WDPM) is a rare variant of epithelioid mesothelioma and is considered to be associated with good prognosis due to its clinically indolent behavior and long survival. Most reported cases involve the peritoneum of women at reproductive age with no history of exposure to asbestos, with pleural involvement being less common. The optimal management, including the role of chemotherapy in the treatment of WDPM, remains unsettled.

Patients And Methods: The authors describe two cases of WDPM in women of the same family (siblings); the elder with WDPM of the pleura and peritoneum with a 12-year survival period and the younger with a WDPM of the peritoneum diagnosed in 2011 and uveal melanoma diagnosed in 2012. Neither patient had any known exposure to asbestos fibers or any other mineral carcinogens.

Results: After the concurrent diagnosis of WDPM and uveal melanoma, genetic diagnosis was carried out taking into consideration that these two malignancies were recently associated with hereditary BAP1 gene mutations and it was positive for both the patients.

Conclusions: To our knowledge, this is the first description of WDPM in two siblings who also presented with a germline BAP1 mutation. This article provides evidence of the wide clinical spectrum of cancer susceptibility associated with a BAP1 germline mutation.
Importance of gender in diffuse malignant peritoneal mesothelioma. C. Cao, T.D. Yan, M. Deraco, et al. 2012;23(6):1494-8. PubMed · Publisher

Abstract

Background: Combined therapy involving cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy has been shown to improve survival outcomes for patients with diffuse malignant peritoneal mesothelioma (DMPM). The present study aims to investigate gender as a potential prognostic factor on overall survival.

Patients And Methods: Over a period of two decades, 294 patients who underwent CRS and perioperative intraperitoneal chemotherapy were selected from a large multi-institutional registry to assess the prognostic significance of gender on overall survival.

Results: Female patients were shown to have a significantly improved survival outcome than male patients (P < 0.001). Staging according to a recently proposed tumor-node-metastasis categorization system was significant in both genders. Older female patients had significantly worse survival than younger female patients (P = 0.019), a finding that was absent in male patients. Female patients with low-stage disease were found to have a very favorable long-term outcome after combined treatment.

Conclusions: Gender has demonstrated a significant impact on overall survival for patients with DMPM after CRS and perioperative intraperitoneal chemotherapy. An improved understanding of the role of estrogen in the pathogenesis of DMPM may improve the prognostication of patients and determine the role of adjuvant hormonal treatment in the future.
The influence of platinum pathway polymorphisms on the outcome in patients with malignant mesothelioma. N. Erčulj, V. Kovač, J. Hmeljak, et al. 2012;23(4):961-7. PubMed · Publisher

Abstract

Background: Platinum-based therapy is widely used in the treatment of malignant mesothelioma (MM); however, the efficacy and toxicity of platinum agents vary greatly between patients. The aim of our study was to evaluate the influence of platinum pathway polymorphisms on treatment outcome in patients with MM.

Patients And Methods: In total, 133 patients with MM treated with (n = 97) or without (n = 36) platinum-based therapy were genotyped for common XPD, ERCC1, and GSTP1 polymorphisms, as well as for GSTM1 and GSTT1 gene deletion. Haplotype analysis was carried out to assess the combined effect of nucleotide excision repair (NER) polymorphisms.

Results: GST polymorphisms were not associated with treatment outcome in patients with MM. In the group of platinum-treated patients with MM, ERCC1 8092C/C wild-type genotype significantly influenced progression-free survival (PFS) in multivariable analysis accounting for clinical variables (P = 0.034). XPD 312Asp/Asp and ERCC1 8092C/C wild-type genotypes also increased the odds of treatment-related toxic effects in univariable as well as multivariable analysis. The association of wild-type NER genotypes with better PFS and higher susceptibility to treatment-related toxic effects was confirmed in haplotype analysis.

Conclusions: Our results suggest that polymorphisms in NER pathway influence platinum-treatment efficacy and toxicity; therefore, these should be further evaluated as potential markers for the prediction of clinical outcome in patients with MM.
Malignant peritoneal mesothelioma: a multicenter study on 81 cases. V.P. Manzini, L. Recchia, M. Cafferata, et al. 2010;21(2):348-353. PubMed · Publisher

Abstract

Background: Malignant peritoneal mesothelioma (MPM) is a rare disease characterized by a difficult diagnosis, different types of presentation, variable course and poor prognosis.

Materials And Methods: Eighty-one patients with MPM observed in 14 Italian oncology institutions from 1982 to 2007 have been examined with the aim of delineating the history of MPM.

Results: Presentation symptoms were ascites, abdominal pain, asthenia, weight loss, anorexia, abdominal mass, fever, diarrhea and vomiting in various associations. Computed tomography scan and echotomography signs were ascites, abdominal mass and peritoneal thickening. Peritoneal fluid cytology (61 cases) was positive for mesothelioma in 31 and for malignancy, not mesothelioma, in 13. Laparoscopy was carried out in 40 cases and laparotomy in 36. Thrombocytosis was present in 59 cases. Associated tumors diagnosed during the lifetime were colorectal cancer in two cases and cheek carcinoma, thyroid carcinoma, tongue carcinoma, bladder carcinoma and testicular seminoma. Thirty patients were treated with surgery and 45 with chemotherapy. The median survival time from diagnosis is 13 months. Ascites, fever and vomiting were significative variables at presentation; only vomiting holds significance in a multivariate analysis.

Conclusions: MPM is a disease with various types of presentation, frequently associated with thrombocytosis, sometimes with other tumors. Survival and diagnosis time can differ in various types of MPM. Prognosis is poor.
Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. R.A. Stahel, W. Weder, Y. Lievens, et al. 2010;21 Suppl 5:v126-8. Guideline PubMed · Publisher

Summary

This clinical practice guideline, written on behalf of the European Society for Medical Oncology (ESMO) Guidelines Working Group and last updated in March 2010, summarised recommendations for the diagnosis, staging, treatment and follow-up of malignant pleural mesothelioma (MPM). The authors described MPM as a rare tumour, with an incidence of 1.25 per 100 000 in Great Britain and 1.1 per 100 000 in Germany, expected to double in many countries within 20 years. They identified asbestos exposure as a well-established cause, with occupational exposure documented in 70%–80% of those affected, and stated that an occupational history must be obtained. Histology including immunohistochemistry was described as the gold standard for diagnosis. Serum mesothelin-related proteins and osteopontin were noted as possible supporting markers whose precise role was yet to be defined. Clinical staging was based on chest CT, and the IMIG staging system and EORTC prognostic scores were discussed. Extra-pleural pneumonectomy, generally combined with chemotherapy and/or radiotherapy, was recommended only for selected patients, by experienced thoracic surgeons, preferably within a clinical trial. Pemetrexed/cisplatin, and to a smaller extent raltitrexed/cisplatin, were reported to improve survival compared with cisplatin alone in randomised trials. The exact role of definitive radiotherapy was described as under investigation. The authors stated that no definitive conclusions could be drawn on the efficacy of prophylactic irradiation of intervention tracts. Recommendations were graded using American Society of Clinical Oncology levels of evidence and grades of recommendation.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Mesothelioma. W. Weder. 2010;21 Suppl 7:vii326-33. Review PubMed · Publisher

Summary

This symposium article reviewed malignant pleural mesothelioma, which the author described as associated with asbestos exposure and nearly invariably fatal once diagnosed. It summarised published research on epidemiology, molecular pathology, diagnosis, surgery, multimodality therapy, radiotherapy, imaging, chemotherapy and new treatments. A first analysis predicted that male mesothelioma deaths in Europe would peak in 2020, while more recent models placed the peak around 2015. Italian registry data showed a median latency of 44.6 years. Mutations in the NF2 gene were reported in 40% of mesotheliomas. A systematic review could not determine whether extrapleural pneumonectomy (EPP) improved survival. A retrospective analysis of 663 patients reported a median survival of 14 months. In a Swiss multicentre phase II trial of 61 patients given neoadjuvant cisplatin and gemcitabine, median survival was 19.8 months by intent to treat and 23 months after EPP. A trial of 456 patients found better response (41% versus 17%) and median survival (12.1 versus 9.3 months) with cisplatin–pemetrexed than with cisplatin alone, and this combination became the preferred regimen. The author concluded that final proof that radical surgery prolongs survival would come only from a randomized study, such as the UK MARS trial.

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New tricks for old biomarkers: thymidylate synthase expression as a predictor of pemetrexed activity in malignant mesothelioma. P.A. Zucali, E. Giovannetti, Y.G. Assaraf, et al. 2010;21(7):1560-1561. Letter PubMed · Publisher

Summary

In this letter to the editor, the authors commented on a retrospective study by Righi et al. that examined expression of thymidylate synthase (TS) and excision repair cross-complementation group-1 (ERCC1) in patients with malignant pleural mesothelioma (MPM) treated with platinum compounds and pemetrexed. They noted that Righi et al. found no relationship between survival and ERCC1 protein levels. They also noted that Righi et al. reported a correlation between TS mRNA and protein expression but none between TS mRNA and outcome, which was ascribed to the small number of tumor cells in MPM specimens. The authors summarized their own previously reported findings in 71 MPM patients treated with carboplatin plus pemetrexed. TS protein expression correlated with shorter progression-free survival (hazard ratio 1.23; P = 0.004) and overall survival (HR 1.21; P = 0.02). It was also associated with a lower probability of disease control (odds ratio 1.57; P = 0.012), and with progression-free survival (HR 1.24; P = 0.005) in a model corrected for disease control. They argued that immunostaining scoring and quantitative RT-PCR methods need optimization and standardization. They also argued that other determinants of pemetrexed activity, and polymorphisms such as TSER-2R/3R and ERCC1-C118T, should be evaluated. They concluded that standardized methods, larger uniformly treated cohorts and genotype studies were needed before prospective trials could identify the best biomarkers for personalized chemotherapy of MPM.

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2000s

A systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for diffuse malignancy peritoneal mesothelioma. T.D. Yan, L. Welch, D. Black, et al. 2007;18(5):827-34. Systematic review PubMed · Publisher

Abstract

Background: In the past, diffuse malignant peritoneal mesothelioma (DMPM) was regarded as a preterminal condition. The length of survival was dependent upon the aggressive versus indolent biologic behavior of the neoplasm. The overall median survival was approximately 1 year after systemic chemotherapy. Cytoreductive surgery (CRS) combined with perioperative intraperitoneal chemotherapy (PIC) has been used as a treatment alternative, but the efficacy of this combined treatment remains to be established.

Patients And Methods: Searches for relevant studies published in peer-reviewed medical journals on CRS and PIC for DMPM before May 2006 were carried out on six databases. The reference lists of all retrieved articles were reviewed for further identification of potentially relevant studies. Expert academic surgeons in Washington, DC, USA were asked whether they knew about any important unpublished data. Two investigators independently evaluated each study according to predefined criteria. The quality of each study was assessed. Clinical effectiveness was synthesized through a narrative review with full tabulation of results of all included studies.

Results: Seven prospective observational studies from six tertiary institutions were available, allowing 240 DMPM patients for assessment. The median survival ranged from 34-92 months. The 1-, 3- and 5-year survival varied from 60% to 88%, 43% to 65% and 29% to 59%, respectively. The perioperative morbidity varied from 25% to 40% and mortality ranged from 0% to 8%.

Conclusions: This systematic review evaluated the current evidence for CRS and PIC for DMPM. Seven observational studies were available for assessment, which demonstrated an improved overall survival, as compared to historical controls, using systemic chemotherapy and palliative surgery.

In plain English

This article was a systematic review, not a new study of patients. The authors searched six medical databases, up to May 2006, for studies of diffuse malignant peritoneal mesothelioma, a cancer of the abdominal lining. Studies had to use cytoreductive surgery (removal of visible tumor) combined with chemotherapy placed directly into the abdomen around the time of surgery. They included seven reports from six specialist centers, covering 240 patients. All seven were observational studies without a comparison group, and no randomized trials were found. Across the studies, median survival ranged from 34 to 92 months, and it was not reached in two studies. Survival ranged from 60% to 88% at 1 year, 43% to 65% at 3 years, and 29% to 59% at 5 years. Complication rates around the time of surgery ranged from 25% to 40%, and death rates around the time of surgery from 0% to 8%. The authors concluded that the studies showed better overall survival than historical patients treated with systemic chemotherapy and palliative surgery. They noted possible selection bias, small studies, short follow-up in some, and differing treatment plans. The review did not study asbestos exposure.

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Epidemiology of peritoneal mesothelioma: a review. P. Boffetta. 2007;18(6):985-90. Review PubMed · Publisher

Abstract

The epidemiology of peritoneal mesothelioma is complicated by possible geographic and temporal variations in diagnostic practices. The incidence rates in industrialized countries range between 0.5 and three cases per million in men and between 0.2 and two cases per million in women. Exposure to asbestos is the main known cause of peritoneal mesothelioma. Results on peritoneal mesothelioma have been reported for 34 cohorts exposed to asbestos, among which a strong correlation was present between the percentages of deaths from pleural and peritoneal mesothelioma (correlation coefficient 0.8, P < 0.0001). Studies of workers exposed only or predominantly to chrysotile asbestos resulted in a lower proportion of total deaths from peritoneal mesothelioma than studies of workers exposed to amphibole or mixed type of asbestos. Cases of peritoneal mesothelioma have also been reported following exposure to erionite and Thorotrast, providing further evidence of common etiological factors with the pleural form of the disease. The role of other suspected risk factors, such as simian virus 40 infection and genetic predisposition, is unclear at present. Control of asbestos exposure remains the main approach to prevent peritoneal mesothelioma.
Occupational asbestos exposure: how to deal with suspected mesothelioma cases--the Dutch approach. P. Baas, N. van 't Hullenaar, J. Wagenaar, et al. 2006;17(5):848-52. PubMed · Publisher

Abstract

Introduction: Patients with asbestos-related diseases, such as malignant mesothelioma (MM), are not uniformly treated in Europe when they apply for compensation. In The Netherlands, the Institute of Asbestos Victims (IAV) acts on behalf of patients with a malignant mesothelioma. In the majority of cases, the diagnosis is clear but in some, uncertainty remains. In these cases a specialist opinion of the Mesothelioma Group of the Dutch Thoracic Society (DTS) is required. The process of data handling and final outcome for these patients is discussed and compared with the situation in other European countries.

Materials And Methods: Dutch patients with a possible malignant mesothelioma and occupational exposure to asbestos presented their cases to the IAV. In 10% of the cases, pathological confirmation of a malignant mesothelioma could not be obtained. These cases were presented to the Mesothelioma Group to obtain a clinical diagnosis based on clinical reports, occupational history, X-ray examination and other factors. Each case was reviewed by three independent pulmonologists experienced in MM. The majority view was binding for acceptance or rejection of the diagnosis.

Results: In the period January 2000 until May 2005, the IAV received 1747 cases for compensation. In 161 cases no definitive diagnosis could be made on pathology and were presented to the Mesothelioma Group. Of these cases, 117 (73%) were considered to be compatible with the clinical diagnosis malignant pleural mesothelioma. Forty-four cases (27%) were rejected. In 75% of the cases (112 of 150), the conclusion of the three independent specialists was unanimous; in 11 cases one specialist refrained from a diagnosis. The median time from request to submission of the report was 34 days (range 1-185 days).

Conclusions: Compared with other European countries, this approach, as determined by the IAV and Mesothelioma Group of the DTS, is an effective and rapid way to investigate claims of patients with a possible occupationally related malignant mesothelioma.
Malignant pleural mesothelioma: a phase II trial with docetaxel. D.A. Vorobiof, B.L. Rapoport, M.R. Chasen, et al. 2002;13(3):412-5. PubMed · Publisher

Abstract

Current cytotoxic therapy has been of limited benefit to patients with malignant pleural mesothelioma. Single agent chemotherapy has been extensively evaluated in small series of phase II clinical trials, with disappointing responses. Docetaxel, an effective taxane in the treatment of advanced breast cancer and non-small-cell lung cancer, was administered intravenously at a dose of 100 mg/m2 every 3 weeks to 30 chemotherapy naive patients with malignant pleural mesothelioma in a prospective multi-institutional phase II clinical trial. An objective response rate (partial responses) of 10% was documented. Additionally, 21% of the patients had minor responses (intention-to-treat analysis). Three patients died within 2 weeks post-first cycle of therapy, although only one patient's death was directly attributed to the investigational drug, whilst in the majority of the patients, manageable and treatable toxicities were encountered. In this phase II clinical trial, docetaxel proved to be mildly effective in the treatment of patients with malignant pleural mesothelioma.
Raltitrexed: current clinical status and future directions. E. Van Cutsem, D. Cunningham, J. Maroun, et al. 2002;13(4):513-22. Review PubMed · Publisher

Abstract

Raltitrexed ('Tomudex') monotherapy is a conveniently administered alternative to 5-fluorouracil (5-FU) in the first-line treatment of advanced colorectal cancer (CRC), and has single-agent activity in a variety of advanced solid tumours. Although both raltitrexed and 5-FU are thymidylate synthase inhibitors, raltitrexed has a specific mode of action and a toxicity profile distinct from 5-FU. The mechanism of action of raltitrexed is also completely different from that of oxaliplatin, irinotecan and other drugs with which it has been combined. These properties, together with preclinical data, suggested that combinations of raltitrexed with 5-FU, other chemotherapeutic agents, or radiotherapy could result in improved therapies for a variety of advanced solid tumours, including advanced CRC. This review outlines the appropriate management of patients treated with raltitrexed, whether as monotherapy or in combination, and discusses the preliminary results of combination studies with raltitrexed in a range of tumour types including advanced CRC, malignant mesothelioma, gastric, pancreatic, head and neck, and non-small-cell lung cancers. Of particular interest is the combination of raltitrexed and oxaliplatin, which has shown promising antitumour effects in first-line treatment of advanced CRC and malignant mesothelioma, a disease that is refractory to chemotherapy.
A phase I study of sequential intravenous topotecan and etoposide in lung cancer patients. C. Huisman, P.E. Postmus, G. Giaccone, et al. 2001;12(11):1567-73. PubMed · Publisher

Abstract

Purpose: The topoisomerase I inhibitor topotecan (T) and the topoisomerase II inhibitor etoposide (E) are active drugs in lung cancer. The complementary functions of their targets may suggest benefit from the combined use of these agents but drug scheduling has been shown to play a critical role in preclinical models. To establish the optimal schedule and assess the impact of sequential administration of the combination of T and E, we conducted a dose finding study of sequential intravenous T and E in a four-weekly-schedule in relapsed lung cancer patients.

Patients And Methods: The importance of drug sequence was assessed in consecutive patients throughout all dose levels; patients received in the first course either T followed by E (the TE group: T on days 1-3 and E on days 4-6) or E before T (the ET group: F on days 1-3 and Ton days 4-6). The sequence of Tand E was alternated in the successive courses. In this crossover design, each patient served as his own control for analysis of hematological toxicity in which TE sequence was compared to that of the ET sequence. Moreover, hematological toxicity after the first course was compared between the TE and the ET groups. The starting dose was T/E 0.75/75 mg/m2 at dose level 1and dose escalation was planned to T/E 1.00/75 mg/nm2 at dose level 2, T/E 1.00/100 mg/m2 at dose level 3, T/E 1.25/100 mg/m2 at dose level 4 and T/E 1.50/100 mg/m2 at dose level 5. Nineteen patients (small-cell lung cancer 7, non-small-cell lung cancer 11, mesothelioma 1 patient) were included.

Results: The principal toxicity was myelosuppression, primarily neutropenia and thrombocytopenia. At dose level 3 several grade 4 toxicities were observed. DLT (febrile neutropenia) occurred in two patients, one in the TE and one in the ET group and precluded further dose escalation. There was no significant difference in WBC and platelet nadirs during the first course between the TE and the ET group. The influence of the sequence of administration of topotecan and etoposide was calculated by comparing the nadir values of cycles I and II for each patient. For none of the dose levels, a significant sequence-dependent effect could be detected. The MTD was reached at the doses of 100 mg/m2 topotecan and 75 mg/m2 etoposide. No objective responses were seen.

Conclusion: Although the combined use of topoisomerase I and II inhibitors is attractive on theoretical grounds, excessive myelosuppression prevents substantial dose escalation.
Phase II trial of liposomal daunorubicin in malignant pleural mesothelioma. J.P. Steele, C.A. O'Doherty, J. Shamash, et al. 2001;12(4):497-9. PubMed · Publisher

Abstract

Background: To assess the response rate, toxicity and survival in patients with malignant pleural mesothelioma treated with liposomal daunorubicin. The study design allowed for dose escalation pending toxicity.

Patients And Methods: Liposomal daunorubicin (DaunoXome, Nexstar, USA) 120 mg/m2 was administered every 21 days to a maximum of 6 cycles. Patients had to have histologically-proven malignant pleural mesothelioma. Patients were all chemotherapy-naïve with ECOG performance status 0-2.

Results: Fourteen patients were enrolled. There were no objective or symptomatic responses though nine patients (64%) had stable disease on therapy. Myelosuppression was the major toxicity with 9 of 11 patients evaluable for toxicity experiencing grade 3 or 4 neutropenia. Other toxicities seen in at least 30% of patients included grade 3 infection and grade 2 nausea and vomiting. The median overall survival by intention-to-treat analysis was 6.1 months from the time of first treatment. The median duration of stable disease from time of first treatment for patients not progressing on therapy was 5.1 months.

Conclusions: Liposomal daunorubicin 120 mg/m2 has no useful clinical activity in patients with malignant pleural mesothelioma. Toxicity was substantial with most patients experiencing at least one episode of grade 3 or 4 neutropenia. Liposomal daunorubicin cannot be recommended for patients with malignant pleural mesothelioma.
The expression of P-glycoprotein and multidrug resistance proteins 1 and 2 (MRP1 and MRP2) in human malignant mesothelioma. Y. Soini, K. Järvinen, R. Kaarteenaho-Wiik, et al. 2001;12(9):1239-45. PubMed · Publisher

Abstract

Background: Malignant mesothelioma is a malignancy with a primary resistance to chemo- and radiotherapies for reasons which are still unclear. Multidrug resistance proteins might explain the observed resistance, but no studies have assessed their expression in mesothelioma.

Patients And Methods: Immunohistochemical expression of P-glycoprotein (P-gp), and the multidrug resistance proteins 1 and 2 (MRP1 and MRP2) were investigated in 36 cases of malignant mesothelioma and in samples from normal mesothelium.

Results: P-gp immunopositivity was found in 61%, MRP1 immunopositivity in 58% and MRP2 positivity in 33% of the cases. Normal mesothelium did not express these multidrug-resistant proteins. There was a significant association between P-gp and MRP2 (P = 0.022) expression. No or weak P-gp, MRP1 or MRP2 immunostaining was significantly more frequent in sarcomatoid mesothelimas than in epithelial or biphasic mesotheliomas (P = 0.031, P = 0.034 and P = 0.024, respectively). There was no significant association between patient survival and expression of the multidrug-resistant proteins.

Conclusions: The results show that P-gp, MRP1 and MRP2 are induced and expressed in malignant mesothelial cells. Regardless of their expression no association with survival of the patients was seen, suggesting that the primary resistance of malignant mesotheliomas is not solely dependent on their expression or function.
A dose-finding study of gemcitabine and vinorelbine in advanced previously treated malignancies. J.P. Delord, E. Raymond, M. Chaouche, et al. 2000;11(1):73-9. PubMed · Publisher

Abstract

Purpose: Gemcitabine and vinorelbine are active drugs with broad spectrum of activity and manageable toxicity in clinical trials. The aims of this study were to describe the toxicity, to determine the dose-limiting toxicity, and to define the doses of gemcitabine and vinorelbine to be recommended for phase II studies in patients with advanced cancers.

Patients And Methods: Drugs were given as 30-min infusions on day 1 and 8 (vinorelbine before gemcitabine) every 3 weeks. Thirty-six patients (male:female ratio 25:11; mean age 54, PS > 60) were treated including 1 retroperitoneal sarcoma, 7 head and neck, 10 lung, 4 thyroid, 6 pancreatic, 1 bladder, 2 ovary, 2 gastric, 1 rectum, 1 unknown primary, and 1 renal cell carcinoma. Doses of gemcitabine/vinorelbine ranged from 800/20 mg/m2 to 1500/30 mg/m2.

Results: The dose-limiting toxicity was neutropenia. A transient grade 2-3 elevation of transaminases was frequently observed at several dose-levels, although this toxicity did not appear to be dose dependant and was reversible at day 21 before the next cycle. Other toxicities were mild and easily manageable, consisting of fatigue and flu-like syndromes. Since the MTD was not reach at the higher dose-level, the recommended dose level of the gemcitabine-vinorelbine combination was 1500/30 mg/m2. One toxic death due to hematologic toxicity was reported in a heavily pretreated patient who underwent prior chemotherapy and pelvic radiotherapy. A total of 12 patients were treated at the recommended dose level which was associated with grade 3-4 neutropenia in 3 of 12 patients and in 22.9% of cycles.

Conclusions: This study estimates that the recommended dose for phase II studies of gemcitabine-vinorelbine is 1500/30 mg/m2 at day 1 and 8 every three weeks. A careful monitoring of the hematologic toxicity is recommended in heavily pretreated patients and in patients who received pelvic radiotherapy. Partial responses observed in a patient with an advanced cisplatin-5-fluorouracil-resistant pancreatic adenocarcinoma and in a patient with mesothelioma support further evaluation of this combination in patients with tumors refractory to classical antitumor agents.
Malignant peritoneal mesothelioma treated by continuous hyperthermic peritoneal perfusion chemotherapy. E. de Bree, M. Christodoulakis, D. Tsiftsis. 2000;11(6):753-6. Case report PubMed · Publisher

Abstract

Malignant mesothelioma of the peritoneum is a rare tumour for which the therapeutic approach has not yet been standardized. The efficacy of the current regimes is limited. Effective locoregional therapy is crucial, since this tumour is most often confined to the peritoneal cavity at the time of the initial diagnosis and remains there for much of its clinical course. If and when haematogenous metastases occur, they rarely contribute to the death of the patient, which is often caused by the overgrowth of the primary tumour and its local complications. A case of diffuse malignant peritoneal mesothelioma treated by cytoreductive surgery and continuous hyperthermic peritoneal perfusion with cisplatin is reported. The patient received systemic combination chemotherapy postoperatively. She is in good condition and free of disease 28 months after her treatment. Continuous hyperthermic peritoneal perfusion chemotherapy has recently been used in patients with secondary peritoneal carcinomatosis from digestive and gynecological malignancies with promising results. It is also possible that the same treatment alone or in combination with systemic chemotherapy may be effective in the treatment of primary peritoneal malignancies, as in the case of diffuse peritoneal mesothelioma.
Randomised phase II study of cisplatin-etoposide versus infusional carboplatin in advanced non-small-cell lung cancer and mesothelioma. S.C. White, H. Anderson, G.C. Jayson, et al. 2000;11(2):201-6. Randomized trial PubMed · Publisher

Abstract

Background: A randomised phase II study was performed to compare standard combination chemotherapy containing cisplatin and etoposide with infusional carboplatin.

Patients And Methods: One hundred twenty patients with locally advanced/metastatic non-small-cell lung cancer or mesothelioma were enrolled. All were chemotherapy-naïve and had a Karnofsky performance status of > or = 50. Patients were randomised to either four cycles of bolus therapy of cisplatin 80 mg/m2 day 1, etoposide 120 mg/m2 day 1-3, or continuous infusion of carboplatin 100/mg/m2/week for six weeks.

Results: No patients on infusional therapy incurred grade 3-4 toxicity while in the bolus arm, grade 3 and grade 4 leucopenia occurred in 17% and 35% of patients, respectively. Grade 4 thrombocytopenia occurred in 8% of patients and there were two instances of grade 3 renal toxicity. No responses occurred in the pump arm. Eight of forty-six patients with non-small-cell lung cancer responded to treatment (response rate 17.3%) with two complete responses and six partial responses. Only one patient with mesothelioma responded to bolus therapy. There was no difference in survival for the subset of NSCLC patients. Survival for mesothelioma patients in the pump arm was superior but this was likely to be a result of early deaths in the bolus arm.

Conclusions: The pump arm was well-tolerated but not active, whilst combination platinum-based therapy demonstrated activity but significantly more toxicity than the pump arm. Further studies of infusional carboplatin with this schedule are not warranted.

1990s

Retinoids in lung cancer chemoprevention and treatment. S. Toma, P. Raffo, L. Isnardi, et al. 1999;10 Suppl 5:S95-102. Review PubMed · Publisher

Abstract

In this review, we aim to synthesize the emerging picture of retinoids in lung cancer through a summary of ongoing investigations in biology, chemoprevention and therapy settings, in an attempt to clarify the possible role of these agents in such a disease. Early work in head and neck cancer has evidenced the capability of retinoids to interrupt field carcinogenesis by reversing premalignant lesions and decreasing the incidence of second primary tumors (SPTs). At this time, the completed randomized trials in lung cancer have failed to demonstrate an evident chemopreventive effect of the tested agents on different study end points, although both a marginally significant benefit of retinol palmitate in time-to-development rates for smoke-related SPTs and a potential preventive effect of retinol supplementation against mesothelioma in selected populations of asbestos-exposed workers have been recently reported. Concerning the role of retinoids in lung cancer treatment, a moderate activity of 13-cis-retinoic acid (13cRA) or all-transretinoic acid (ATRA) as single agents has been reported in small series of advanced, mostly pretreated lung cancer patients. More encouraging findings derive from combination studies, in which retinoids, especially ATRA, are added to either alpha-interferon or chemotherapy and radiotherapy. Major recent advances have been made towards the understanding of retinoids mechanisms of action; at this regard, the role of RAR-beta basal or treatment-induced levels seems to be of particular interest as intermediate end point and/or independent prognostic factor, besides their known importance in lung carcinogenesis. Future research for chemopreventive and therapeutic programs with retinoids in lung cancer should be focused on the investigation of new generation compounds with a specificity for individual retinoid nuclear receptors. Such selective molecules may have a greater activity against lung cancer, with a more favourable toxicity profile, as recently suggested by our preliminary data on Ro 41-5253.
Phase I clinical and pharmacokinetic study of the oral platinum analogue JM216 given daily for 14 days. C. Sessa, C. Minoia, A. Ronchi, et al. 1998;9(12):1315-22. PubMed · Publisher

Abstract

Background: The oral bis (acetate) ammine dichloro cyclohexylamine platinum (IV) analogue (BMS-182751) was brought into clinical development because it was shown to be cytotoxic against some human tumour cell lines and to have an antitumor activity in murine tumours at least comparable to that of parenteral cisplatin and carboplatin. In early clinical studies in which the optimal schedule of treatment was daily for five consecutive days, dose-dependent nausea and vomiting occurred in about two-thirds of patients.

Patients And Methods: To evaluate if the use of lower daily doses for longer periods of time could result in a better tolerability, JM216 was given once daily for 14 consecutive days every four to five weeks to adult patients with solid tumors. Oral antiemetics were given prophylactically only at the highest doses. The pharmacokinetics of total and ultrafiltrable platinum were studied on days 1 and 14 of the first cycle by Inductively Coupled-Mass-Spectrometry (ICP-MS).

Results: Forty-six patients were treated at doses ranging from 10 mg/m2/d to 50 mg/m2/d and 39 were evaluable for hematologic toxicity over 74 cycles. MTDs were reached at 45 mg/m2/d and 50 mg/m2/d x 14 repeated every five weeks in patients with extensive, or limited/no prior treatment, respectively. The dose-limiting toxicity was neutropenia which was delayed and variable among patients. Other non-hematological toxicities were severe vomiting (22% of cycles), diarrhea (28% of cycles) and drug-associated fever (32% of patients), controlled with paracetamol. Subjective improvement with disappearance of tumour-related pain was observed in one patient with chemotherapy-resistant metastatic prostate cancer and in one previously untreated patient with malignant mesothelioma. Cmax and AUC values of both total and ultrafiltrable platinum on days 1 and 14 were highly variable among patients. Only Cmax on day 1 was linearly related to the dose. Total and ultrafiltrable platinum were still detectable two weeks after the last dose. No relationship could be established between AUC values and toxicities.

Conclusions: Daily doses of JM216 of 40 mg/m2 and 45 mg/m2 for 14 consecutive days every five weeks with oral antiemetic prophylaxis are selected for phase II evaluation of single agent in patients with extensive or limited/no prior treatment, respectively. The administration of JM216 on a day x 14 schedule produced nausea and vomiting comparable to that observed with the day x 5 regimen but of longer duration. The variability of pharmacokinetics and pharmacodynamics, even though limited at the doses proposed for phase II evaluation of JM216 as single agent, recommend a careful monitoring of the patients.
A phase II trial of dose-escalated doxorubicin and ifosfamide/mesna in patients with malignant mesothelioma. L.Y. Dirix, J. van Meerbeeck, D. Schrijvers, et al. 1994;5(7):653-5. PubMed · Publisher

Abstract

Background: This study investigated the feasibility and efficacy of doxorubicin dose-escalated chemotherapy in combination with ifosfamide in patients with malignant mesothelioma.

Patients And Methods: In this single institution phase II study, 24 chemotherapy-naive, eligible patients were entered. The chemotherapy regimen consisted of doxorubicin 75 mg/m2 in combination with ifosfamide 5 gr/m2 given as a continuous 24 hour infusion, every 21 days with either rhG-CSF (5 micrograms/kg) or rhGM-CSF (250 micrograms/m2) as haematopoietic support from d3 to d14. Cycles were repeated every 3 weeks.

Results: We treated 24 patients, of whom 22 are evaluable for tumour response. One of the two inevaluable patients died from a cerebral haemorrhage during a period of grade III thrombocytopenia after the second course. In 7 patients a partial response was observed, resulting in a response rate of 32% (95% confidence interval 13%-51%). Median response duration was 6 months (range 1-13) and median survival was 7 months (range 1-18).

Conclusions: The high-dose regimen with growth factor support is feasible in this group of patients and leads to an interesting response rate. The limiting toxicity for further dose increments and more courses of treatment, was cumulative thrombocytopenia. There seems to be a subgroup of patients with malignant mesothelioma which is less susceptible to develop thrombocytopenia. However, the overall toxicity and the poor response duration limit the use of this schedule in the treatment of malignant mesothelioma.
Meningeal and brain metastases in primary malignant pericardial mesothelioma. U. Bohn, J.L. Gonzalez, L.M. Martin, et al. 1994;5(7):660-1. Case report · Letter PubMed · Publisher

Summary

The authors reported a case of primary malignant pericardial mesothelioma, an uncommon tumour of which about 150 cases had been reported, with spread to the meninges and brain. The patient was a 51-year-old Spanish furrier and heavy smoker who developed weakness, weight loss (16 pounds in three months), cough and progressive breathlessness from December 1987. In February 1988 he was admitted in cardiac tamponade. CT showed extensive pericardial infiltration with pleural involvement, and bone studies showed multiple lytic metastases and marrow infiltration by mesothelial cells. A partial pericardiectomy confirmed malignant pericardial mesothelioma, and he received CYVADIC chemotherapy (cyclophosphamide, adriamycin, vincristine and dacarbazine). One month later he developed weakness of both legs, and spinal fluid cytology was positive for malignant mesothelial cells. Intrathecal cytarabine with steroids, given twice weekly for one month, did not clear these cells, and he died on 13 May 1988. At necropsy the heart was encased in tumour and the pleura was infiltrated. Malignant cells were found in the dura mater and in the leptomeninges of the brain stem and pons, with brain micrometastases, a 0.5 cm parietal nodule and metastases in several other organs. The authors stated that, to their knowledge, this was the first reported case with meningeal metastases diagnosed before and after death, and that brain metastases had not been described at necropsy. The report did not mention asbestos.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Oral etoposide in the treatment of malignant mesothelioma. A phase II study. L. Tammilehto, P. Maasilta, M. Mäntylä, et al. 1994;5(10):949-50. PubMed · Publisher

Summary

This short report described a phase II trial of low-dose oral etoposide in malignant mesothelioma. Between 1990 and 1992, 42 patients at Helsinki University Central Hospital in Finland were diagnosed histologically with malignant mesothelioma. Of these, 23 were entered in the trial. They received daily oral etoposide (100 mg) for 21 days, followed by 2 weeks without treatment. Nineteen patients were evaluable for response. Three were non-evaluable because of previous treatment and one because of a wrong diagnosis. The evaluable patients were 15 men and 4 women with a median age of 63 years (range 44-76). Eleven tumours were epithelial and 8 mixed, and two patients had peritoneal mesothelioma. Asbestos exposure was classed as definite, probable or possible in 14 patients. Tumours were assessed by contrast-enhanced CT before treatment and every 3 months thereafter, and toxicity was graded according to WHO guidelines. Ten patients received 1-3 cycles and 13 (57%) received 4 or more. Thirteen of 122 cycles were reduced because of treatment-related myelosuppression. There were no complete responses and one partial response, lasting 16 months. Disease was stabilised in 15 patients (2-10 months), and 3 had progressive disease. Median survival was 17 months after diagnosis, and 13 of the 23 patients were still alive. The authors concluded that toxicity was acceptable, with no treatment-related deaths. However, etoposide was active against less than 20% of tumours at this dosage, and routine chemotherapy for mesothelioma remained controversial.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Phase I study of the novel distamycin derivative tallimustine (FCE 24517). C. Sessa, O. Pagani, M.G. Zurlo, et al. 1994;5(10):901-7. PubMed · Publisher

Abstract

Background: Tallimustine, a benzoyl nitrogen mustard derivative of the antiviral agent distamycin A, is a new alkylating agent which binds to A-T rich regions of DNA in the minor groove producing highly sequence-specific alkylations. Its main preclinical features are a significant antitumor activity in animal models and a lack of cross-resistance in vitro and in vivo with L-PAM. Myelotoxicity was dose-limiting in animals, with a more than 100-fold difference in bone marrow sensitivity between mice and dogs.

Patients And Methods: Forty adult patients (pts) with solid malignancies were entered in the study. The drug was administered as an IV bolus every 4 weeks. CBC was repeated twice a week and serial assessments of renal function were performed in the week following the first cycle. From the starting dose of 50 micrograms/m2, corresponding to 1/3 of the highest non-toxic dose (HNTD) in dogs, there were increases through 10 dose levels, with reliance only on the features of the myelotoxicity observed.

Results: The main toxic effect was neutropenia which was dose-limiting, selective and short-lasting. Only previously-untreated pts received doses of 750 micrograms/m2 or more, with grade 4 neutropenia occurring in > or = 75% of the cycles. The maximally tolerable dose (MTD) was defined as 1250 micrograms/m2, with 3 of 3 pts developing febrile neutropenia requiring IV antibiotics. A platelet count of < 100 x 10(3)/microliters was observed in only one pt. Bone marrow aspiration performed in selected pts on days 8 and 15 confirmed a highly selective impairment by tallimustine of the myeloid lineage, with rapid recovery of the proliferative compartment. Pharmacokinetic studies performed at 1000 micrograms/m2 and 1250 micrograms/m2 showed a rapid fall of the plasma levels within the first 2 hours with drug concentrations between 100 ng/ml and 400 ng/ml within the first hour. A partial response of 4 months' duration was reported in one previously-untreated pt with cutaneous recurrences of malignant mesothelioma.

Conclusions: The report of some antitumour efficacy, the high selectivity of neutropenia, the lack of significant non-hematological toxic effects and the occurrence of detectable but still low plasma drug concentrations suggest that further clinical evaluation of higher doses of tallimustine in combination with colony-stimulating factors would be justified.
Phase I/II study of intraperitoneal mitoxantrone in refractory ovarian cancer. A.M. Oza, W. ten Bokkel Huinink, R. Dubbelman, et al. 1994;5(4):343-7. PubMed · Publisher

Abstract

Background: Mitoxantrone has demonstrable clinical activity when administered intravenously in a wide range of malignancies. The feasibility and toxicity of intra-peritoneal administration was established in a phase I study. The optimal dose from the phase I was subsequently evaluated in a phase II study.

Patients And Methods: 19 patients with refractory malignancies and extensive abdominal disease (13 ovarian cancer, 4 breast cancer, 2 mesothelioma) were entered in a phase I study. The dose of intraperitoneal mitoxantrone was escalated from 10 mg/m2, administered in 21 of fluid via a Tenckhoff catheter, to 55 mg/m2, in increments of 5 mg/m2. Cycles were repeated every three weeks. Sixty-seven cycles of mitoxantrone were administered, the maximum tolerable dose being 25 mg/m2. A phase II study at this dose was conducted in 14 patients with refractory ovarian cancer, all of whom had previously received systemic platinum based therapy. Five of the 14 had also previously been treated with intraperitoneal carboplatin. Fifty-one cycles were administered.

Results: The dose limiting toxicity in the phase I study was peritoneal irritation and pain. Leucopenia was frequent at doses equal or greater than 30 mg/m2. Three complete remissions were documented in the phase I study (2 breast cancer and 1 ovarian cancer). There was no significant haematological toxicity in the phase II assessment, though local toxicity precluded further therapy in 2 patients. No objective responses were seen in the phase II evaluation.

Conclusions: These studies demonstrate the feasibility of intra-peritoneal mitoxantrone therapy in patients with peritoneal disease, but do not support its routine use in ovarian cancer.
Weekly high-dose cisplatin in malignant pleural mesothelioma. A.S. Planting, J.H. Schellens, S.H. Goey, et al. 1994;5(4):373-4. PubMed · Publisher

Abstract

Background: Cisplatin at conventional doses has marginal activity in mesothelioma. A dose-response relation for cisplatin has been suggested in other tumor types. In a phase I study on weekly cisplatin administration, 3 of 5 patients with mesothelioma responded. Therefore, a phase II study with weekly cisplatin was started with the recommended dose of 80 mg/m2/week for six weeks.

Patients And Methods: Fourteen patients with mesothelioma stage II, with measurable lesions, were treated with cisplatin at a dose of 80 mg/m2 weekly for six weeks. Cisplatin was administered in 3% NaCl and combined with ondansetron as antiemetic.

Results: Five patients had partial responses (response rate 36%; 95% confidence interval 12%-65%) lasting 2-8 months. Seven patients had stable disease. Ototoxicity, grade 2 in 3 patients and grade 3 in 2, was the most troublesome side effect.

Conclusions: Cisplatin given at a higher dose intensity than in conventional schedules is active in mesothelioma. The response duration is short, however, possibly due to lack of effective maintenance therapy.
Local treatment of malignant pleural mesothelioma with intracavitary cytosine-arabinoside and cisplatin. E. Aitini, E. Pasquini, G. Cavazzini, et al. 1992;3(9):771-2. Letter PubMed · Publisher

Summary

This letter reported the use of chemotherapy given directly into the pleural cavity (intracavitary or intrapleural treatment) for malignant pleural mesothelioma. The authors were based at medical oncology departments in Mantova and Rimini, Italy. The letter does not say when the patients were treated.

Five patients were treated: four men and one woman, with a median age of 52 years (range 37-68). All had cytologically and histologically confirmed tumours, and none had a documented history of asbestos exposure. Three had previously received doxorubicin or epirubicin. After the pleural cavity was drained, cytosine arabinoside (Ara-C, 100 mg) and cisplatin (100 mg/m2) in 0.4 L of saline were instilled and drained again 4 hours later, with intravenous hydration and furosemide. Response and toxicity were assessed using WHO criteria.

The patients received a total of 27 courses (range 3-8). Three patients had a complete response, one a partial response and one progressive disease. Responses lasted 9 to 23 months, and survival ranged from 6 to 51 months. The main side effect was modest myelosuppression: the median white cell nadir was 2100/mm3 and the median platelet nadir 170,000/mm3. No fever or sepsis occurred, and two patients had mild nausea and vomiting. Two long-term survivors later developed peritoneal and hepatic involvement.

The authors stated that the small number of cases did not allow definitive conclusions. They suggested that this treatment could play an important role in local control of non-metastatic pleural mesothelioma, with minimal systemic toxicity.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Treatment of malignant mesothelioma with epirubicin and ifosfamide: a phase II cooperative study. M.D. Magri, S. Foladore, A. Veronesi, et al. 1992;3(3):237-8. PubMed · Publisher

Abstract

From May 1988 to March 1990, 17 consecutive patients with histologically proven malignant mesothelioma were treated with epirubicin 75 mg/sqm i.v. on day 1 and ifosfamide 1.8 gr/sqm/day i.v. from day 1-5. Treatment was repeated every 3 weeks until progression. Fifty-three chemotherapy cycles were administered to the 17 patients treated (median, 3 cycles/patient). No complete responses, 1 partial response, 8 stable diseases and 8 progressions were noted. Toxocity was acceptable and no treatment-related deaths occurred. Actuarial median survival was 6 months. In this study, a combination of full doses of epirubicin and ifosfamide did not prove to be active in malignant mesothelioma.
Mediastinal germ cell tumour with an uncommon micropapillary architecture on histology. A. von Rohr, A. Zimmermann, K.W. Brunner, et al. 1991;2(10):771-2. Case report · Letter PubMed · Publisher

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