Kindler HL.

Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA. hkindler@medicine.bsd.uchicago.edu

Abstract

Systemic therapy is the only treatment option for the majority of mesothelioma patients, for whom age, co-morbid medical illnesses, non-epithelial histology, and locally advanced disease often preclude surgery. For many years, chemotherapy had a minimal impact on the natural history of this cancer, engendering considerable nihilism. Countless drugs were evaluated, most of which achieved response rates below 20% and median survival of <1 year. Several factors have hampered the evaluation of systemic regimens in patients with mesothelioma. The disease is uncommon, affecting only about 2500 Americans annually. Thus, most clinical trials are small, and randomized studies are challenging to accrue. There is significant heterogeneity within the patient populations of these small trials, for several reasons. Since all of the staging systems for mesothelioma are surgically based, it is almost impossible to accurately determine the stage of a patient who has not been resected. Patients
with very early stage disease may be lumped together with far more advanced patients in the same study. The disease itself is heterogenous, with many different prognostic factors, most notably three pathologic subtypes—epithelial, sarcomatoid, and biphasic—that have different natural histories, and varying responses to treatment. Finally, response assessment is problematic, since pleural-based lesions are difficult to measure accurately and reproducibly. Assessment criteria often vary between trials, making some cross-trial comparisons difficult to interpret. Despite these limitations, in recent years, there has been a surge of optimism regarding systemic treatment of this disease. Several cytotoxic agents have been shown to generate reproducible responses, improve quality of life, or prolong survival in mesothelioma. Drugs with single-agent activity include pemetrexed, raltitrexed, vinorelbine, and vinflunine. The addition of pemetrexed or raltitrexed to cisplatin prolongs survival.
The addition of cisplatin to pemetrexed, raltitrexed, gemcitabine, irinotecan, or vinorelbine improves response rate. The combination of pemetrexed plus cisplatin is considered the benchmark front-line regimen for this disease, based on a phase III trial in 456 patients that yielded a response rate of 41% and a median survival of 12.1 months. Vitamin supplementation with folic acid is essential to decrease toxicity, though recent data suggests that there may be an optimum dose of folic acid that should be administered; higher doses may diminish the effectiveness of pemetrexed. There are also several unresolved questions about the duration and timing of treatment with pemetrexed that are the subject of planned clinical trials. It is essential to recognize that the improvements observed with the pemetrexed/cisplatin combination, though real, are still modest. Other active drugs or drug combinations may be more appropriate for specific individuals, and further research is still needed
to improve upon these results. Since the majority of mesotheliomas in the United States occur in the elderly, non-cisplatin-containing pemetrexed combinations may be more appropriate for some patients. Now that effective agents have been developed for initial treatment, several classical cytotoxic drugs and many novel agents are being evaluated in the second-line setting. These include drugs targeted against the epidermal growth factor, platelet-derived growth factor, vascular endothelial growth factor, src kinase, histone deacetylase, the proteasome, and mesothelin. Given the progress made in recent years, there is reason to believe that more effective treatments will continue to be developed.

Sørensen JB, Frank H, Palshof T.

1Department Oncology, Finsen Centre/National University Hospital, 9 Blegdamsvej, Copenhagen DK-2100, Denmark.

Abstract

The aim was to evaluate the activity of cisplatin and vinorelbine in previously untreated, inoperable patients having histologically verified malignant pleural mesothelioma (MPM), normal organ function, and performance status 0-2. Treatment was vinorelbine 25 mg m(-2) i.v. weekly and cisplatin 100 mg m(-2) i.v. every 4 weeks with hydration and standard prophylactic antiemetic treatment. Patients gave written informed consent. Characteristics of 54 consecutive patients were: males 85%, epithelial subtype 74%, IMIG stages III and IV 35 and 46%, performance status 0, 1, and 2, 26, 69, and 6%, and median age 63 years (31-78 years). CTC grade 3 or 4 toxicity occurred with respect to leukocytopenia (48% of patients, grade 4 in 13%), nausea (13%), neurotoxicity (11%), nephrotoxicity (4%), and other toxicities (9%). There were no toxic deaths. The median number of cycles was four. The fraction of patients alive at 1-, 2-, and 3-years were 61, 31, and 4%, respectively, and median survival and median time to progression were 16.8 months (0.5 to 46.4 +months) and 7.2 months (1.6 to 40.6 + months). There were two CRs and 14 PRs (response rate 29.6%). Cisplatin and intravenous vinorelbine is a highly active regimen in MPM with a response rate and survival comparable to the most active regimens so far reported.

Karpathiou G, Argiana E, Koutsopoulos A, Froudarakis ME.

Department of Pneumonology, Medical School Democritus University of Thrace, Alexandroupolis, Greece.

Abstract

We report the case of a 56-year-old patient with malignant pleural mesothelioma of epithelial type, who responded to second-line chemotherapy with lipoplatin plus gemcitabine. Diagnosis and staging of the disease was done by medical thoracoscopy with biopsies of the right pleura in December 2003, when he was treated with talc pleurodesis. Eighteen months later, he presented with pleural effusion of the left side and underwent first-line chemotherapy with cisplatin plus vinorelbine. After 8 cycles, the patient presented renal toxicity limiting further cisplatinum chemotherapy and disease progression with peritoneal invasion of the tumor and ascites. Treatment with lipoplatin-gemcitabine was decided on in November 2006, and the patient showed important improvement in the clinical status and peritoneal effusion. He survived for 36 weeks, with symptom-free survival of 34 weeks.

Keywords: Lipoplatin, Gemcitabine, Mesothelioma, Second-line chemotherapy, Thoracoscopy, Cisplatin, Vinorelbine

Stebbing J, Powles T, McPherson K, Shamash J, Wells P, Sheaff MT, Slater S, Rudd RM, Fennell D, Steele JP.

Department of Medical Oncology, St. Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, UK.

Abstract

Malignant pleural mesothelioma (MPM) is a rapidly progressive invariably lethal tumor. Treatment options remain limited and the outcome in relapsed disease is poor warranting new therapeutic options. Following our previous experience in the first-line setting, we conducted a phase 2 open-label non-comparative study to assess the safety and efficacy of weekly vinorelbine chemotherapy, each cycle consisting of 30mg/m(2) for 6 weeks, in patients with previous exposure to chemotherapy. In 63 individuals with relapsed MPM who had not received previous vinorelbine, we observed an objective response rate of 16% and an overall survival of 9.6 months (95% confidence interval 7.3-11.8 months). The main grade III/IV toxicity observed was neutropenia and toxicity was similar to weekly vinorelbine when used in the first-line setting. Weekly vinorelbine appeared to have a reasonable response rate with an acceptable toxicity profile in the second-line treatment of MPM. Its use should be prospectively evaluated in a randomised trial in the first or second-line therapy of MPM.

Muers MF, Stephens RJ, Fisher P, Darlison L, Higgs CM, Lowry E, Nicholson AG, O’Brien M, Peake M, Rudd R, Snee M, Steele J, Girling DJ, Nankivell M, Pugh C, Parmar MK; on behalf of the MS01 Trial Management Group.

Leeds General Infirmary, Leeds, UK.

Abstract

Background: Malignant pleural mesothelioma is almost always fatal, and few treatment options are available. Although active symptom control (ASC) has been recommended for the management of this disease, no consensus exists for the role of chemotherapy. We investigated whether the addition of chemotherapy to ASC improved survival and quality of life.

Methods: 409 patients with malignant pleural mesothelioma, from 76 centres in the UK and two in Australia, were randomly assigned to ASC alone (treatment could include steroids, analgesic drugs, bronchodilators, palliative radiotherapy [n=136]); to ASC plus MVP (four cycles of mitomycin 6 mg/m(2), vinblastine 6 mg/m(2), and cisplatin 50 mg/m(2) every 3 weeks [n=137]); or to ASC plus vinorelbine (one injection of vinorelbine 30 mg/m(2) every week for 12 weeks [n=136]). Randomisation was done by minimisation, with stratification for WHO performance status, histology, and centre. Follow-up was every 3 weeks to 21 weeks after randomisation, and every 8 weeks thereafter. Because of slow accrual, the two chemotherapy groups were combined and compared with ASC alone for the primary outcome of overall survival. Analysis was by intention to treat. This study is registered, number ISRCTN54469112.

Findings: At the time of analysis, 393 (96%) patients had died (ASC 132 [97%], ASC plus MVP 132 [96%], ASC plus vinorelbine 129 [95%]). Compared with ASC alone, we noted a small, non-significant survival benefit for ASC plus chemotherapy (hazard ratio [HR] 0.89 [95% CI 0.72-1.10]; p=0.29). Median survival was 7.6 months in the ASC alone group and 8.5 months in the ASC plus chemotherapy group. Exploratory analyses suggested a survival advantage for ASC plus vinorelbine compared with ASC alone (HR 0.80 [0.63-1.02]; p=0.08), with a median survival of 9.5 months. There was no evidence of a survival benefit with ASC plus MVP (HR 0.99 [0.78-1.27]; p=0.95). We observed no between-group differences in four predefined quality-of-life subscales (physical functioning, pain, dyspnoea, and global health status) at any of the assessments in the first 6 months.

Interpretation: The addition of chemotherapy to ASC offers no significant benefits in terms of overall survival or quality of life. However, exploratory analyses suggested that vinorelbine merits further investigation.

Zucali PA, Ceresoli GL, Garassino I, De Vincenzo F, Cavina R, Campagnoli E, Cappuzzo F, Salamina S, Soto Parra HJ, Santoro A.

Department of Medical Oncology and Hematology, Humanitas Clinical Institute of Rozzano, Milan, Italy.

Abstract

Background: Pemetrexed-cisplatin chemotherapy is the standard of care in the first-line treatment of unresectable malignant pleural mesothelioma (MPM). Second-line cytotoxic therapy is considered for a growing group of patients, but the optimal treatment has not been defined to date. Gemcitabine and vinorelbine have shown activity in the first-line setting. The objective of this study was to evaluate the activity and toxicity of the gemcitabine-vinorelbine combination in pemetrexed-pretreated patients with MPM.

Methods: From January 2004 to September 2006, 30 consecutive patients who were pretreated with pemetrexed with or without a platinum-derivative were enrolled. Gemcitabine 1000 mg/m2 and vinorelbine 25 mg/m2 were administered intravenously on Days 1 and 8 every 3 weeks. Treatment was repeated for a maximum of 6 cycles or until progression or unacceptable toxicity.

Results: A partial response was observed in 3 patients (10%; 95% confidence interval [CI], 2.1-26.5%), and 10 patients (33.3%; 95% CI, 17.3-52.8%) had stable disease after treatment. Overall, 13 patients (43.3%; 95% CI, 25.5-62.6%) achieved disease control. The median time to progression was 2.8 months (range, 0.6-12.1 months), and the median survival was 10.9 months (range, 0.8-25.3 months). Hematologic toxicity was acceptable, with grade 3 or 4 neutropenia occurring in 11% of patients and thrombocytopenia occurring in 4% of patients; no case of febrile neutropenia was observed. Nonhematologic toxicity generally was mild.

Conclusions: The gemcitabine and vinorelbine combination was moderately active and had an acceptable toxicity profile in pemetrexed-pretreated patients with MPM. The role of second-line treatment in MPM needs to be evaluated in prospective trials in large series of patients who are stratified according to previous treatment and prognostic factors.

Cordony A, Le Reun C, Smala A, Symanowski JT, Watkins J.

M-TAG Pty Ltd, A Unit of IMS Health, St Leonards, NSW, Australia. acordony@au.imshealth.com

Abstract

Objectives: Findings from the largest randomized phase III trial in patients with unresectable malignant pleural mesothelioma (EMPHACIS study; n = 448) were used to examine the cost-effectiveness of pemetrexed plus cisplatin therapy versus cisplatin monotherapy in patients with the disease. The cost-effectiveness of pemetrexed/cisplatin versus alternative treatments was also examined.

Methods: Two cost-effectiveness analyses were designed to model best survival outcome over time for a number of patient cohorts. First, trial-based patient-level data were utilized and resource use was costed for the study arm and comparator. A second cost-effectiveness analysis then compared the mean costs and outcomes associated with pemetrexed/cisplatin with the most commonly used (unlicensed) regimens in the United Kingdom—mitomycin-C, vinblastine, and cisplatin (MVP); vinorelbine; and active symptom control—using trial-based data and data extrapolated from a review of the literature.

Results: The total pemetrexed/cisplatin cost per patient varied between £8779 and £9020 for all cohorts studied in model 1. Average life-years gained per patient were between 0.20 and 0.28. Quality-adjusted life-years, based on mean and median survival, ranged from 0.13 to 0.31. Incremental cost per life-year gained and quality-adjusted life-year ratios, using both mean and median survival, ranged from £20,475 to £68,598. The second cost-effectiveness analysis resulted in ratios ranging from £14,595 to £32,066.

Conclusions: Pemetrexed/cisplatin demonstrated acceptable cost-effectiveness when compared with cisplatin monotherapy and alternative treatments commonly used in UK clinical practice.

Katayam N, Tokuda A, Nakatsumi Y, Oribe Y, Fujimura M.

Department of Respiratory Medicine, Kanazawa Municipal Hospital.

Abstract

A 71-year-old man was found to have right hydropneumothorax by chest X-ray film on a regular checkup. Thoracic drainage and bullectomy by thoracoscopy did not improve the pneumothorax, so pleurodesis with OK-432 was done. Pneumothorax recurred twice, requiring thoracic drainage and pleurodesis. Although pneumothorax was treated successfully, increased pleural effusion, pleural thickening and subcutaneal tumor at the thoracic drainage suture site developed. The concentration of hyaluronic acid in the pleural fluid was very high. The histological examination of the biopsied subcutaneous tumor showed mixed type malignant pleural mesothelioma. Chemotherapy with gemcitabine and vinorelbine could not control the progression.

Maruyama R, Sakai M, Nakamura T, Suemitsu R, Okamoto T, Wataya H, Nishiyama K, Kamei T, Ichinose Y.

Department of Thoracic Oncology, Kyushu Cancer Center, Fukuoka, Japan.

Abstract

Malignant pericardial mesothelioma (MPM) is a relatively rare neoplasm in Japan, and no standard treatment regimens have been established for this disease. A 47-year-old woman with MPM presenting with cardiac tamponade was treated using four cycles of chemotherapy consisting of cisplatin (CDDP) 40 mg/m(2), gemcitabine (GEM) 800 mg/m(2) and vinorelbine (VNR) 20 mg/m(2) on days 1 and 8 every 4 weeks after pericardial drainage alone. The diagnosis of MPM was confirmed by an immunohistochemical procedure using either positive or negative markers of malignant mesothelioma in addition to conventional cytological examinations using pericardial effusion. The patient experienced no severe non-hematological or hematological toxicities except for grade 3 neutropenia. The patient has returned to her usual activities and has remained well for 24 months after the last chemotherapy without any evidence of disease progression.

Jacoulet P.

Service de Pneumologie, CHU, Besancon, France.

Abstract

Chemotherapy is often the only treatment possible for locally advanced or metastatic mesothelioma. This paper recalls which drugs might have therapeutic benefits in this condition and reviews recent studies of chemotherapy or targeted therapy. If the patient cannot be enrolled in a therapeutic trial the first line therapy in the absence of contraindications is a combination of cisplatin and pemetrexed, the latter having received a licence for this indication in September 2004. Among the alternatives reviewed are taxanes, liposomal anthracyclines, topoisomerase inhibitors, cisplatin derivatives, vinca alkaloids, and antimetabolites. Although the first three have show little or no benefit the vinca alkaloids (vinorelbine, vinflunine) and particularly the antimetabolites (gemcitabine, raltitrexed, pemetrexed) are very promising. Recent studies have looked most frequently at combinations of an anti-metabolite and a platinum salt, with data available from nearly 200 patients treated with gemcitabine. These studies have had fairly homogeneous results showing a one year survival of about 50%. Some preliminary data from studies of second line chemotherapy is also available. Finally studies of targeted therapies such as anti-EGFR, anti VEGF and anti PDGF are underway but have not as yet demonstrated major therapeutic benefit.