Berghmans T.

Département des Soins Intensifs et Oncologie Thoracique, Institut Jules-Bordet (Centre des Tumeurs de l’Université Libre de Bruxelles), 1 Rue Héger-Bordet, Brussels, Belgium. thierry.berghmanns@bordet.be

Abstract

Malignant pleural mesothelioma is a rare tumour of poor prognosis. Available therapeutics have restricted efficacy. Pleuro-pneumonectomy is the only treatment with curative intent but it could be offered to a limited and well selected group of patients. The role of radiotherapy is palliative and its preventive role on malignant seeding after invasive procedures is controversial. There are few active cytotoxic drugs in this disease. Currently, based on two randomised trials, the most efficacious chemotherapy regimen consists in a combination of cisplatin and an antifolate agent, pemetrexed or raltitrexed.

Keywords: Mesothelioma, Surgery, Radiotherapy, Chemotherapy

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.

Bottomley A, Coens C, Efficace F, Gaafar R, Manegold C, Burgers S, Vincent M, Legrand C, van Meerbeeck JP; EORTC-NCIC.

EORTC Data Center, Quality of Life Unit, Avenue E. Mounier, 83, 1200 Brussels, Belgium. andrew.bottomley@eortc.be

Abstract

Purpose: Malignant pleural mesothelioma (MPM) is a rare disease. Unlike other advanced cancer types, little is known about patient-reported symptoms or health-related quality of life (HRQOL) and their possible prognostic value. This study reports an evaluation of the prognostic value of these factors using data gathered from a recent randomized controlled trial.

Patients and Methods: Patients were entered onto this trial if they had a histologically proven unresectable MPM, not pretreated with chemotherapy, WHO performance status < or = 2, and adequate hematologic, renal, and hepatic function. Patients were randomly assigned to receive cisplatin 80 mg/m2 intravenously on day 1, without or with preceding infusion of raltitrexed 3 mg/m2. HRQOL was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30/Lung Cancer 13 tool. The Cox proportional hazards regression model was used for the univariate and multivariate analyses of survival, along with a bootstrap validation technique. Included were the EORTC prognostic index (PI) composed of stage of disease, histology type, time since diagnosis, and WBC, and, in addition, 10 selected key symptoms and HRQOL scales.

Results: Two hundred fifty patients were randomly assigned (80% male; median age, 58 years; WHO performance status 0, 1, 2 in 25%, 62%, and 13% of cases, respectively). Two hundred twenty-nine patients (91.6%) had a valid HRQOL assessment. The final multivariate model retained the PI, pain (P < .0001), and appetite loss (P = .0100) as independent prognostic indicators of survival.

Conclusion: Results suggest that the PI, pain, and appetite loss may be independent prognostic factors in patients with advanced MPM.

Ceresoli GL, Gridelli C, Santoro A.

Dipartimento di Oncologia Medica e Ematologia, Istituto Clinico Humanitas IRCCS, Via Manzoni, Rozzano (MI), Italy. giovanni_luca.ceresoli@humanitas.it

Abstract

The incidence of malignant pleural mesothelioma (MPM) is increasing worldwide, and is predicted to peak in the next 10-20 years. Difficulties in MPM diagnosis and staging, especially of early disease, have thwarted the development of a universally accepted therapeutic approach. Single modality therapies (surgery, radiotherapy, chemotherapy) have generally failed to significantly prolong patient survival. As a result, multimodality treatment regimens have been developed. Radical surgery with extrapleural pneumonectomy and adjuvant treatments has become the preferred option in early disease, but the benefits of such an aggressive approach have been questioned because of significant treatment-related morbidity and mortality. In the past few years, there have been several major advances in the management of patients with MPM, including more accurate staging and patient selection, improvements in surgical techniques and postoperative care, novel chemotherapy regimens with definite activity such as antifolate (pemetrexed or raltitrexed)-platinum combinations, and new radiotherapy techniques such as intensity-modulated radiation therapy. Induction chemotherapy followed by surgery and adjuvant radiotherapy has shown promising results. A number of molecular alterations occurring in MPM have been reported, providing broader insights into its biology and leading to the identification of new targets for therapy. However, currently available treatments still appear to have modest results. Further studies are needed to provide evidence-based recommendations for the treatment of early and advanced stages of this disease.

Ellis P, Davies AM, Evans WK, Haynes AE, Lloyd NS; Lung Cancer Disease Site Group of Cancer Care Ontario’s Program in Evidence-based Care.

McMaster University at Hamilton Health Sciences and Juravinski Cancer Centre, Hamilton, Ontario, Canada. vanderja@mcmaster.ca

Abstract

Background: This clinical practice guideline, based on a systematic review, was developed to determine which chemotherapeutic agents (or combinations of agents) show the highest response rates, improved survival, quality of life, or symptom control in patients with advanced malignant pleural mesothelioma.

Methods: A thorough systematic search of the literature was conducted for published articles and conference proceedings for applicable abstracts. Relevant trials, published as articles and abstracts, were selected and assessed. External feedback was obtained from Ontario clinicians, and the guideline was approved by the provincial Lung Cancer Disease Site Group.

Results: One hundred nineteen studies were eligible, including eight randomized trials and 111 phase II trials. The pooled response rates from phase II trials suggest that response rates with combination chemotherapy are higher than with single agents. Data from the largest randomized controlled trial demonstrated that chemotherapy with cisplatin and pemetrexed significantly improves response rates (41% versus 17%, p < 0.001), time to progression (5.7 months versus 3.9 months, p = 0.001), and overall survival (median, 12.1 months versus 9.3 months, hazard ratio = 0.77, p = 0.020) in comparison to single-agent cisplatin. A second trial demonstrated cisplatin and raltitrexed significantly improved median survival compared to single-agent cisplatin (11.4 months versus 8.8 months; hazard ratio = 0.76, p = 0.0483). Overall response rate (24% versus 14%, p = 0.056) was greater in the combination treatment arm, but this difference was not statistically significant.

Conclusions: There is good evidence to recommend chemotherapy with pemetrexed and cisplatin for adult patients with symptomatic advanced malignant pleural mesothelioma. Such treatment should be administered with supplementation of vitamin B12 and folic acid. If pemetrexed is not available, cisplatin plus raltitrexed is a reasonable alternative.

Bottomley A, Gaafa R, Manegold C, Burgers S, Coens C, Legrand C, Vincent M, Giaccone G, Van Meerbeeck J.

European Organisation for Research and Treatment of Cancer, EORTC Data Center, Brussels; University Hospital, Ghent, Belgium; National Cancer Center, Cairo, Egypt; Thoraxklinik Heidelberg, Germany; Erasmus MC, Rotterdam; NCIC DC, Ontario, Canada; Free University Medical Center, Amsterdam, the Netherlands.

Abstract

Purpose: For malignant pleural mesothelioma (MPM) patients with a poor prognosis, maintaining health-related quality of life (HRQOL) is important. This article compares the impact on HRQOL of first-line treatment with cisplatin versus raltitrexed and cisplatin.

Patients and Methods: Patients with histologically-proven unresectable MPM, not pretreated with chemotherapy were randomly assigned to receive cisplatin 80 mg/m2 intravenously on day 1, with or without preceding infusion of raltitrexed 3 mg/m2. HRQOL was assessed with the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire C30 (EORTC QLQ-C30) and EORTC Lung Cancer Module (QLQ-LC13) tools. Assessments were conducted at baseline, immediately before every treatment cycle, at the end of treatment, and every six weeks for 12 months.

Results: Two hundred fifty patients were randomly assigned, 80% were male with a median age of 58 years, WHO performance status 0, 1, and 2, in 25%, 62%, and 13% of cases. The clinical results found raltitrexed and cisplatin to be superior to cisplatin with regard to overall survival (P = .048). The global HRQOL scale was comparable at baseline on both treatment arms (P = .848); at no point was any significant difference apparent on this end point. Both treatments led to an improvement, over time, in dyspnoea. This effect is an important clinically meaningful reduction from baseline in the cisplatin/raltitrexed arm. However, the majority of scales of the EORTC QLQ-C30 or LC13 showed stabilization of HRQOL with few clinically significant differences between the treatment arms.

Conclusion: This study provides important information about the HRQOL of chemotherapy-treated MPM patients.

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.

Journal of Clinical Oncology. Vol 23, No 28 (October 1), 2005: pp. 6881-6889 [Link]

Jan P. van Meerbeeck, Rabab Gaafar, Christian Manegold, Rob J. Van Klaveren, Eric A. Van Marck, Mark Vincent, Catherine Legrand, Andrew Bottomley, Channa Debruyne, Giuseppe Giaccone

From the University Hospital, Ghent, Belgium; National Cancer Center, Cairo, Egypt; UMC Mannheim, Germany; Erasmus MC, Rotterdam, the Netherlands; University Hospital, Antwerp, Edegem, Belgium; NCIC DC, Ontario, Canada; EORTC DC, Brussels, Belgium; and Free University Medical Center, Amsterdam, the Netherland

Abstract

Purpose: We conducted a phase III trial to determine whether first-line treatment with raltitrexed, a thymidine synthase inhibitor, and cisplatin results in superior outcome compared with cisplatin alone in patients with malignant pleural mesothelioma (MPM).

Patients and Methods: Eligible patients with histologically proven advanced MPM, not pretreated with chemotherapy, WHO performance status (PS) 0 to 2, and adequate hematological, renal, and hepatic function were randomly assigned to receive cisplatin 80 mg/m2 IV on day 1, alone (arm A) or combined with raltitrexed 3 mg/m2 (arm B). In patients with measurable disease, response was monitored using the Response Evaluation Criteria in Solid Tumors criteria. Health related quality of life (HRQOL) was measured using the European Organisation for Research and Treatment of Cancer QLQ-C30 and Lung Module (QLQ-LC13).

Results: Two hundred fifty patients were randomized: 80% male; median age, 58 years; and WHO PS, 0, 1, 2 in 25, 62, and 13% of cases, respectively. There were no toxic deaths. The main grade 3 or 4 toxicities observed were neutropenia and emesis, reported twice as often in the combination arm. Among 213 patients with measurable disease, response rate was 13.6% (arm A) versus 23.6% (arm B; P = .056). No difference in HRQOL was observed on any of the scales. Median overall and 1-year survival in arms A and B were 8.8 (95% CI, 7.8 to 10.8) v 11.4 months (95% CI, 10.1 to 15), respectively, and 40% v 46%, respectively (P = .048).

Conclusion: A combination of raltitrexed and cisplatin improves overall survival compared with cisplatin alone. This study confirms that a combination of cisplatin and an antifolate is superior to cisplatin alone in patients with MPM, without harmful effect on HRQOL.

Bennett, Rachel; Maskell, Nick

Abstract

Abstract: Purpose of review: Although malignant pleural effusions are a common medical problem, research into their optimal management remains sparse. The aim of this review is to summarise recent developments in this area.

Recent findings: Talc remains the most efficacious pleurodesis agent. However, concerns remain about its side effect profile, with a number of cases of acute respiratory distress syndrome documented in the literature. A recent trial showed that using calibrated talc particles reduced the risk of morbidity from this procedure. Work on novel pleurodesis agents, such as transforming growth factor-[beta], appears to induce pleurodesis in animal models without any unwanted side effects. This is a promising development and human trials are awaited. With regard to mesothelioma, recent chemotherapy trials with pemetrexed/cisplatin and raltitrexed/cisplatin are encouraging and appear, for the first time, to offer a small but real survival advantage.

Summary: In the authors’ opinion, the major developments in the management of malignant effusions during the past year are the development of safer pleurodesis agents and the promise of better combination chemotherapy agents for the treatment of mesothelioma.

Porta C, Zimatore M, Bonomi L, Imarisio I, Paglino C, Sartore-Bianchi A, Mutti L.

Medical Oncology, I.R.C.C.S. San Matteo University Hospital, Piazzale C. Golgi, I-27100 Pavia, Italy. c.porta@smatteo.pv.it

Abstract

Within a single-institution phase II trial, we investigated the antitumor activity of the Raltitrexed-Oxaliplatin combination as second-line therapy for malignant pleural mesothelioma (MPM). Fourteen patients were enrolled and all were assessable for response. The trial was then closed because chemotherapy, though well tolerated, yielded no objective responses. The best response observed was disease stabilization in 4 patients only (28.57%), while the other 10 patients (71.42%) progressed despite treatment. Median time to progression (TTP) was 8 weeks (average: 9.85, range: 7-20), while median overall survival was just 14 weeks (average: 21.69, range: 9-66+).