CONCLUSION: These preliminary results suggest that (18)F-FDG-CI appears to be an accurate method to diagnose and to define the extent of disease in patients with diffuse malignant pleural mesothelioma.

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RESULTS: E-cadherin was expressed in all adenocarcinomas and in 22% of the mesotheliomas. TTF-1 expression was detected in 69% of the adenocarcinomas and none of the mesotheliomas. Positive staining with polyclonal anticalretinin was detected in 80% of the mesotheliomas and 6% of the adenocarcinomas. N-cadherin was expressed in 78% of mesotheliomas and 26% of adenocarcinomas. Thrombomodulin was expressed in 6% of the adenocarcinomas and in 53% of the mesotheliomas. Cytokeratin 5/6 expression was detected in 6% of the adenocarcinomas and 63% of the mesotheliomas. The results were compared with the standard laboratory panel for mesothelioma diagnosis: anticarcinoembryonic antigen (anti-CEA), LeuM1, BerEP4, and HBME-1.

CONCLUSION: Of the antibodies used in this study, E-cadherin was 100% sensitive for pulmonary adenocarcinoma and TTF-1 was 100% specific for pulmonary adenocarcinoma. The application of these two antibodies alone was adequate for the diagnosis of 69% of adenocarcinomas and 78% of mesotheliomas. Where TTF-1 is negative and E-cadherin is positive, a secondary panel of antibodies, including BerEP4 and LeuM1 (CD15) and antibodies directed against CEA, calretinin, cytokeratin 5/6, thrombomodulin, and N-cadherin, is required for differentiation between malignant mesothelioma and pulmonary adenocarcinoma.

Our previous phase II study of cisplatin and gemcitabine in malignant mesothelioma showed a 47.6% (95% CI 26.2-69.0%) response rate with symptom improvement in responding patients. Here we confirm these findings in a multicentre setting, and assess the effect of this treatment on quality of life and pulmonary function. Fifty-three patients with pleural malignant mesothelioma received cisplatin 100 mg m(-2) i.v. day 1 and gemcitabine 1000 mg m(-2) i.v. days 1, 8, and 15 of a 28 day cycle for a maximum of six cycles. Quality of life and pulmonary function were assessed at each cycle. The best response achieved in 52 assessable patients was: partial response, 17 (33%, 95% CI 20-46%); stable disease, 31 (60%); and progressive disease, four (8%). The median time to disease progression was 6.4 months, median survival from start of treatment 11.2 months, and median survival from diagnosis 17.3 months. Vital capacity and global quality of life remained stable in all patients and improved significantly in responding patients. Major toxicities were haematological, limiting the mean relative dose intensity of gemcitabine to 75%. This schedule of cisplatin and gemcitabine is active in malignant mesothelioma in a multicentre setting. Investigation of alternative scheduling is needed to decrease haematological toxicity and increase the relative dose intensity of gemcitabine whilst maintaining response rate and quality of life.

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Treatment of malignant pleural mesothelioma

Minerva Chir 2001 Jun;56(3)243-50

Melloni G, Puglisi A, Ferraroli GM,
Universita Vita-Salute San Raffaele, Divisione e Cattedra di Chirurgia Toracica, Ospedale San Raffaele, Milan, Italy.

BACKGROUND:  In this study all patients observed between January 1993 and October 1997 with malignant pleural mesothelioma (MPM) have been analyzed in order to describe the impact of treatment modality on survival.

METHODS:  Medical records of 56 patients with MPM (44 male, 12 female, median age = 59 yrs) were reviewed. In 34 cases the histotype was ephithelial, in 4 sarcomatoid, in 4 mixed, in 3 desmoplastic, and in 11 not specified. Four treatment modalities were identified1) Surgery (subtotal pleurectomy) = 20 patients; 2) Chemoterapy = 19 patients; 3) Surgery+Chemo-therapy = 8 patients; 4) Supportive care = 9 patients.

RESULTS:  The median survival was1) Surgery = 12.4 months; 2) Chemotherapy = 7.5 months; 3) Surgery+Chemotherapy = 12 months; 4) Supportive care = 11.4 months. Using univariate analysis, 8 prognostic factors were studied (age, sex, asbestos exposure, side, histotype, performance status, stage, treatment). Among these, only the stage and the performance status had shown a prognostic value on survival (p<0.05), while the treatment modality had not significantly influenced the prognosis. Using multivariate analysis only performance status showed to be significatively associated with survival (p=0.01 and odds ratio = 1.9, I.C. 1.2-3.2).

CONCLUSIONS:  Despite the limits of a retrospective study, personal experience confirms the ineffectiveness of current therapeutical approaches to MPM. A better understanding of MPM is required to develop new therapeutical approaches and alter the dismal prognosis of this disease.

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Trimodality management of malignant pleural mesothelioma

Eur J Cardiothorac Surg 2001 Mar;19(3)346-50

Maggi G, Casadio C, Cianci R, Rena O, Ruffini E. Department of Thoracic Surgery, University of Torino, San Giovanni Battista Hospital, via Genova 3, 10126, Torino, Italy. giuliano.maggi@unito.it

OBJECTIVE:  We reviewed our experience with trimodality management of malignant pleural mesothelioma (MPM).

METHODS:  From September 1998 to August 2000, 32 consecutive patients with histological diagnosis of MPM underwent trimodality therapy, including surgery followed by adjuvant chemotherapy and radiation therapy. Surgery consisted of pleurectomy/decortication (P/D) or pleural-pericardial-pneumonectomy and diaphragm (PPPD). Pre-operative staging according to the Brigham Staging System was accomplished using computed tomography (CT) and magnetic resonance imaging (MRI); patients with evident extrapleural spread were excluded.

RESULTS:  Our series included 21 men and 11 women with a median age of 53.5 years (range 40-69). Histologically, there were 26 epithelial, four mixed and two sarcomatous MPM. Post-surgical staging was as followssix patients were at Stage I; of these, two received a P/D and four a PPPD. Ten patients were at Stage II and all received a PPPD; 16 patients were at Stage III (under-staged pre-operatively)of these, nine patients presented extrapleural lymph node metastases (N2) and all received a PPPD, seven patients presented with chest wall or mediastinal invasion (T4) with macroscopic residual tumour, and all received a de-bulking P/D. We observed major complications in ten patientssix bleeding, two respiratory insufficiency and two nerve paralysis. There were two perioperative deaths (6.25% mortality). Twenty-seven patients out of 30 surviving surgery had a follow-up greater than 6 months; 21 patients out of 27 are alive with a median follow-up of 12.5 months.

CONCLUSIONS:  (1) Trimodality therapy is feasible in selected patients with MPM and has an acceptable operative mortality rate. (2) Our current pre-operative staging based on CT/MRI looks rather inaccurate and needs to be improved. (3) The high rate of post-surgical N2 patients or with diffusion to the inferior surface of the diaphragm may suggest the use of routine mediastinoscopy and laparoscopy for a more appropriate patient selection.

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Malignant pleural mesothelioma

Cancer Treat Res 2001;105327-73

Ho L, Sugarbaker DJ, Skarin AT. M.D. Anderson Cancer Center, Houston, TX 77030, USA.

Malignant pleural mesothelioma remains a difficult tumor to treat, much less cure. Currently, the best chance for long-term survival lies with early diagnosis and aggressive surgical extirpation, but given the typically long delay between the onset of symptoms and diagnosis, this is only possible with a high index of suspicion and an aggressive diagnosis workup. Early referral to a tertiary center experienced in the treatment of MPM may be important for several reasons(1) decreased risk of tumor spread along multiple thoracenesis/biopsy tracts, (2) the availability of specialized pathologic assays for definitive diagnosis, (3) the availability of critical staging modalities (aggressive mediastinoscopy +/- thoracoscopy, MRI scans performed according to specific mesothelioma protocols, and perhaps PET scans), (4) surgical experience with pleurectomy/decortication and/or extrapleural pneumonectomy, that may decrease morbidity and mortality, and (5) the availability of novel adjuvant protocols. Single-modality therapy is unlikely to result in long-term survival. Aggressive surgery is required for optimal debulking, and extrapleural pneumonectomy may offer better local control compared with pleurectomy/ecortication. Delivery of optimal radiation schedules, which may involve large fractions as well as large total doses, is limited by the presence of nearby dose-limiting structures. Current chemotherapy is severely lacking in producing objective responses and improved survival although gemcitabine and IL-2 may be active agents to be combined with radiation and/or other agents. Hyperthermia, photodynamic therapy, intracavitary therapy, and gene therapy are all relatively new techniques under active investigation that should be supported by enrollment in on-going protocols. Predictably, many of these techniques provide greater benefit when used in the setting of adjuvant protocols or minimal residual disease, emphasizing the importance of multimodality therapy.

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Mesothelioma of the pleura and peritoneum. Diagnostic and therapeutic sequelae

Dienemann H, Trainer C. Chirurgische Abteilung, Thoraxklinik-Heidelberg gGmbH.

In patients with pleural or peritoneal mesothelioma, surgery is a technically difficult procedure. Whereas those rare forms of localized pleural mesotheliomy are being detected incidentally and can be cured by complete resection, most patients with diffuse malignant mesothelioma present with an advanced stage of disease. Most of these patients survive less than 12 months irrespective of the treatment modality. For diffuse pleural mesothelioma, some favorable prognostic factors were identifiedIMIG (International Mesothelioma Interest Group), stages I and II, epithelial type, age under 50, female gender. In IMIG stages I and II, extended pleuropneumonectomy followed by chemo- and/or radiotherapy is recommended. For this subset of patients, a median survival time of between 20 and 30 months is reported. Pleurectomy and decortication are recommended as palliative surgical strategies against pleural effusion. In patients with technically inoperable infiltration of the thoracic wall, irradiation is helpful; sometimes partial remission and relief of pain can be achieved by chemotherapy.

Mesothelioma--VATS biopsy and lung mobilization improves diagnosis and palliation

Eur J Cardiothorac Surg 1999 Dec;16(6)619-23

Grossebner MW, Arifi AA, Goddard M, Ritchie AJ. Department of Cardiothoracic Surgery, Papworth Hospital, Papworth Everard, Cambridge, UK.

OBJECTIVES:  Mesothelioma is an increasingly frequent malignancy in which diagnosis is often delayed and disease diagnosed at an advanced stage. Earlier diagnosis and therapeutic intervention that can control recurrent pleural effusion may improve outlook and survival.

METHODS:  A prospective series of 25 patients in whom mesothelioma was suspected was referred for histological diagnosis by video assisted-thoracoscopy (VAT) after failure of other methods. At the same operative procedure drainage of pleural effusion, cytoreductive pleurectomy and lung mobilization was performed where possible. Complete follow-up was obtained.

RESULTS:  All patients had a histological diagnosis (100%) from the material sent for biopsy. In 23 patients this was mesothelioma, in two patients chronic empyema. All patients undergoing drainage of effusion, cytoreductive pleurectomy and lung mobilization subsequentl were diagnosed of having mesothelioma stages III to IV. Fifteen out of 21 who underwent lung mobilization had closure of the pleural space. Post operative air leak in this group was a mean of 5 days (2-12 days). Recurrent effusion occurred in only one patient. Eleven patients remain alive at 1-2 years post operation with no hospital admissions for recurrent pleural effusion. In the six out of 21 who did not have closure of the pleural space, one remained alive 9 months post surgery. Five died within 1-6 months of the procedure. The average number of further hospital admissions for repeat drainage of effusion was 3 (1-6).

CONCLUSIONS:  VATs provides adequate tissue for histological diagnosis where other methods fail. At the same operative sitting it provides a therapeutic intervention that allows drainage of effusion cytoreductive pleurectomy and lung mobilization in a significant number of cases. Where the pleural space can be closed this results in significantly fewer hospital admissions and appears to improve quality of life and length of survival. The price is a longer hospital stay due to prolonged air leak.

Contemporary management of malignant pleural mesothelioma

Oncologist 1999;4(6)488-500

Butchart EG. University Hospital of Wales, Cardiff, United Kingdom. egbutchart@aol.com

The rapidly increasing incidence of malignant pleural mesothelioma underlines the urgency to achieve a consensus in the management of this tumor, which is biologically distinct from most other tumors. For patients with stage I tumors of epithelial type and good performance status, pleuropneumonectomy combined with chemotherapy and radiotherapy provides the best chance of prolonged survival, but further investigation is required to determine the optimum combination of adjuvant therapy. Debulking pleurectomy/decortication combined with adjuvant therapy is a worthwhile alternative for patients with more advanced disease, impaired performance status or tumors of less favorable histology (sarcomatous or biphasic). More clinical trials are urgently required to identify better adjuvant therapy for tumors containing sarcomatous elements. On currently available evidence, neither radiotherapy nor chemotherapy offer worthwhile prolongd disease control when used in isolation, although both have an important role as part of multimodality therapy. Hyperthermia may enhance the effect of both radiotherapy and chemotherapy, and newer radiosensitizing agents also need evaluating. Research into immunotherapy and gene therapy suggests that these newer approaches may have a place if tumor volume is small. In practice they will probably need to be combined with other therapeutic modalities, and further clinical trials are required. Consensus in mesothelioma management currently remains elusive but it seems clear that the way forward will involve striving for much earlier diagnosis, the use of multimodality therapy and collaboration between centers with special expertise in mesothelioma treatment to organize multicenter trials.

Chest 1999 Dec;116(6 Suppl)450S-454S

Grondin SC, Sugarbaker DJ. Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

STUDY OBJECTIVES:  Malignant pleural mesothelioma (MPM) is predominantly a local/regional disease that results in a survival time that ranges from 4 to 12 months without treatment. Single-modality therapy using surgery, chemotherapy, or radiotherapy alone is largely ineffective. The objective of the study was presentation of the use of pleuropneumonectomy in a multimodality treatment setting and the results.

DESIGN:  Didactic presentation.

SETTING:  Academic tertiary-care hospital.

PATIENTS:  One hundred eighty-three patients who underwent multimodality therapy.

INTERVENTIONS:  Of all the single-modality treatment approaches, pleuropneumonectomy has been associated most consistently with long-term disease-free survival and has provided the greatest amount of tumor cytoreduction. The technique of pleuropneumonectomy traditionally has been linked with high perioperative mortality and morbidity when compared with that of other cytoreductive techniques such as pleurectomy/decortication. Recently, improvements in operative mortality (< 5%) have been reported, largely due to improvements in patient selection and perioperative management. Multimodality therapy, including chemotherapy, radiotherapy, and extrapleural pneumonectomy, was used to treat patients.

RESULTS:  Outcomes were presented for 183 patients with MPM who underwent multimodality therapy.

CONCLUSIONS:  With the development of multimodality therapy, pleuropneumonectomy followed by sequential chemotherapy and radiotherapy has demonstrated a significant survival benefit, especially for patients who have epithelial tumor histology, tumor-free resection margins, and tumor-free extrapleural node status.

Surgical treatment of mesothelioma pleurectomy

Chest 1999 Dec;116(6 Suppl)446S-449S

Roberts JR. Department of Cardiac and Thoracic Surgery, Vanderbilt Hospital, Nashville, TN, USA.

Malignant diffuse mesothelioma is the most common type of mesothelioma, with a median survival ranging from 8.5 to 18 months after diagnosis. Good performance status, absence of chest pain, age < 50 years, and epithelial histology are all associated with improved survival. Several investigators have described staging systems for this tumor and have emphasized the importance of thoracoscopy in the diagnosis and staging of the disease. Pleurectomy is the most common surgery employed to manage patients with diffuse mesothelioma, and this procedure is associated with minimal postoperative morbidity and mortality. Because mesothelioma usually recurs locally after surgery, efforts at optimizing local control have included both intraoperative phototherapy and chemotherapy. However, neither of these techniques has demonstrated any significant benefit to date and thus should not be considered as standards of care. No studies have compared pleurectomy to extrapleural pneumonectomy (EPP) in randomized trials. However, nonrandomized series suggest a significant improvement in disease-free survival for those undergoing EPP versus pleurectomy. Other data suggest that EPP may improve local control but may predispose the patient to distant metastases. A randomized comparison of these techniques may be beneficial in identifying the most effective procedure for patients with malignant diffuse mesothelioma.

Important prognostic factors in patients with malignant pleural mesothelioma, managed surgically

Ann Thorac Surg 1999 Nov;68(5)1799-804

Related Articles, Books Rusch VW, Venkatraman ES. Department of Surgery, and Biostatistics Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. ruschv@mskcc.org

BACKGROUND:  The factors influencing outcome after resection of malignant pleural mesothelioma (MPM) are controversial. This analysis of a prospective surgical database identifies important prognostic factors. \

METHODS:  Tumors were staged by the International Mesothelioma Interest Group staging system, and patients were followed until death. Prognostic factors were analyzed by log rank and Cox regression, and were considered significant if p was less than 0.05.

RESULTS:  From Oct 1983 to May 1998, 231 patients underwent thoracotomy, 115 had extrapleural pneumonectomy (EPP), and 59 pleurectomy/decortication (P/D). Among patients having EPP or P/D, 142 received adjuvant therapy. The median survival for stage I tumors was 29.9 months, for stage II 19 months, for stage III 10.4 months, and for stage IV 8 months. By multivariate analysis, stage, histology, gender, adjuvant therapy, but not the type of surgical resection, were significant.

CONCLUSIONS:  The better survival previously reported for P/D compared with EPP is not seen in a large database with long follow-up. Stages I and II have better survival rates than generally assumed for MPM. Locally advanced T and N status, and nonepithelial histology, identify poor prognosis patients who should be considered for novel treatment regimens.

*** POSTED AUGUST 1, 2001 ***