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

Flores RM, Routledge T, Seshan VE, Dycoco J, Zakowski M, Hirth Y, Rusch VW.

Thoracic Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. floresr@mskcc.org

Abstract

Objectives: The propensity of malignant pleural mesothelioma to metastasize to N1 or N2 nodes and their corresponding prognostic value is unclear. The American Joint Committee on Cancer staging system groups N1 and N2 disease together as stage III. The goal of this study was to define the prognostic value of specific nodal stations.

Methods: Patients with malignant pleural mesothelioma who underwent resection were identified from an institutional database. Nodal stations were defined by the American Joint Committee on Cancer lung cancer node map classification. Survival was analyzed by the Kaplan–Meier method, log-rank test, and Cox proportional hazards analysis.

Results: From 1990 to 2006, 348 patients were identified: 279 men and 69 women with a median age of 67 years (range 26–85 years). Extrapleural pneumonectomy was performed in 223 cases, and pleurectomy/decortication was performed in 125 cases. Survival differences (P < .01) were observed between 2 groups: N0 or N1(+) (median survival = 19 months) and N2(+), N2/N1(+) and internal thoracic(+) (median survival = 10 months). Survival was influenced by the number of involved N2 stations (0, 1, 2, or more: P < .001). Multivariate analysis grouping all N2 and internal thoracic(+) versus N1(+) and N0 demonstrated a hazard ratio for survival of 1.7 (P < .0001) controlling for T3/T4 status (hazard ratio = 1.3, P < .01), non-epithelioid histology (hazard ratio = 1.7, P < .0001), extrapleural pneumonectomy (1.1, P = .4), and male gender (hazard ratio 1.4, P < .01).

Conclusion: This study confirms a preferential pattern of drainage of malignant pleural mesothelioma to N2 rather than N1 lymph nodes, but suggests that N1 only nodal involvement should be classified as lower stage disease. Multiple N2 nodal site involvement could potentially be classified as higher stage disease than single station N2. Our results emphasize the need for larger, confirmatory multicenter studies that could lead to revision of the current staging system.

Ramalingam SS, Belani CP.

Emory University School of Medicine, Winship Cancer Institute, Atlanta, Georgia, USA.

Abstract

Malignant pleural mesothelioma clinically manifests after decades of initial exposure to etiologic agents, such as asbestos, and presents with nonspecific symptoms such as dyspnea, pain, or weight loss. In patients with limited, resectable disease, surgical therapy with extrapleural pneumonectomy or pleurectomy is recommended, although, it is unclear which approach is superior. Radiation has a limited role and is used primarily for palliation. The palliative efficacy of traditional chemotherapeutic agents and combination regimens is modest at best. The combination of cisplatin and pemetrexed, a novel multitargeted antifolate agent, is the approved "standard of care" for patients with unresectable malignant pleural mesothelioma. A number of molecularly targeted agents are currently under evaluation for mesothelioma such as the Histone deacetylase (HDAC) inhibitors that have demonstrated promising anticancer activity. Vorinostat, a small molecule inhibitor of HDAC, which targets select members of class I and II HDACs, has shown early evidence of activity and is currently being evaluated in a randomized study for patients who progress with standard therapy for advanced mesothelioma. It is hoped that the HDAC inhibitors and other novel targeted agents will pave the way for improved outcomes for patients with this disease.

Kent M, Rice D, Flores R.

Thoracic Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

Abstract

Opinion statement: The clinical presentation of malignant pleural mesothelioma (MPM) is nonspecific. The process to obtain the correct diagnosis can be challenging and requires a high index of suspicion. Once the diagnosis is made, there is no universally accepted standard of care and treatment decisions are strongly influenced by physician bias. Physicians who see few numbers of patients tend to treat based on symptoms alone by drainage of the pleural effusion and talc pleurodesis, while physicians at several tertiary referral centers tend to take an aggressive multimodality approach incorporating surgical resection, chemotherapy, and radiation. The primary goal of surgery in this setting is the resection of all gross disease. The choice of operation, extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D), depends on disease stage, pulmonary function, philosophy of the treating physician, and type of planned adjuvant therapy.

Nakas A, Trousse DS, Martin-Ucar AE, Waller DA.

Department of Thoracic Surgery, Glenfield Hospital, Groby Road, Leicester LE3 9QA, United Kingdom.

Abstract

Objective: To identify the optimal debulking procedure in patients with malignant pleural mesothelioma who are not suitable for extrapleural pneumonectomy (EPP).

Methods: We reviewed 102 consecutive patients (93 male; 9 female, mean age 63 years) who were not suitable for EPP because of either advanced tumour stage or suboptimal fitness. Patients underwent either a non-radical tumour decortication to obtain lung expansion (group NR) or latterly a radical pleurectomy/decortication to obtain macroscopic tumour clearance (group R). We analysed the comparative perioperative courses and long-term survival.

Results: The two groups were similar for age and gender distribution but epithelioid type was more predominant in group R: 78% compared to 55% epithelioid in group NR. Thirty-day mortality was similar (5.9% in group R and 9.8% in the group NR, p = 0.36) but 90-day mortality was significantly higher in the group NR (29.4% vs 9.8% in group R, p = 0.012). More patients in group R received adjuvant chemotherapy (65% vs 28%, p = 0.000) and radiotherapy (65% vs 26%, p = 0.000). Median survival for all cell types was significantly higher in group R (15.3 months vs 7.1 months, p < 0.000). Group R survival rates at 1, 2, 3 and 4 years were 53, 41, 25 and 13%, respectively while for group NR they were 32, 9.6, 2 and 0%, respectively. For epithelioid cell type there was still a significant median survival advantage in group R (25.4 months vs 10.2 months, p < 0.000), but there was no difference for sarcomatoid (9.3 months vs 3.2 months, p = 0.16) or biphasic cell types (9.4 months vs 7 months, p = 0.38).

Conclusion: If a patient with epithelioid MPM is fit enough to tolerate a thoracotomy then macroscopic clearance of the tumour is the preferred option as part of a multimodality regime including chemotherapy.

Keywords: Malignant pleural mesothelioma; Radical surgery; Pleurectomy/decortication

Neragi-Miandoab S, Winer S, Sugarbaker DJ.

New York Medical College, School of Medicine, New York, USA.

Abstract

Extrapleural pneumonectomy (EPP) and pleurectomy are the surgical procedures for the treatment of pleural mesothelioma. However, EPP increases the risk for postoperative atrial fibrillation (AF) in this patient population, which might be partly explained by increase in right heart stress after EPP. We conducted a retrospective chart review of 130 patients who were treated for malignant pleural mesothelioma with either pleurectomy or EPP between 2001 and 2003 in a single institution. Risk factors for AF were evaluated with logistic regression and the postoperative AF events were evaluated. The absence of a history of cardiac arrhythmia was an inclusion criterion. Seventy patients (excluding the 3 patients with a prior history of AF) underwent EPP and 57 patients underwent pleurectomy. The mean ages were 60+/-11 and 63+/-13, and the male to female ratios were 50/20 and 44/13, respectively. Postoperative AF was observed in 45 patients with 36 (51%) of these cases occurring after EPP and 9 (17%) after pleurectomy (p<0.0001). There were no significant differences between the two treatment groups for gender, age, side of affected lung, preoperative heart rate and history of beta-blocker use, coronary heart disease, and chronic obstructive pulmonary disease. There were significant differences between the two groups for cancer histology (p=0.03) with the EPP group having a larger proportion of epithelial-type histology. Through logistic regression, EPP (OR=7.1, 95% CI: 2.9, 17.8) and age over 65 (OR=2.9, 95% CI: 1.2, 6.8) were found to be risk factors for AF. Abnormal cardiac structure and function were identified as important possible confounder, which could not be adequately evaluated due to missing data. Most of these patients had at least one additional expected risk factor for AF. EPP versus pleurectomy and age over 65 are risk factors for postoperative AF. The increased odds of having AF after EPP could be due to right heart stress caused by pneumonectomy. Increased right heart stress might not be sufficient to cause AF alone, but may be an important risk factor that warrants further investigation.

Keywords: Right heart stress; Extrapleural pneumonectomy; Pleurectomy; Atrial fibrillation.

Hasegawa S, Tanaka F.

Department of Thoracic Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, 663-8501, Japan, hasegawa@hyo-med.ac.jp.

Abstract

Malignant pleural mesothelioma (MPM) is associated with a poor prognosis; and to make things worse, its incidence is increasing throughout the world. Surgical management of MPM is comprised of two aspects: diagnosis and resection. Surgical biopsy with thoracoscopy provides a higher yield but a higher rate of tumor cell seeding than blind biopsy. In some surgical cases, extended surgical staging with mediastinoscopy, laparoscopy, and contralateral thoracoscopy is required for the preoperative evaluation for resectablity. There are two types of surgical resection for MPM. Pleurectomy/decortication (P/D) involves removal of as much of the visceral, parietal, and pericardial pleura and the tumor as possible without removing the underlying lung. Because P/D is less radical but less invasive compared to extrapleural pneumonectomy (EPP), it can be tolerated by poor-risk patients. EPP comprises en bloc resection of visceral, parietal, and pericardial pleura and adjacent components such as ipsilateral lung, pericardium, and diaphragm, without opening the pleural cavity. EPP was considred a highly dangerous procedure with a surgical mortality of more than 30% decades ago, but its current operative mortality/morbidity rates are 4%-9% and 60%, respectively. As macroscopic complete resection is the primary goal of surgery for MPM because of its diffuse intrapleural growth, surgical resection alone is associated with poor survival. In this context, combination therapy with surgery plus chemotherapy and/or radiotherapy is currently considered the standard treatment for patients with respectable MPM. A national survey of EPP was conducted recently in Japan, and a few multicenter clinical trials will start soon

Keywords: Malignant pleural mesothelioma – Pleurectomy – Extrapleural pneumonectomy – Chemotherapy – Multimodality treatment

van Sandick JW, Kappers I, Baas P, Haas RL, Klomp HM.

Department of Surgical Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. j.v.sandick@nki.nl

Abstract

Background: A minority of patients with malignant pleural mesothelioma (MPM) are considered for surgery. To achieve a microscopically radical resection, combination with other treatment modalities is mandatory. The most effective combination is unknown. In our institute we have retrospectively analyzed the results of two combined modality regimens containing surgery.

Patients: Between January 2002 and September 2005, 15 MPM patients were treated with extrapleural pneumonectomy (EPP) and postoperative hemithoracic radiation (RT; 54 Gy). Previously, between January 1999 and December 2001, 20 patients underwent a combination of cytoreductive surgery – pleurectomy or EPP – and intraoperative hyperthermic intrathoracic chemotherapy (HITHOC), followed by radiotherapy to the thoracotomy scar and drainage tracts (24 Gy).

Results: The median operating time for EPP/RT was shorter (5.3 versus 6.9 h; P < 0.0001). Postoperative complications occurred in 8 EPP/RT patients (53%) and in 14 HITHOC patients (70%). Two HITHOC patients died postoperatively. Median overall survival was 29 months for EPP/RT patients and 11 months for HITHOC patients (P = ns). The median time to local recurrence was not reached for EPP/RT patients, and was 9 months for HITHOC patients (P = 0.003). Local control was achieved in ten EPP/RT patients (67%) with a follow-up of 5–59 months compared to four HITHOC patients (20%) with a follow-up of 4–27 months.

Conclusions: In highly selected patients local control can be achieved with combination therapy but is accompanied by a high rate of (surgical) complications. Distant failure rates warrant further studies exploring the role of systemic chemotherapy while the use of cytoreductive surgery with intraoperative chemoperfusion for MPM is not supported.

Keywords: Malignant pleural mesothelioma – Extrapleural pneumonectomy – Intraoperative hyperthermic intrathoracic chemotherapy – Adjuvant radiotherapy – Combined modality treatment

Flores RM, Pass HI, Seshan VE, Dycoco J, Zakowski M, Carbone M, Bains MS, Rusch VW.

Thoracic Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. floresr@mskcc.org

Abstract

Objective: The optimal procedure for resection of malignant pleural mesothelioma is controversial, partly because previous analyses include small numbers of patients. We performed a multi-institutional study to increase statistical power to detect significant differences in outcome between extrapleural pneumonectomy and pleurectomy/decortication.

Methods: Patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy or pleurectomy/decortication at 3 institutions were identified. Survival and prognostic factors were analyzed by the Kaplan–Meier method, log-rank test, and Cox proportional hazards analysis.

Results: From 1990 to 2006, 663 consecutive patients (538 men and 125 women) underwent resection. The median age was 63 years (range, 26–93 years). The operative mortality was 7% for extrapleural pneumonectomy (n = 27/385) and 4% for pleurectomy/decortication (n = 13/278). Significant survival differences were seen for American Joint Committee on Cancer stages 1 to 4 (P < .001), epithelioid versus non-epithelioid histology (P < .001), extrapleural pneumonectomy versus pleurectomy/decortication (P < .001), multimodality therapy versus surgery alone (P < .001), and gender (P < .001). Multivariate analysis demonstrated a hazard rate of 1.4 for extrapleural pneumonectomy (P < .001) controlling for stage, histology, gender, and multimodality therapy.

Conclusion: Patients who underwent pleurectomy/decortication had a better survival than those who underwent extrapleural pneumonectomy; however, the reasons are multifactorial and subject to selection bias. At present, the choice of resection should be tailored to the extent of disease, patient comorbidities, and type of multimodality therapy planned.

Aarts F, Bleichrodt RP, Oyen WJ, Boerman OC.

Department of Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Abstract

Radioimmunotherapy (RIT) potentially is an attractive treatment for radiosensitive early-stage solid tumors and as an adjuvant to cytoreductive surgery. Topical administration of RIT may improve the efficacy because higher local concentrations are achieved. We reviewed the results of locally applied radiolabeled monoclonal antibodies for the treatment of solid tumors. Intracavitary RIT in patients with ovarian cancer and glioma showed improved targeting after local administration, as compared to the intravenous administration. In addition, various studies showed the feasibility of locally applied RIT in these patients. In studies that included patients with small-volume disease, adjuvant RIT in ovarian cancer and glioma showed to be at least as effective as standard therapy. The information about RIT for peritoneal carcinomatosis of colorectal origin is scarce, while results from preclinical data are promising. RIT may be applied for other, relatively unexplored indications. Studies on the application of radiolabeled antibodies in early urothelial cell cancer have been performed, showing that intracavitary RIT may hold a promise. Moreover, in patients with malignant pleural mesothelioma or malignant pleural effusion, RIT may play a role in the palliative treatment. Intracavitary RIT limits toxicity and improves tumor targeting. RIT is more effective in patients with small-volume disease of solid cancers. RIT may have potential for palliation in patients with malignant pleural mesothelioma or malignant pleural effusion. The future of RIT may, therefore, not only be in the inclusion in contemporary multimodality treatment, but also in the expansion to palliative treatment.