MPM is a locally aggressive disease. Complete macroscopic cytoreduction can only be achieved with EPP. It begins with exposure of the parietal pleura, followed by its dissection from the chest wall, diaphragm and mediastinum. Mediastinal node dissection is performed, followed by en bloc resection of the diaphragm, pericardium, lung and pleura. However, despite the best surgical efforts, the cancer recurs and patients eventually die from disease progression. Many centers have combined EPP with adjuvant radiotherapy and/or systemic chemotherapy (3,8-10). One of the advantages with EPP is that the lung has been removed. Consequently, radiation toxicity is not as limiting as it is for pleurectomy/decortication, and higher does can be delivered. Patients who can undergo complete cytoreductive surgery and tolerate adjuvant chemoradiation have experienced improved median survival as compared with historical controls.

The present study demonstrated locoregional recurrence is the most common cause of treatment failure after complete EPP. The local disease recurrence rate was 51% and the median local DFS was 22 months. This could be related to the presence of microscopic residual disease and/or biological aggressiveness of the tumor. Baldini and co-workers studied the patterns of failure after EPP with or without adjuvant chemoradiotherapy and found a recurrence rate of 54% and a median time to first failure of 19 months (18). Stewart and colleagues reported a local disease recurrence rate of 68% and a median time to local disease progression of 21 months after EPP (19). However, it has to be acknowledged that a direct comparison of recurrence rates between series is difficult as patient characteristics and treatment protocols may differ.

One of the objectives of this study was to identify clinical and treatment-related data that influence the risk of treatment failure. The univariate analysis indicated that a short local DFS was associated with absence of prior occupational exposure of asbestos, non-epithelial histologic subtype and not receiving adjuvant radiotherapy. The association between the absence of prior occupational exposure of asbestos and reduced local DFS is unclear and this prognostic factor fell out in the multivariate analysis. A possible explanation of this correlation is related to both the absence of an appreciable threshold for asbestos-induced mesothelioma and the fact that MPM can occur with very low-level exposure (20,21). It has been hypothesized that some patients may have higher inherent susceptibility and these susceptible individuals may suffer from more aggressive disease (22). Outside this high susceptibility group, there may be a dose-response relationship between asbestos fiber burden and the prognosis (22).

This paper confirmed that patients with sarcomatoid or biphasic histologic subtypes fared as a group less well than patients with epithelial histology. Stewart et al. also showed that in patients who underwent EPP, epithelial histology was associated with delayed disease progression when compared with biphasic subtype (19). Sugarbaker and colleagues identified that the individuals with epithelial histology who had no positive lymph nodes and complete EPP achieved a 46% estimated 5-year survival (2). A limitation of EPP surgery from a surgical oncologic standpoint has been that the margin of resection is usually a single tissue plane, which means that with an aggressive histology, EPP may be insufficient to result in a reliable cure.

Adjuvant radiotherapy after EPP was described by the Brigham group in 1997 (18). Thirty-five of 49 patients were given four to six cycles of postoperative chemotherapy followed by radiation (median dose 31 Gy). Sixteen irradiated patients developed local recurrence (18). They noted that many patients developed disease recurrence in the chest and abdomen despite aggressive therapy.The relapse in the abdomen was hypothesized to result from the continuity of the chest and peritoneal cavity after resection of the diaphragm. This establishment of the continuity of the chest and abdominal cavities presumably allows tumor cells disseminate in the abdomen. In the present study, although the most common site of relapse after EPP was the ipsilateral thorax, 12% of patients presented with abdominal recurrence. Encouraging results were reported from Memorial Sloan Kettering Cancer Center. From 1995 to 1998, 54 patients underwent EPP followed by adjuvant radiotherapy (median dose 54 Gy) (3). The median survival was 18 months. Only 7 patients (13%) developed locoregional treatment failure and in contrast, 35 patients (65%) had distant recurrence, with the peritoneum and contralateral pleural being the most common sites (3). The present study demonstrated that adjuvant radiotherapy was associated with an improved local disease control compared with patients who did not receive radiotherapy. However, outside the setting of a randomized controlled trial, subgroup analysis comparing the patients with or without adjuvant treatments is fraught with potential biases, in that the beneficial treatment effects may be attenuated by confounding factors, such as patient selection and performance status that were not revealed by this comparative analysis.