A comprehensive analysis of the available literature assessing outcomes with partial pleurectomy and complete P/D in MPM has also been performed.62 If the analysis is restricted to those patients who underwent complete P/D, resultant median survivals ranged from 11.5 to 18.1 months, and 5-year survival rates from 0% to 23% were reported. Operative mortality rates were 0%–6%, and morbidity rates were not consistently stated. A recent systematic review of the literature to evaluate perioperative and long-term outcomes with EPP and P/D in MPM patients was conducted by Cao et al. Seven studies including 632 EPP patients and 513 P/D patients were analyzed. Perioperative mortality rates were significantly higher with EPP (6.8% versus 2.9%, P=0.02) as were perioperative morbidity rates (62% versus 27.9%, P<0.0001). Median survivals ranged from 13 to 29 months for P/D patients and from 12 to 22 months for EPP patients, with a trend in favor of P/D. The authors cautioned that while these results are based on non-randomized comparisons of the two procedures, the available data suggest lower rates of perioperative morbidity and mortality and similar (and possibly superior) long-term survival with P/D.63 At the present time, there is not complete agreement on the role of aggressive surgery in this disease or the most appropriate surgical procedure. All would agree that patients considered for these procedures require rigorous staging (as outlined earlier) to evaluate for mediastinal nodal involvement and to exclude extrathoracic spread. An extensive cardiac and pulmonary evaluation is also necessary to insure the patient’s ability to tolerate surgery. In addition, there is general agreement that patients with involvement of mediastinal lymph nodes or non-epithelioid histology do not appear to benefit from EPP, and current consensus guidelines from a number of international organizations also advocate that these procedures be restricted to centers with extensive experience in the management of this disease.64–68

Multimodality therapy

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Following either EPP or P/D, the rates of both local and distant recurrence are high.14,69,70 This provides a logical rationale for the evaluation of adjuvant therapy in this setting. Rusch et al reported their single-institution experience in 57 patients who received postoperative hemithoracic radiation to 54 G following EPP. They observed that this approach was feasible and appeared to decrease local recurrence rates in comparison to historical controls.70 More recently, neoadjuvant intensity-modulated RT to 25 G followed by a 5 G boost to “areas of risk” delivered prior to EPP was also shown to be safe and feasible in 25 patients with MPM.71 The role of adjuvant chemotherapy has also been evaluated to a very limited degree. The largest series includes 183 patients who underwent EPP at a single institution between 1980 and 1997.72 Postoperatively, they received a variety of different chemotherapy regimens (doxorubicin and cyclophosphamide with or without cisplatin or carboplatin and paclitaxel) followed by RT. For the 176 patients who survived EPP, the median survival was an encouraging 19 months. However, no firm conclusions can be drawn regarding the benefit of adjuvant therapy based on this single-arm study.

Several centers have evaluated the feasibility of preoperative chemotherapy followed by EPP followed by postoperative hemithoracic radiation. As shown in Table 2, 37%–71% of patients successfully completed all therapy, and in the intent-to-treat analyses, median survivals ranged from 14 to 25.5 months.73–79 While these survivals appear superior to those reported for patients receiving either surgery or chemotherapy alone, the impact of patient selection is likely significantly influencing these results. This is best illustrated by the MARS randomized feasibility study.80 In this trial, patients determined to be medically fit and eligible for EPP after a comprehensive evaluation received three cycles of platinum-based chemotherapy. Those who completed chemotherapy and were felt to still be candidates for EPP following restaging were randomized to EPP followed by radiation or no EPP. The first 50 patients were enrolled in the feasibility portion of the study to determine if accrual would allow for successful completion of a larger Phase III trial. While the accrual end point was not met, results from these 50 patients demonstrated median survivals in the EPP and no-EPP groups of 14.4 and 19.5 months, respectively. The hazard ratio for overall survival in the EPP group versus the no-EPP group was 1.9 (P=0.082). When one considers that overall survival in this trial was measured from the time of randomization (following the completion of preoperative chemotherapy), the median survivals for those patients in the no-EPP arm compare favorably with those shown in Table 4. In addition, Stahel et al recently reported a randomized Phase II trial of hemithoracic radiation versus observation in 54 MPM patients with complete macroscopic resection after EPP. All patients had also received neoadjuvant chemotherapy with cisplatin and pemetrexed for three cycles prior to EPP. There was no difference in median locoregional relapse-free survival between the two treatment arms, and the authors concluded that their findings did not support the routine use of hemithoracic radiation in MPM patients following neoadjuvant chemotherapy and EPP.81 Both the MARS and Stahel et al studies provide further evidence that patient selection is heavily influencing the outcomes reported in the single-arm multimodality trials and that definitive randomized trials will be necessary to truly delineate the role of multimodality therapy in MPM.

(To view a larger version of Table 4, click here.)