Malignant pleural mesothelioma (MPM) is a tumor that arises from the surfaces of the pleural and peritoneal cavities, the pericardium, or the tunica vaginalis. There are over 2,000 cases in the United States each year, with about 80% originating from the pleura. Patients with MPM most commonly present with symptoms of dyspnea or pleuritic chest pain. Chest roentgenograms will often show a unilateral pleural effusion. In addition, in light of the association between mesothelioma and asbestos exposure, many plain films in MPM will also exhibit pleural plaques.
To date, treatment options have been limited. A small minority of mesothelioma patients may be appropriate for surgical intervention and multimodality therapy. For those patients with unresectable disease, systemic treatment with chemotherapy has achieved some success. Recent efforts have focused on exploring the role of multimodality therapy, improving patient selection for this aggressive strategy, and investigating new agents and new combinations of systemic therapies in MPM. Here we review recent data presented at the 2007 ASCO Meeting (Chicago, IL, June 2007) and at the 12th World Conference on Lung Cancer (Seoul, South Korea, September 2007).
Role of Surgery
The role of surgery in the management of MPM remains unclear. As yet, there have been no published randomized results comparing surgery to nonoperative management with conventional chemotherapy. However, among the case series that exist, there have been some encouraging preliminary results. In a case series published by Sugarbaker et al., there was a group of 31 patients who had epithelioid histology, clear resection margins, and no extrapleural nodes. For this specific group, median survival was 51 months. These results have encouraged investigators at a number of centers to attempt to refine both the optimum treatment regimen and the selection of appropriate patients.
At the ASCO 2007 Meeting in Chicago, IL, Krug et al. presented results of a multi-center Phase II feasibility study of trimodality therapy. Eligible patients had T1-3, N0-2, M0 malignant pleural mesothelioma, demonstrated good performance status (ECOG PS 0-1), were treatment-naïve, and had a post-operative FEV1 > 35%. Planned therapy included four cycles of cisplatin and pemetrexed. Following chemotherapy, non-progressing patients underwent extrapleural pneumonectomy followed by hemithoracic radiation to a total of 54 Gy. The 75 patients enrolled in the trial were predominantly male (70%) and most had epithelioid histology (80%). A total of 87% completed the planned four cycles of chemotherapy. Fifty-six patients (75%) eventually proceeded to extrapleural pneumonectomy (EPP), with 42 patients (56%) subsequently receiving radiation. Median time to progression for the entire group was 13.1 months, with a median overall survival of 16.6 months.
More recently, at the 12th World Conference on Lung Cancer in Seoul, South Korea, Smith et al. presented the results of a retrospective analysis of MPM patients at the Ottawa Hospital Regional Cancer Center. A total of 147 MPM patients were identified. Multivariate analysis showed higher tumor stage, weight loss, poorer performance status, and an elevated platelet count to be independently associated with poor prognosis. In addition, the authors performed a case control analysis comparing MPM patients who underwent extrapleural pneumonectomy (n=15) with matched controls who did not undergo the radical surgery. Patients undergoing EPP had a median overall survival of 25.4 months (95% CI 12.2 – 43.6), with the result approaching but not reaching statistical significance compared with matched controls (p=0.007).
With the publication of the EMPHACIS trial in 2003, combination treatment with cisplatin plus pemetrexed became the standard first-line therapy for patients with MPM. In that study, patients were randomized to receive cisplatin alone vs. cisplatin plus pemetrexed. Median time to progression favored the combination therapy arm (5.7 months vs. 3.9 months, p=0.001); median overall survival also showed a benefit for patients treated with the two-drug regimen (12.1 months vs. 9.3 months, p = 0.02).
Pemetrexed and pemetrexed-based combinations
In the last six months, investigators have presented several analyses from the pemetrexed International Expanded Access Program (EAP). At the 2007 ASCO Meeting, Santoro et al. presented a comparison of pemetrexed plus cisplatin (P+Cis) vs. pemetrexed plus carboplatin (P + Cb). In this retrospective, non-randomized comparison, the two arms demonstrated similar response rates (26% for P+Cis, 22% for P+Cb) and one-year survival rates (63% and 64%, respectively). Median survival for each group could not be estimated due to the high number of censored patients.
More recently, the same authors presented results of a 3-arm, non-randomized, open-label study of pemetrexed alone (P), pemetrexed plus cisplatin (P+Cis), and pemetrexed plus carboplatin (P+Cb) in chemo-naïve patients who were treated as part of the EAP. Not surprisingly, the pemetrexed arm of this nonrandomized study contained a greater proportion of patients with poorer performance status. While pemetrexed monotherapy was associated with a lower treatment response rate, all three arms showed similar one-year survival rates and median time to disease progression (see Table 1).
Vinorelbine plus a platinum agent
Investigators from Denmark have explored the use of vinorelbine, rather than pemetrexed, in combination with a platinum agent. Dr. Sorensen et al. recently presented the results of two such nonrandomized Phase II studies at the 12th World Conference on Lung Cancer. The first, conducted from 2003 – 2006, treated 57 MPM patients with cisplatin (100 mg/m2 day 1 of a 28-day cycle) and vinorelbine (25 mg/m2 weekly). Patients were predominantly male (83%), had epithelioid histology (76%), had good performance status (95% PS 0-1), and were of advanced stage (82% stage III or IV). There were 15 partial responses and 1 complete response (RR 28%), with a median survival of 11.6 months (range 0.5 – 41.7+ months). However, 47% of patients developed leukocytopenia of grade 3 or greater, and 14% developed nausea of grade 3 or greater. There were no toxic deaths.
A second study from Denmark treated chemo-naïve MPM patients with vinorelbine plus carboplatin (AUC=5). The 27 patients who were accrued from 2005 – 2007 were predominantly male (89%), had epithelioid subtype (67%), had advanced stage (89% Stage III or IV), and had good performance status (78% PS 0-1). There have been five partial responses (RR 19%); median survival has not yet been reached but exceeds nine months. There have been seven cases of febrile neutropenia (25%) but no toxic deaths.
In light of advances with targeted therapies in other tumor types, investigators have begun to explore the use of angiogenesis inhibitors and other targeted therapies in MPM. Unfortunately, recent results have not proved encouraging. In a randomized, multi-center Phase II trial of gemcitabine/cisplatin (GC) plus bevacizumab (B) or placebo, chemo-naïve patients were randomized to receive either GC plus placebo x 6 cycles or GC plus bevacizumab x 6 cycles followed by bevacizumab maintenance. Patients were stratified by performance status and tumor histology (epithelioid vs. other). The results were presented at the 2007 ASCO Meeting and showed that the addition of bevacizumab was not associated with any significant improvement in median progression-free survival (6.9 months for GCB vs 6.0 months for GC, p = 0.88) or median overall survival (15.6 months for GCB vs 14.7 mo for GC, p = 0.91).
Understanding DNA Damage Response or DDR and Cancer Treatment
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There has been only one published study dedicated exclusively to the second-line treatment of mesothelioma, and there are currently no agents approved by the United States Food and Drug Administration in this setting. In attempt to fill this treatment void, several targeted agents have been studied for the second-line treatment of mesothelioma.
In a single-arm, multi-center Phase II study presented at the 12th World Conference on Lung Cancer, the use of bevacizumab plus erlotinib was explored in patients with unresectable mesothelioma who had previously received one prior chemotherapy regimen. Unfortunately, in this clinical trial, there were no clinical responses, though there were a few patients with prolonged stable disease (up to 21 months). Median survival was eight months, and the one-year survival rate was 25%.
In another single-arm, multi-center Phase II study, patients who were either treatment naïve or had received prior chemotherapy were treated with the multi-targeted tyrosine kinase inhibitor sorafenib. Among 51 enrolled patients, there were two partial responses, below the level required to meet the primary statistical response rate endpoint. Median failure-free survival was 3.7 months, and the median overall survival was 10.7 months. Median survival was better in the previously treated patients (14.7 months) compared with the chemo-naïve patients (4.9 months), though this was likely due to patient selection.
The management of malignant pleural mesothelioma continues to present difficult challenges for patients and their treating physicians. While there have been a number of long-term survivors in case series of multimodality therapy, it is not completely clear that this is truly attributable to the aggressive management rather than to more indolent disease. There have not yet been any randomized trials comparing surgery/multimodality therapy to chemotherapy alone. Moreover, if one considers the eligibility criteria (good performance status, no metastatic disease) for the Krug trial (above), the 16.6 month median survival may not represent a marked improvement over the 12.1 month median survival for cisplatin plus pemetrexed in patients with unresectable disease in the EMPHACIS trial. Until randomized trials can more clearly document an attributable benefit to multimodality therapy over chemotherapy alone, physicians need to proceed cautiously when recommended multimodality therapy in mesothelioma and improve methods for optimum patient selection for this treatment strategy.
The combination of cisplatin plus pemetrexed remains the systemic treatment of choice for previously untreated patients with mesothelioma. For those patients who cannot receive cisplatin, the substitution of carboplatin appears to be associated with roughly equivalent efficacy. For those patients who are deemed unfit for a combination regimen, pemetrexed monotherapy remains a reasonable option. However, in the absence of randomized data comparing monotherapy with a combination regimen, the use of pemetrexed plus a platinum agent remains the treatment of choice for those patients who are fit enough to tolerate it.
Systemic options beyond cisplatin plus pemetrexed remain unclear. The addition of bevacizumab to combination therapy with cisplatin and gemcitabine was not associated with any clinical benefit. Moreover, neither sorafenib nor the combination of erlotinib plus bevacizumab showed sufficient clinical benefit to warrant additional investigation in mesothelioma at this time. Trials with other targeted agents (vorinostat, bortezomib) are underway and may prove clinically useful in the care of patients with mesothelioma.
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 Sugarbaker DJ, Flores RM, Jaklitsch MT, et al. Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients. J Thorac Cardiovasc Surg. 1999;117(1):54-63; discussion 63-5.
 Krug LM, Pass H, Rusch VW, et al. A multicenter U.S. trial of neoadjuvant pemetrexed plus cisplatin (PC) followed by extrapleural pneumonectomy (EPP) and hemithoracic radiation (RT) for stage I-III malignant pleural mesothelioma (MPM). J Clin Oncol. 2007;25(18S): Abstract# 7561.
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