IMIG 2012

Dr. Cameron’s proposed text for use in a surgical consensus statement being developed by IMIG surgeons

The optimal treatment of malignant pleural mesothelioma requires an appropriately aggressive and coordinated multimodality therapy approach with the participation of surgeons, medical and radiation oncologists, pathologists, radiologists, pulmonologists, nurses, respiratory therapists, and other support personnel. Recently the publication of the Mesothelioma And Radical Surgery (MARS) Trial results led some to not only question the role of extrapleural pneumonectomy but to question the role of surgery in this disease entirely. The International Mesothelioma Interest Group (IMIG) met from September 12-14, 2012 in Boston, MA, and during this comprehensive meeting more than 500 participants representing all the involved specialty groups listed above met in multiple comprehensive sessions to review, critique, and extend the state of knowledge regarding the treatment of malignant mesothelioma, including the role of surgery. We, the authors, feel that it would be both helpful and instructive for mesothelioma patients as well as the oncology community in general to summarize the consensus of this meeting regarding the interpretation of the MARS results and the role of surgery in malignant mesothelioma.

Some key MARS trialists were present at the IMIG sessions and helped to put the MARS Trial and its results into perspective. First, MARS was designed as a pilot trial to determine the feasibility of randomly assigning mesothelioma patients to undergo or not to undergo radical surgery, both in terms of patient acceptance and in recruitment rate. The goal was to accrue 50 patients within 1 year before embarking on a larger definitive randomized study, which would require 670 patients according to statistical calculations. The MARS Trial required more than 3 years to accrue the required 50 patients, and therefore, failed to meet its primary objective. The larger definitive trial then was appropriately aborted. Data analysis regarding the primary study objectives led to the suitable statement (abstract interpretation section) that “a larger study is not feasible,” and in the study discussion, the authors properly concluded that “the study is small and the conclusions must be guarded, and that “a much larger study with longer follow-up would be needed to provide reliable evidence on mortality patterns and long-term survival for any extirpative surgery for mesothelioma whether EPP or lung-sparing surgery.”

During data analysis and subsequent publication, however, a number of observations, most of which were not original trial objectives, were included, published, and used as the basis for rather broad statements. For instance, the final definitive statement (abstract) that “radical surgery in the form of EPP with trimodal therapy offers no benefit and possibly harms patients” is not justified by the study. Many of the challenges in the interpretation of the MARS Trial results were articulated in an editorial which accompanied the publication in Lancet. Many of these and others were raised at the IMIG meeting. One major problem was the very small numbers in the trial—appropriate for a pilot but not for a definitive study (planned 670 patients). Although the trial provides a good accounting of the selection process, only 112 patients (<37.2%) actually were registered for the trial out of a population in excess of 301 patients screened, and only 50 patients (<16.6%)were ultimately randomized. Of the 24 patients randomized to EPP, only 19 (79.2%) underwent attempted surgery with only 16 completing the procedure (66.7% of the surgery group and only 14.3% of the registered group). Furthermore, protocol compliance was poor with a relatively large number of patients essentially crossing over to the other group with 6 of the 26 patients (23.1%) randomized to no surgery actually undergoing surgery off study (3 EPP and 3 non-EPP). The 5 patients (20.8%) in the EPP group who did not undergo surgery also de facto crossed over to the non-surgical arm. This high rate of crossover in both directions further compounds the problem with small numbers in the study. These two factor alone most likely explain some of the Trial’s findings which vary significantly from the historical experience of many centers. These findings include 1) a high early mortality rate, i.e., 3/24 (12.5%) of randomized patients or 3/19 (15.8%) of operated patients (1 perioperative death and 2 other early deaths), 2) a low overall median survival in the EPP group of 14.4 months, although as the authors pointed out this improves to 18 months when combined with chemotherapy time, and 3) a high overall median survival in the no surgery group of 19.5 months. Other trial factors potentially open to criticism are 1) the chemotherapy was not standardized, 2) complete pathologic staging was not reported, and 3) a discrepancy between the 18 month period used for survival data and the 24 month period reported for quality of life data.

During the IMIG meeting, the MARS Trial findings also were compared to a large amount of contemporary data from other centers including data from six institutional series from the US, Europe, and Japan involving “macroscopic complete resection” (MCR) by either extrapleural pneumonectomy and extended pleurectomy in a multimodality treatment setting. Mortality reported was 0-2% and median overall survival was as high as 25-37 months in the selected population of epithelial patients with negative lymph nodes. Additionally, a world-wide registry sponsored by the IASLC and reported by Dr. Valerie Rusch included 1359 surgically treated patients with a 19-month median overall survival in epithelial patients (all stages). The patterns of failure following surgery were again shown by Dr. Baldini and others at the IMIG meeting to be predominantly local supporting the use of aggressive local therapy to improve survival.

By the end of the meeting, IMIG participants felt that the limitations of the MARS Trial precluded any definitive conclusions regarding the role of radical surgery in the multimodality treatment of malignant mesothelioma. Furthermore, it was the consensus of meeting attendees in light of the current data the goal of therapy in mesothelioma, like nearly all solid tumors, is to achieve complete surgical resection with adequate macroscopic margins and to prevent recurrence. Therefore, mesothelioma patients should be offered surgery to achieve complete macroscopic resection (MCR) with additional adjuvant therapy to control residual microscopic disease. The exact surgical procedure should be based on disease distribution, surgeon preference and experience, and institutional experience and should be performed with a morbidity and mortality consistent with published literature.

Additional recommendations from IMIG participants included:

• Pathological diagnosis including histologic subtype should be established by
tissue biopsy

• Clinical staging be performed prior to initiation of therapy and should include
PET with lymph node sampling and/or MRI as indicated

• Surgery should be considered in appropriate patients with the goal of macroscopic
complete resection (MCR)

• The type of surgery (EPP, P/D, etc) should be based on clinical factors as well as
individual surgical judgment and expertise

• Complete surgical stating should include hilar and mediastinal lymph node
removal