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Journal of Thoracic Oncology:
doi: 10.1097/JTO.0b013e3181b7d470
Editorial

The MARS Trial: Resolution of the Surgical Controversies in Mesothelioma?

Rusch, Valerie W. MD

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Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.

Disclosure: The author declares no conflicts of interest.

Address for correspondence: Valerie W. Rusch, MD, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. E-mail: ruschv@mskcc.org

Few cancers generate as impassioned debate about treatment as does malignant pleural mesothelioma (MPM). The relative merits of surgery, radiation, and chemotherapy are endlessly discussed, often with limited scientific evidence to support strongly held viewpoints. One of the perennial controversies in the treatment of MPM is whether extrapleural pneumonectomy (EPP) is more effective than less extensive operations such as pleurectomy/decortication (P/D) in patients who are candidates for surgical resection.1–3 EPP offers the benefit of complete resection of all gross tumor and permits the delivery of high-dose adjuvant hemithoracic radiotherapy (RT) but is associated with greater morbidity and mortality than lesser operations. Moreover, despite the excellent local control provided by EPP and hemithoracic RT, many of these patients experience rapid progression of disease in distant sites and have a limited life expectancy.4,5 The Mesothelioma and Radical Surgery (MARS) trial reported in this issue of the Journal of Thoracic Oncology is an effort to determine the potential benefit (or lack thereof) of EPP in the treatment of MPM. Led by Mr. Tom Treasure,6,7 who has been a vocal critic of the lack of randomized controlled trials in MPM, this multicenter study from the United Kingdom was open to patients whose extent of disease and overall medical condition permitted consideration of multimodality therapy and EPP. Patients first consented to receive induction chemotherapy and if they completed that treatment successfully, were then potentially consented to randomization between EPP versus no surgical intervention. The study end point of this first MARS trial was to determine whether patients would agree to being randomized to surgery versus no surgery. The trial successfully met its accrual goal of 50 randomized patients. The design of a second trial is currently under discussion.8

The demonstration that patients and their physicians will agree to a randomization between two very different treatments, i.e., EPP versus no resection, is an important achievement and sets the stage for a subsequent trial that will answer a therapeutic surgical question definitively. Although physicians in other countries can certainly be criticized for not undertaking similar randomized trials, oncologists and surgeons in the United Kingdom are perhaps uniquely positioned to perform the MARS trial by virtue of disease incidence, geography, and the British national health care system. As indicated by the authors, the United Kingdom now has the highest incidence of MPM in the world. By comparison, the United States has a similar number of MPM cases annually but scattered across a much larger population and geographical area. Unlike the more common cancers the current treatment strategies for MPM, especially with respect to surgery and RT, require highly specialized expertise that is not widely available in the community setting. Indeed, as noted by the authors, experience gained during this trial improved the expertise of multidisciplinary oncologic teams in centers of excellence in diagnosing, staging, and treating MPM. For the small numbers of MPM patients scattered across large geographic areas in countries such as the United States, access to complex multimodality therapy within or outside of clinical trials is often not available. The health care system in the United Kingdom is also particularly well suited to trials in MPM. Although the United States (as one example) has highly fragmented health insurance coverage with many health care organizations refusing to support patient participation in clinical trials, as well as multiple clinical trial groups that sometimes pursue competing agendas, and no system for the regionalization of oncologic care, the United Kingdom has national health care insurance, a single major source of funding for cancer clinical trials and a system for the potential regionalization of care for rare diseases into centers of excellence. Illustrating these differences, this report indicates that more than 300 patients were screened by only 11 participating centers, that surgery was performed by only five centers and that RT was provided by only 10 centers. This concentration of eligible patients and health care providers enhances the chances of successfully completing a randomized trial of complex design for a rare malignancy. Finally, participation in a study such as the MARS trial demands equipoise on the part of both physicians and patients about two treatments that are conceptually very different. Evidently, there has been sufficient equipoise in the United Kingdom to permit successful accrual to the MARS trial. Whether a similar degree of equipoise could be achieved in other countries that potentially have different views of MPM and its treatment remains an open question.

Experience from this first MARS trial raises issues that are relevant to the design of the next trial. Two aspects of study design seem to have been particularly effective in this first trial, namely the use of a virtual multidisciplinary team to review patient eligibility and the two stage consent process. It would probably be beneficial to retain both of these components in the next trial. Differences in survival observed in this small group of 50 patients (presumably the subject of future analyses) will obviously help to establish the sample size necessary for a randomized trial asking a therapeutic question. The authors proudly point out that 45% of the patients eligible for surgery after chemotherapy underwent randomization. However, these 50 patients were drawn from a pool of more than 300 patients who were originally screened for the trial. This considerable drop out rate will need to be considered in planning the next trial since potentially the number of patients who need to be screened for the study may be six times the number of patients ultimately randomized. It would be useful to require screening logs in the next trial to determine whether the drop out rates have changed over time. This trial did not stratify for known prognostic factors including tumor histology or T, N, and overall stage or positron emission tomography standardized uptake value. Adding these important stratification factors to the next trial will, of course, increase the sample size and affect the feasibility of the next trial. Conversely, in this first trial, patients who had biopsy-proven N2 disease were excluded. The rationale for this exclusion is unclear because this group of patients is at high risk for systemic disease progression and may benefit significantly from a combined modality approach that starts with induction chemotherapy.9–11 Including such patients, but stratifying for N stage, may improve accrual to the next trial and will answer an important secondary end point.

This report does not indicate whether there was any standardization of the induction chemotherapy regimens or of surgical and RT techniques. Such standardization will be important in a randomized trial testing a therapeutic question. Some limitations need to be placed on the types and doses of induction chemotherapy regimens allowed. In addition, there can be considerable variation in the approaches used for EPP and in surgical morbidity and mortality, even across a small number of institutions. Key elements of the operation need to be codified by participating surgeons. Institutional or surgeon-related differences in surgical adverse events that may be apparent from this first MARS trial need to be addressed in designing the next trial. RT technique and dose also affect the risk of serious adverse events and need to be carefully specified. Standard approaches for collecting adverse event data need to be implemented across the entire duration of patient treatment and follow-up. Surgical complications are often recorded separately from chemotherapy and radiation-related adverse events and reported in a nonstandardized manner. Use of the internationally accepted Common Terminology Criteria for Adverse Events for the reporting of all adverse events including surgical complications would provide the best means of comparing morbidity and mortality between two study arms in the next trial. It will also be important to examine late as well as early adverse events. Finally, the next MARS trial offers the opportunity to study two additional issues in MPM patients undergoing complex multimodality treatment: quality of life and tumor biology. There are few quality of life studies in MPM patients and quality of life endpoints may become important if the differences in survival between two study arms are not significant. The body of knowledge about MPM tumor biology is still modest and a prospective randomized therapeutic trial offers a superb opportunity to collect tumor tissue before and after induction therapy and to correlate molecular abnormalities with a rich and highly reliable clinical database. Again, in a geographically small area such as the United Kingdom with a small number of participating centers, acquisition, and centralized storage of tumor tissue should be straightforward.

In the Discussion section of the report, the authors hint that recent studies suggesting that EPP and P/D may be associated with similar overall survival have led them to rethink what operation would be performed in the surgical arm of the next trial.3,12–14 This is unfortunate. The authors correctly point out that the data regarding the relative impact of EPP and P/D are retrospective and therefore cannot provide definitive evidence on this topic. Other issues, including a staging system for MPM which is rudimentary, and our relative ignorance of prognostic factors and tumor biology, make it difficult to assess surgical treatments reliably in retrospective studies. With the successful completion of the first trial, the MARS investigators are uniquely positioned to perform a definitive therapeutic trial that will answer a highly controversial question, namely whether EPP adds to nonsurgical therapy. Muddying the waters by asking a different surgical question or allowing multiple operations within the trial will lead to unclear results. If the MARS investigators do not avail themselves now of the opportunity to define the role of EPP, this therapeutic question may never be answered. If the next MARS trial successfully defines the role of EPP, subsequent trials can be designed to test the role of other surgical procedures such as P/D. It is vitally important that the MARS investigators finish what they have so admirably begun.

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REFERENCES

1. 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 of 183 patients. J Thorac Cardiovasc Surg 1999;117:54–65.

2. Rusch VW, Venkatraman E. The importance of surgical staging in the treatment of malignant pleural mesothelioma. J Thorac Cardiovasc Surg 1996;111:815–826.

3. Flores RM, Pass HI, Seshan VE, et al. Extrapleural pneumonectomy (EPP) versus pleurectomy/decortication (P/D) in the surgical management of malignant pleural mesothelioma (MPM): results in 663 patients. J Thorac Cardiovasc Surg 2008;135:620–626.

4. Rusch VW, Rosenzweig K, Venkatraman E, et al. A Phase II trial of surgical resection and adjuvant high dose hemithoracic radiation for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2001;122:788–795.

5. Rice DC, Stevens CW, Correa AM, et al. Outcomes after extrapleural pneumonectomy and intensity-modulated radiation therapy for malignant pleural mesothelioma. Ann Thorac Surg 2007;84:1684–1693.

6. Treasure T, Utley M. Ten traps for the unwary in surgical series: A case study in mesothelioma reports. J Thorac Cardiovasc Surg 2007;133:1414–1418.

7. Treasure T, Utley M. Mesothelioma: benefit from surgical resection is questionable. J Thorac Oncol 2007;2:885–886.

8. Treasure T, Waller D, Tan C, et al. The mesothelioma and radical surgery randomized controlled trial: the MARS feasibility study. J Thorac Oncol 2009;4:1254–1258.

9. Flores RM, Routledge T, Seshan VE, et al. The impact of lymph node station on survival in 348 patients with surgically resected malignant pleural mesothelioma: implications for revision of the American Joint Committee on Cancer staging system. J Thorac Cardiovasc Surg 2008;136:605–610.

10. Weder W, Stahel RA, Bernhard J, et al; Swiss Group for Clinical Cancer Research. Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma. Ann Oncol 2007;18:1196–1202.

11. Krug LM, Pass HI, Rusch VW, et al. Multicenter phase 2 trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural pneumonectomy and radiation for malignant pleural mesothelioma. J Clin Oncol 2009;27:3007–3013.

12. Schipper PH, Nichols FC, Thomse KM, et al. Malignant pleural mesothelioma: surgical management in 285 patients. Ann Thorac Surg 2008;85:257–264.

13. Nakas A, Trousse DS, Martin-Ucar AE, Waller DA. Open lung-sparing surgery for malignant pleural mesothelioma: the benefits of a radical approach within multimodality therapy. Eur J Cardiothorac Surg 2008;34:886–891.

14. Martin-Ucar AE, Nakas A, Edwards JG, Waller DA. Case-control study between extrapleural pneumonectomy and radical pleurectomy/decortication for pathological N2 malignant pleural mesothelioma. Eur J Cardiothorac Surg 2007;31:765–771.

© 2009International Association for the Study of Lung Cancer

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