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Eur J Cardiothorac Surg 2007;31:534-535. doi:10.1016/j.ejcts.2007.01.011
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved
Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, C-868, New York, NY 10021, United States
* Tel.: +1 212 639 8695; fax: +1 212 717 3682. (Email: ruschv{at}mskcc.org).
Malignant pleural mesothelioma (MPM) is an uncommon and usually fatal malignancy for which novel therapies are clearly needed. In this issue of the journal, Lucchi et al. [1] report the results of a phase II trial of combined modality therapy for patients with clinical stages II and III MPM, including preoperative intrapleural immunochemotherapy, pleurectomy/decortication (P/D), adjuvant radiation (30 Gy), and systemic chemotherapy followed by long-term subcutaneous interleukin-2 (IL-2). From 1999 to 2004, 49 patients were entered on study and all patients completed the planned treatment with acceptable toxicity. The 5-year actuarial survival was 23.3% and the most common site of relapse was local (37 of 49 patients). The authors conclude that this treatment strategy provides good palliation and deserves further study, perhaps through the addition of intracavitary hyperthermic chemotherapy or the use of new drugs.
It is important to consider the design of this trial within the context of recent studies in MPM. The authors contend that ‘nothing has changed in the early diagnosis and, more important, in the prognosis of MPM patients’, implying that a lack of standard treatment justifies their selection of a complex multimodality treatment strategy. However, during the past 20 years, there have been major advances in several areas, including diagnostic and staging methods, the selection of patients for surgery, a reduction in surgical mortality, significant improvements in local control through the addition of high dose hemithoracic radiation to extrapleural pneumonectomy (EPP), the development of more effective chemotherapy drugs, and an emerging understanding of MPM biology. These advances have enabled an increasing number of well-designed prospective multimodality clinical trials to be performed in MPM. Although it is still associated with a poor prognosis overall, important strides have been made in systematically studying this difficult disease with resulting improvements in outcome for select patients [2,3]. Thus, a nihilistic attitude towards MPM is no longer warranted and new clinical trials should methodically test clear hypotheses, building on the results of completed studies and established knowledge about this malignancy.
The patients included in the study by Lucchi et al. represented a typical MPM patient population with respect to patient age and gender, and tumor histology and stage. The authors should be congratulated on using uniform staging and eligibility criteria for patient entry on study as well as uniform methods of follow-up. These are critical to the valid testing of new therapies in MPM and to the safety of surgically based trials, but have not always been implemented in the past. Not surprisingly, the smaller number of stage II tumors had a better outcome than did the stage III. Previous surgical studies suggest that the greatest difference in prognosis is seen between stages I/II versus stages III/IV MPM [4].
The treatment approach used by Lucchi et al. incorporates several therapeutic strategies tested in previous studies. MPM is known to be associated with immunologic dysfunction and to be sensitive to various forms of immunotherapy including the interferons and IL-2 [5–8]. For example, in a study of 22 patients, Astoul et al. found that intrapleural IL-2 alone led to one complete and 11 partial responses and was associated with a median survival of 28 months in patients responding to this treatment [7]. In a study of 29 patients, Rudd et al. showed that IL-2 was also active as a single agent when administered intravenously and subcutaneously although perhaps less so than when given intrapleurally [6]. Therefore, previous studies support the use of IL-2 in the clinical trial setting.
The choice of operation (EPP vs P/D) remains controversial in MPM. P/D is a lower risk operation because the lung is left in place but does not allow removal of all gross tumor in patients with locally advanced disease and is associated with a high rate of local relapse [9,10]. Adjuvant hemithoracic radiotherapy is notoriously difficult to administer after P/D because of the risk of radiation pneumonitis after even low radiation doses. Most patients treated in this manner relapse locally and die of respiratory insufficiency from a combination of local tumor progression and radiation pneumonitis [11]. In contrast, high dose hemithoracic radiation after EPP has been shown to yield excellent local control with the predominant mode of disease progression being distant metastases [4,12]. The information provided about the treatment planning for adjuvant radiation used in this trial is scant, but based on previous experience it is not surprising that 38 of 45 patients receiving adjuvant radiation in this study required steroids for radiation pneumonitis and that 37 patients relapsed locally. Whether the hypofractionated treatment scheme (30 Gy in three fractions) used by Lucchi et al. contributed to pulmonary toxicity is unclear because this approach has only been previously tested to treat chest wall incisions after thoracoscopy without irradiating any of the lung [13].
The choice of adjuvant intrapleural chemotherapy in this study theoretically takes advantage of potential synergism between chemotherapy and immunotherapy. Doxorubicin and its analogs have modest activity in MPM when administered intravenously [14] but data to support their use intrapleurally or in sequence with IL-2 or as adjuvant therapy are lacking. Systemic cisplatin and gemcitabine is a widely accepted chemotherapy combination considered to be the most active regimen at the time this study was initiated, and thus represents reasonable induction or adjuvant therapy. Other studies confirm the feasibility and efficacy of combining systemic cisplatin and gemcitabine with surgery, generally as induction therapy before EPP [15,16]. On the other hand, the rationale for administering subsequent maintenance subcutaneous IL-2 until disease progression is unclear.
In summary, Lucchi et al. report the results of a complicated multimodality treatment plan for which there are varying amounts of preliminary data to support the trial design. It appears that their approach was associated with acceptable toxicity, but the length of treatment (not defined in their paper) appears to be significant, requiring at least 4 months from study entry up to the initiation of maintenance IL-2. Whether this protracted treatment strategy achieves the authors’ stated goal of ‘good palliation’ is unknown as no quality of life measurements were included in the study. Overall survival appears to be relatively good, especially in a population of patients who have predominantly stage III disease and a median survival of approximately 12 months in some studies [3]. The problem of local disease progression is entirely consistent with previous studies that have used P/D in conjunction with intrapleural therapy [8,9]. However, the most disappointing aspects of this trial are that it does not build logically upon previous studies and does not answer a specific hypothesis. As a result the reader is left confused about the trial outcomes and the authors do not have a clear result from which to design their next study. Which of the many therapies used in this trial potentially had a beneficial result and which should be discarded? The authors suggest adding hyperthermic intrapleural chemotherapy or changing the systemic therapy in their next trial but the rationale for doing either of these cannot be gleaned from the current study because there is no way to assess which components of their previous treatment strategy were more or less effective. Perhaps the most important lesson to be learned from this study is that while novel therapies are needed in MPM, new treatment approaches should be tested in trials that ask simple, straightforward questions leading to unequivocal answers about response, survival and sites of relapse. The impact of new treatments on patient quality of life must also be carefully measured utilizing validated instruments. Only in this manner will progress be made in this difficult malignancy.
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