To the Editor:

The recent phase III study demonstrating that cisplatin plus pemetrexed results in longer survival (12 months) than cisplatin alone (9 months) in the treatment of malignant mesothelioma, is ambitious in its design and its scope, including some 456 patients from around the world.¹ However, the enthusiasm for premetrexed expressed in its conclusions and in the accompanying editorial² should be tempered by some unmentioned considerations. (1) The quality of life of patients is deferred to a later publication. Hopefully, this future publication will include a true control group that received neither a thoracotomy nor any chemotherapeutic interventions. What were the total days of hospital and clinic care, and the ratio of these days to days of survival? (2) Although the groups were “balanced for...pain level at entry,” weight loss has also been associated with shorter survival and should have been included. (3) Although referenced, the 1984 article from the Brompton Hospital was not discussed.³ This study reported on 64 patients who were not treated, but who lived a mean of 18 months after the onset of the symptoms. This could have been used as the historical control to compare with their 12-month survival in the pemetrexed/cisplatin group. One may counter that we have no basis for comparability between the Brompton patients and the present study, but the same may be said for the authors’ choice (in their opening paragraph) of a historical report of 6 months’ median survival.⁴ (4) Another potential control group for survival could be the patients who were refused entry into the pemetrexed study because of the exclusion of those requiring regular use of nonsteroidal anti-inflammatory drugs. This information should be easily obtainable from the hospital cancer registries. (5) The authors do not relate how the diagnosis was made. Clearly, those who had a thoracotomy for diagnosis are more accurately staged; thoracoscopic staging may not be comparable. We should know the methods of diagnosis in each group. (6) We clinicians would like to know the outcomes of those who received neither thoracotomy nor chemotherapy. Several retrospective studies from the 1980s indicated that thoracotomy and whatever surgical procedure was performed did not lead to better outcomes.⁵ Since only the youngest and fittest with early-stage disease were subjected to thoracotomy, presumably, thoracotomy and other surgical procedures shortened life span compared with the best supportive care. We will not know if this remains the case until thoracoscopically diagnosed patients without further resection and chemotherapy are used as a control group. Our own series of 26 consecutive mesothelioma patients presenting with large pleural effusions lived for a mean duration of 23 ± 13 months (median, 19 months) when thoracoscopic talc pleurodesis was the primary mode of therapy.⁶ Our study suffers from not having a randomized, aggressively treated group to compare. (7) Staging with positron emission tomography scans is available in some centers, which may or may not have excluded some patients from the trial. Are the numbers of positron emission tomography scans equal in the two treatment groups? (8) We recently reported that mesothelioma patients with pleural pH less than 7.32 lived for 13 months, while those with pH more than 7.32 lived an average of 27.4 months. Pleural pH data should be part of the staging process.⁷ (9) If the requested data is difficult to retrieve in retrospect, it must surely be included in the “multicenter study open for accrual later this year,” referred to in the editorial.² (10) An underlying presumption inherent in recent mesothelioma studies is that the International Mesothelioma Interest Group TNM staging technique permits comparisons of groups of patients without a randomized control group of “best supportive care.” Nevertheless, some recent studies failed to correlate TNM staging with survival after thoracoscopy or with thoracotomy, unless additional factors were considered^7,8—All the more reason to include a control group with thoracoscopic talc poudrage in future studies!

The pemetrexed study—requiring great expenditure of time and funds—is a prodigious and courageous effort to palliate a horrible, so-far incurable disease. These studies deserve our strong support. However, providing further information as indicated above will make the data in this study and subsequent ones more meaningful.

Author’s Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.