Raltitrexed and Pemetrexed Studies in. Mesothelioma Have Not Shown. Improved Quality of Life nor. Prolonged Survival Compared With. Effective Pleurodesis ...
Correspondence
Raltitrexed and Pemetrexed Studies in Mesothelioma Have Not Shown Improved Quality of Life nor Prolonged Survival Compared With Effective Pleurodesis With Thoracoscopic Talc Poudrage TO THE EDITOR: The recent publication by Bottomley et al1 is an ambitious attempt to define possible therapeutic benefits in an otherwise dismal disease with a short life expectancy—malignant pleural mesothelioma. The study had already been shown to demonstrate an increased life expectancy of 2.6 months in those patients treated with raltitrexed plus cisplatin compared with cisplatin alone. The Bottomley et al article1 deals primarily with the health related quality of life (QOL) scales. The authors correctly conclude that adding raltitrexed to cisplatin treatment improves the QOL as well as the life expectancy. However, this QOL study does not indicate that raltitrexed plus cisplatin is associated with a better QOL in mesothelioma patients treated with an alternate therapy—thoracoscopic talc poudrage. A significant percentage of the chemotherapy patients in both groups suffered nausea and vomiting, which progressively worsened with each treatment.1 Nausea and vomiting would not occur in a true control group, with no chemotherapy. More importantly, pain was unaffected by chemotherapy while dyspnea subjectively improved with treatment. Because most dyspnea early in this disease is relieved by thoracentesis and subsequent pleurodesis,2 we know the breathlessness is due to the collection of fluid in the pleural cavity. In this study, therefore, one can only conclude that the patients were not successfully pleurodesed before entry into the study. So the positive effect of the two-drug chemotherapy may merely reflect greater control of pleural fluid with two drugs instead of one. We published a series of 26 consecutive mesotheliomatous pleural effusions treated with thoracoscopic talc poudrage, in which there were no significant ancillary treatments.2 The average survival was 24 months (median, 19 months). Although our extended longevity compared with all other unselected studies could be fortuitous in a small series, it certainly raises the issue as to the survival benefit of effective pleurodesis. Another recent study, on indwelling pleural catheters, provides further suggestive evidence for pleurodesis as a survival benefit: those malignant pleural effusion patients who spontaneously pleurodesed after catheter placement lived for 254 days while those who failed to pleurodese lived only 71 days.3 These studies2,3 provide further evidence for the need of a talc poudrage control arm in future mesothelioma studies: a control arm that has a zero incidence of nausea and vomiting, no associated (cisplatin) fatigue with the treatment, and provides immediate relief of dyspnea in a 3-day hospital stay, with no known decline of QOL for the first 3 months of treatment, as seen in the pemetrexed plus cisplatin study.4 It is time for the mesothelioma research community to admit that innovative surgical and nonsurgical treatments all have a negative morbidity, QOL, and mortality potential, which can only be quantified with a true control group. Thoracoscopic talc poudrage is currently the least morbid, least expensive, most effective (in long-term relief of dyspnea), and most readily available control modality of care.
Although this study1 seeks to fairly quantitate QOL on a twodrug treatment versus one drug, we still do not know if the two drugs prolong life— on the average— compared with talc poudrage; nor if the QOL, number of quality lifetime days, number of hospital days, number of clinic visits/year of life compare favorably or unfavorably with nondrug treatment. The unstated cost of the chemotherapy and its adverse effects are an additional item which has been studiously unmentioned in the publications on what remain unproven benefits to the patient.
Yossef Aelony Los Angeles County Harbor–UCLA Medical Center, Rancho Palos Verdes, CA
REFERENCES 1. Bottomley A, Gaafa R, Manegold C, et al: Short-term treatment-related symptoms and quality of life: Results from an international randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: An EORTC Lung-Cancer Group and National Cancer Institute, Canada, Intergroup study. J Clin Oncol 24:1435-1442, 2006 2. Aelony Y, Yao J: Prolonged survival after talc poudrage for malignant pleural mesothelioma: Case series. Respirology 10:649-655, 2005 3. Tremblay A, Michaud G: Single-center experience with 250 tunnelled pleural catheter insertions for malignant pleural effusion. Chest 129:362-368, 2006 4. Boyer MJ, Nassem J, Liepa AM, et al: Symptom and quality of life advantages for pemetrexed ⫹ cisplatin versus cisplatin in treatment of malignant pleural mesothelioma. Lung Cancer 41:S19, 2003 (suppl 2)
DOI: 10.1200/JCO.2006.08.0267 ■ ■ ■
Author’s Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest.
IN REPLY: Although we acknowledge the palliative effects on dyspnea by chemical pleurodesis, as described by Aelony in his letter, it is hazardous to compare data from small selected single institutional phase II series with those from large multicenter series. A recent meta-analysis on chemical pleurodesis concludes that talc is the better sclerosant agent and that thoracoscopic administration might be superior to bedside one.1 In contrast, the Cancer and Leukemia Group B could not confirm the superiority of thoracoscopic instillation in a large prospective randomized trial.2 There was a 6% incidence of treatment related death in this trial. Dr Aelony will be aware that pleurodesis is only effective in selected patients, in whom there is repetitive symptomatic pleural fluid accumulation and in whom the lung is re-expanding after thoracentesis. This is in fact the case in early stage disease. With disease progression, dyspnea becomes multifactorial (for example, by invasion of the chest wall, the mediastinum, or the presence of anemia or a trapped lung). The median interval between diagnosis and random assignment in our trial is 52 days, two thirds of patients had a WHO performance status of 1 to 2%, and 80% or more were in clinical stage III-IV.3,4 These facts illustrate that these patients had more advanced disease. In fact, 20.4% of the patients in the cisplatin arm and 23.4% of the patients in the combined treatment arm actually had a pleurodesis with talc before being registered. Most clinicians consider any kind of pleurodesis as part of active supportive care, delivered as needed. It is highly unlikely that pleurodesis will prolong survival in mesothelioma, as it is unlikely that single-agent cisplatin will shorten it.5 The Medical Research Council MS 01 study, that recently reached its planned accrual and has formal symptom and quality of life assessment included, will ultimately address the issue whether chemotherapy—platinum or nonplatinum containing—improves the different objective and subjective outcome 4667
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