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Symptoms and Patient-Reported Well-Being: Do They Predict Survival in Malignant Pleural Mesothelioma? A Prognostic Factor Analysis of EORTC-NCIC 08983: Randomized Phase III Study of Cisplatin With or Without Raltitrexed in Patients With Malignant Pleural Mesothelioma

Andrew Bottomley, Corneel Coens, Fabio Efficace, Rabab Gaafar, Christian Manegold, Sjaak Burgers, Mark Vincent, Catherine Legrand, Jan P. van Meerbeeck

From the European Organisation for Research and Treatment of Cancer Data Center, Brussels; University Hospital, Ghent, Belgium; National Cancer Center, Cairo, Egypt; University Medical Center Mannheim, Heidelberg University, Mannheim, Germany; National Cancer Institute, Amsterdam; Free University Medical Center, the Netherlands; and London Regional Cancer Center, Ontario, Canada

Address reprint requests to Andrew Bottomley, PhD, EORTC Data Center, Quality of Life Unit, Avenue E. Mounier, 83, 1200 Brussels, Belgium; e-mail: andrew.bottomley{at}eortc.be

	ABSTRACT

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Purpose Malignant pleural mesothelioma (MPM) is a rare disease. Unlike other advanced cancer types, little is known about patient-reported symptoms or health-related quality of life (HRQOL) and their possible prognostic value. This study reports an evaluation of the prognostic value of these factors using data gathered from a recent randomized controlled trial.

Patients and Methods Patients were entered onto this trial if they had a histologically proven unresectable MPM, not pretreated with chemotherapy, WHO performance status 2, and adequate hematologic, renal, and hepatic function. Patients were randomly assigned to receive cisplatin 80 mg/m² intravenously on day 1, without or with preceding infusion of raltitrexed 3 mg/m². HRQOL was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30/Lung Cancer 13 tool. The Cox proportional hazards regression model was used for the univariate and multivariate analyses of survival, along with a bootstrap validation technique. Included were the EORTC prognostic index (PI) composed of stage of disease, histology type, time since diagnosis, and WBC, and, in addition, 10 selected key symptoms and HRQOL scales.

Results Two hundred fifty patients were randomly assigned (80% male; median age, 58 years; WHO performance status 0, 1, 2 in 25%, 62%, and 13% of cases, respectively). Two hundred twenty-nine patients (91.6%) had a valid HRQOL assessment. The final multivariate model retained the PI, pain (P < .0001), and appetite loss (P = .0100) as independent prognostic indicators of survival.

Conclusion Results suggest that the PI, pain, and appetite loss may be independent prognostic factors in patients with advanced MPM.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Malignant pleural mesothelioma (MPM) is a rare, but aggressive and nearly always fatal disease.^1,2 Survival prospects are frequently very poor, with a median of 7 to 11 months after diagnosis.³ Asbestos is the most important risk factor associated with the development of MPM. The number of new cases in Europe is expected to double between 1998 and 2018.⁴ Patients with locally advanced MPM mostly present with symptoms as pain, dyspnea, cough, chest pain, weight loss, and excessive sweats.⁵ Treatment intent is palliative and results also in symptom control.⁶

Several clinical models that predict survival exist.³ Recently, Legrand et al⁷ proposed a modified European Organisation for Research and Treatment of Cancer (EORTC) prognostic index (PI) for advanced MPM, composed of histologic subtype, interval since diagnosis, platelet count, hemoglobin, and disease stage. Although few studies have examined patient self-reported symptoms of health-related quality of life (HRQOL), which may play a role in predicting survival, several recent studies across different disease sites show that HRQOL parameters such as pain, fatigue, hypoxia, and physical functioning can be independently prognostic.^8-12 Five studies have also been conducted in non–small-cell lung cancer (NSCLC), but the findings are inconsistent.^13-16 Only one published study assesses the value of HRQOL in MPM patients.¹⁷ This study, using the EORTC Quality of Life Questionnaire C30 (QLQ-C30, version 3) and Lung Cancer 13 Module (QLQ-LC13) for MPM patients, reported that HRQOL baseline scores were considered prognostic. For the 54 patients included in the analysis, several HRQOL factors, including pain and fatigue, were found to be significantly predictive of survival. However, given the small numbers of patients involved, confirmatory data were required. In addition, because no validation of the models was undertaken, the stability of the final model was not confirmed.

In light of this information, there is a need to examine in greater detail the following question: Do HRQOL and symptom data predict survival in MPM patients more than other known prognostic factors compared with the modified EORTC PI? Therefore, this article reports whether patient-reported symptoms or HRQOL contribute to predicting survival in a population of advanced MPM patients prospectively enrolled onto a large randomized clinical trial.

	PATIENTS AND METHODS

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Study Design
In this international, multicenter study (EORTC trial 08983 and the National Cancer Institute of Canada Clinical Trials Group BR17) the primary outcome was overall survival, measured from date of random assignment to death resulting from any cause. Secondary outcomes included—among others—HRQOL. Patients were randomly assigned to raltitrexed and cisplatin or cisplatin alone. Stratified patient random assignment used the following baseline determinants: institution, performance status (0 v 1-2) and WBC (WBC; < 8.3 x 10⁹/L v 8.3 x 10⁹/L). To be eligible, patients needed proven MPM histology diagnosis, not amenable to radical resection, WHO performance status 0 to 2, age at least 18 years, and adequate hepatic and renal functions and bone marrow reserve. The trial was approved by the EORTC protocol review committee and the ethics committee of each participating center, and was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent before randomization. Full details on the trial conduct and clinical outcome have been reported elsewhere.¹⁸ In brief, the clinical results have already been published, and there was a borderline significant difference between the treatment arms (P = .048) in favor of the raltitrexed addition.

Treatment
Cisplatin administered intravenously at 80 mg/m² over 1 to 2 hours and raltitrexed was administered intravenously at 3 mg/m² over 15 minutes preceding cisplatin. Drugs were administered on day 1 of each cycle and repeated every 3 weeks until progression, severe toxicity, or patient refusal.

HRQOL Measures and Data Collection
The EORTC QLQ-C30¹⁹ and the QLQ-LC13²⁰ were used. The QLQ-C30 measure comprises five functional scales: physical, role, emotional, cognitive, and social; three symptom scales: fatigue, nausea and vomiting, and pain; six single-item scales: dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact; and the overall health and global QOL scale. The QLQ-LC13, designed for use with a wide range of lung cancer patients,²⁰ includes 13 items assessing associated lung cancer symptoms (cough, hemoptysis, dyspnea, and site-specific pain), treatment-related adverse effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia), and pain medication. The dyspnea scale is a multi-item scale; the remainders are single-item scales.

The measured items were scaled and scored using the recommended EORTC procedures.²¹ Raw scores were transformed to a linear scale ranging from 0 to 100, with a higher score representing a higher level of functioning or higher level of symptom(s). Provided that at least half of the items in the scale were completed, the scale score was calculated using only those items for which values existed.

Assessments were performed at baseline (ie, before start of therapy) and not earlier than 14 days before random assignment. Follow-up assessments were taken at the start of treatment, before the start of every cycle,^1-9 at the end of treatment, and eight times post-treatment. This analysis considers only baseline patient-reported symptoms and HRQOL.

Statistical Analysis
The sample size was based on the primary end point (survival). Survival curves and probabilities were calculated with the Kaplan-Meier method. Differences between survival curves were assessed using the log-rank test. The Cox proportional hazards regression model stratified by treatment was used for univariate and multivariate analyses of survival. For the analysis of prognostic factors for survival, the proportionality assumption was checked for each of the variables under study by testing the dependency of their hazard ratio (HR) over time. Differences in patient characteristics were assessed via ² tests. The HRQOL and symptom-related scales were included as continuous factors, using data from baseline assessment only. Pearson's correlation coefficients were used to investigate the association between different covariates. When using a stepwise variable selection procedure to identify independent factors prognostic for survival, variables were included according to a selection entry criterion of .05 and removed using backward elimination according to a selection-stay criterion of .05. The importance of a prognostic factor was assessed via two-sided Wald-type test statistics, the HR, and its 95% CI for survival. Both clinical and patient-assessed HRQOL variables were evaluated at a 5% level of significance. C-indexes were used to explore the potential predictive value of the fitted models to predict survival.²²

The replication stability of the final model, predicting overall survival, was investigated using a bootstrap resampling procedure²³ applied in the HRQOL context as recommended by Van Steen.²⁴ This technique generates a number of samples, each the same size as the original data set, by randomly selecting patients and replacing them before selecting the next patient (ie, bootstrap resampling). The frequency of inclusion of the component variables in the Cox proportional hazard regression models, including all of the selected covariates and stratified for treatment, fitted to each data set using automatic forward stepwise selection (entry level of = .05), can be considered indicative for the importance of the factors. Alternatively, these inclusion frequencies can be seen as estimates of the posterior probabilities that the regression coefficients are different from zero. However, given the interest in the best set of prognostic factors rather than in the best independent prognostic factor, the correlation structure of the potential prognostic factors under consideration needed to be taken into account. Therefore, the calculation of the model selection probabilities will be based on how many times a permissible model is selected in the bootstrap samples. These probabilities were then used as weights to obtain weighted-average parameters. All data analyses were performed using Statistical Analysis Software (SAS) version 9.1 (SAS Institute, Cary, NC). Only patients with a valid self-reported HRQOL baseline were included in the analysis.

HRQOL and Symptom Variables Analyzed
Certain scales were excluded to reduce the risk of false-positive results: those not expected to have any prognostic value or those too highly intercorrelated with other scales, thereby limiting the overall results. The selected eight scales are global QOL, dyspnea, physical functioning, social functioning, cognitive functioning, appetite loss, nausea and vomiting, and pain. Three scales were also included from the EORTC LC13 module: dysphagia, dyspnea (combined with dyspnea of the QLQ-C30), and coughing. Despite its low internal robustness, the cognitive function scale was selected because it can quickly pick up key issues in these patients. The total 10 HRQOL and symptom variables were all included as continuous factors, using data from baseline assessment. Key biomedical parameters, contained in the modified EORTC PI, included histologic subtype, interval since diagnosis, platelet count, hemoglobin difference, and disease stage.⁷ All of these variables were included in the univariate regressions. For the multivariate model building, the 10 selected HRQOL and symptom variables were combined with the dichotomized PI. If the PI were not significant after model reduction, it would be substituted by its component factors.

	RESULTS

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From March 2000 to January 2003, 250 patients were recruited onto this trial: 126 patients received raltitrexed and cisplatin, and 124 received cisplatin alone. In brief, the clinical results showed a slight positive effect in favor of the experimental arm (P = .048). Of the 250 patients enrolled in the original trial, 229 (91.6%) had a valid HRQOL assessment at baseline. The distributions of the most important baseline characteristics between the patients with and without HRQOL baseline data are provided in Table 1. No significant differences were detected between the two groups. There was no significant difference in median survival between patients with and without baseline HRQOL data. The 229 patients with a valid baseline HRQOL form had a median survival time of 10.1 months, and a total of 195 deaths were reported, allowing for an adequately powered analysis. At baseline, there were no significant survival differences between the two treatment groups on any HRQOL scale. The HRQOL and symptoms were quite impaired on many scales compared with a normative population. Figure 1 presents the HRQOL scores for the EORTC QLQ-C30 for all the patients compared with a reference data set for the EORTC QLQ-C30.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Functional scales: physical (PF), role (RF), emotional (EF), cognitive (CF), and social (SF), and global quality of life (GL). Symptom scales/items: fatigue (FA), nausea and vomiting (NV), and pain (PA); six single-item scales: dyspnea (DY), sleep disturbance (SL), appetite loss (AP), constipation (CO), diarrhea (DI), and GL. A high score for a functional scale represents a high level of functioning, and a high score on GL represents high health-related quality of life. A high score on a symptom scale represents a high level of symptoms. Normative data from the European Organisation for Research and Treatment of Cancer manual.31 MPM, malignant pleural mesothelioma.

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Duration of survival by the pain (PA) self-reported score and the prognostic index (PI). O, observed number of deaths; N, number of patients.

	DISCUSSION

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It is possible to compare these results to those found by Nowak et al.¹⁷ In their study of 54 MPM patients, they found that HRQOL was predictive, but that the final model was unstable. Therefore, two prognostic models were proposed: one of them contained sex and pain (based on a composite pain score from the LC13), and the other hemoglobin and fatigue. When results like these are generated, it often reflects the inherent complexities of the harmful effects of multicollinearity (ie, the problematic issue of intercorrelated HRQOL items) in the data. Also, given the relatively small sample size and the instability of their final model, it is difficult to draw firm similarities between the findings of our results. While other studies in NSCLC have often found inconsistent results, the ones using the EORTC QLQ-C30 also found that pain is a prognostic factor. Herndon et al¹⁴ found in a baseline sample of 206 advanced NSCLC patients that, in the multivariate analysis of the 16 scales and items of the EORTC QLQ-C30, only pain was predictive. In addition, earlier work recently presented found that, in 391 NSCLC patients, baseline pain scores from the EORTC QLQ-C30 are prognostic.²⁵

The prognostic importance of appetite loss may appear to be a less obvious result. However, one might hypothesize that this scale consists of a mixture of physical status and nausea symptoms that are themselves too weak and too correlated to be significant on their own. This explanation is speculative but is supported in part by the fact that replacing the appetite loss scale with the nausea and vomiting or physical functioning scale gives similar (but less significant) results. The fact that appetite loss was found as prognostic is also seen in many other studies,^12,25-30 and it may reflect the development of the disease. Hence, our results are not essentially different from what others have reported.

Therefore, the key finding from the present research is to provide data that support the value of pain and appetite loss as prognostic in patients with advanced MPM. Pain is a common symptom, not only for MPM patients, but also for many other patients with advanced cancer. Indeed, examination of baseline scores indicates that patients had a considerable degree of pain. As regarding appetite loss, one may argue that cachexia, from a pathophysiologic view, is an indicator of advanced disease; therefore, appetite loss could act as a proxy to predict survival. Indeed, one can deduce from the tables that appetite loss, pain, and also physical functioning are in competition with each other.

However, the results of prognostic factor analysis of HRQOL data are open to criticism because of the harmful effects of multicollinearity. This point was addressed by using a complex, but rigorous, sensitivity analysis using the bootstrap technique. Overall, the results from this appear to lend support for the initial findings, as does the noted improvement in the C-index when self-reported pain and appetite loss are added to the model. It should be noted that the C-index values remain rather low, indicating only a modest concordance between the predicted and observed survival times. At the same time, although this study has several strengths, it also has some limitations, particularly that this was an exploratory analysis. As such, further results need to confirm the findings. Although 229 patients represent a considerable sample, particularly for this rare disease, it is not large enough to permit an internal validation. Ideally, another data set is required to validate the findings discussed herein.

However, overall, we think our article has answered several important questions that we aimed to address; that is, that the PI, pain, and appetite loss may be independent prognostic factors in patients with advanced MPM. Also, our study has raised questions we are not able to address fully. Ideally, a large-scale study over different disease sites, using robust methodology, will be needed to give a conclusive answer to the important question, "What are the effects of symptoms and quality of life on survival?"

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Christian Manegold, Eli Lilly (C); Mark Vincent, AstraZeneca (C) Stock Ownership: Mark Vincent, AstraZeneca Honoraria: Christian Manegold, Eli Lilly; Mark Vincent, AstraZeneca Research Funding: Christian Manegold, Eli Lilly Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Andrew Bottomley, Fabio Efficace, Catherine Legrand, Jan P. van Meerbeeck

Administrative support: Rabab Gaafar

Provision of study materials or patients: Rabab Gaafar, Christian Manegold, Sjaak Burgers, Mark Vincent, Jan P. van Meerbeeck

Collection and assembly of data: Andrew Bottomley, Rabab Gaafar, Christian Manegold, Sjaak Burgers, Jan P. van Meerbeeck

Data analysis and interpretation: Andrew Bottomley, Corneel Coens, Fabio Efficace, Catherine Legrand, Jan P. van Meerbeeck

Manuscript writing: Andrew Bottomley, Corneel Coens, Fabio Efficace, Rabab Gaafar, Sjaak Burgers, Jan P. van Meerbeeck

Final approval of manuscript: Andrew Bottomley, Corneel Coens, Fabio Efficace, Rabab Gaafar, Christian Manegold, Sjaak Burgers, Mark Vincent, Catherine Legrand, Jan P. van Meerbeeck

	Appendix

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The following institutions with their respective investigators and accrual have contributed data for this analysis: the Netherlands: Erasmus MC Rotterdam (J. van Meerbeeck, R. van Klaveren, S. Burgers, M. de Jonge): 52; UMC, Utrecht, the Netherlands (N. Schlösser): 7; Egypt: National Cancer Institute Cairo (R. Gaafar): 43; Germany: Thoraxklinik Rorhbach, Heidelberg (C. Manegold): 33; United Kingdom: Weston PK, Sheffield, (Hatton): 10; City Hospital, Nottingham (P. Woll): 10; Western General Hospital, Edinburgh (A. Price): 7; Royal Marsden Hospital, London, UK (M. O'Brien): 3; Poland: Gdansk Medical University (J. Jassem): 11; Regional Lung Center, Poznan (R. Ramlau): 10; Canada: Cancer Center, London, Canada (M. Vincent): 6; Mc Gill University, Montreal (Hirsch): 6; Princess Margaret Hospital, Toronto (F Shepherd): 4; Regional Cancer Center, Hamilton, Canada (Neville): 2; Trillium Health Center (Gapski): 2; France: Centre Hospitalier Universitaire de Marseille (P. Astoul): 13; Hopital C Nicolle, Rouen (L. Thiberville): 1; Belgium: UZ Gasthuisberg Leuven (K. Nackaerts, J. Vansteenkiste): 10; Peru: Institut Enferm Neoplast, Lima (G. Gomez): 10; Italy: Universita di Genova (A. Ardizzoni): 6; Switzerland: Kantonspital St Gallen (D'Addario): 2; Inselspital, Bern (D. Betticher): 1; and Kantonspital Basel (Pless): 1.

	ACKNOWLEDGMENTS

 
This initial clinical trial was conducted by the EORTC and NCIC Clinical Trials Group. We thank the reviewers for their excellent suggestions to improve our article.

	NOTES

 
Supported in part by grants (5U10CA11488-30 through 5U10CA11488-34) from the National Cancer Institute. AstraZeneca provided the raltitrexed and an educational grant for data management and study conduct. This work was also supported, in part, by the EORTC Charitable Trust.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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Submitted May 10, 2007; accepted September 13, 2007.

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