Originally published as JCO Early Release 10.1200/JCO.2005.03.3027 on January 30 2006

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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

Andrew Bottomley, Rabab Gaafa, Christian Manegold, Sjaak Burgers, Corneel Coens, Catherine Legrand, Mark Vincent, Giuseppe Giaccone, Jan Van Meerbeeck

From the European Organisation for Research and Treatment of Cancer, EORTC Data Center, Brussels; University Hospital, Ghent, Belgium; National Cancer Center, Cairo, Egypt; Thoraxklinik Heidelberg, Germany; Erasmus MC, Rotterdam; NCIC DC, Ontario, Canada; Free University Medical Center, Amsterdam, the Netherlands

Address reprint requests Andrew Bottomley, Head of the Quality of Life Unit, European Organization for Research and Treatment of Cancer Data Center, Ave E Mounier 83, Box 11, Brussels, Belgium 1200; e-mail: andrew.bottomley{at}eortc.be

	ABSTRACT

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PURPOSE: For malignant pleural mesothelioma (MPM) patients with a poor prognosis, maintaining health-related quality of life (HRQOL) is important. This article compares the impact on HRQOL of first-line treatment with cisplatin versus raltitrexed and cisplatin.

PATIENTS AND METHODS: Patients with histologically-proven unresectable MPM, not pretreated with chemotherapy were randomly assigned to receive cisplatin 80 mg/m2 intravenously on day 1, with or without preceding infusion of raltitrexed 3 mg/m2. HRQOL was assessed with the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire C30 (EORTC QLQ-C30) and EORTC Lung Cancer Module (QLQ-LC13) tools. Assessments were conducted at baseline, immediately before every treatment cycle, at the end of treatment, and every six weeks for 12 months.

RESULTS: Two hundred fifty patients were randomly assigned, 80% were male with a median age of 58 years, WHO performance status 0, 1, and 2, in 25%, 62%, and 13% of cases. The clinical results found raltitrexed and cisplatin to be superior to cisplatin with regard to overall survival (P = .048). The global HRQOL scale was comparable at baseline on both treatment arms (P = .848); at no point was any significant difference apparent on this end point. Both treatments led to an improvement, over time, in dyspnoea. This effect is an important clinically meaningful reduction from baseline in the cisplatin/raltitrexed arm. However, the majority of scales of the EORTC QLQ-C30 or LC13 showed stabilization of HRQOL with few clinically significant differences between the treatment arms.

CONCLUSION: This study provides important information about the HRQOL of chemotherapy-treated MPM patients.

	INTRODUCTION

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Malignant pleural mesothelioma (MPM) is a relativity rare, yet very aggressive and often fatal disease.^1,2 In general, survival is poor, with a median of 7 to 11 months after diagnosis.³ The single highest risk associated with the development of MPM is exposure to asbestos. In the United States, more than 2,500 cases are diagnosed every year. The number of new cases in Europe is expected to double between 1998 and 2018.⁴

Given the advanced and aggressive nature of this disease, it is not surprising that MPM patients can have impaired health-related quality of life (HRQOL). While there is extensive research into HRQOL in non–small-cell lung cancer⁵ and small-cell lung cancer,⁶ the data on the HRQOL of MPM patients is relatively sparse. Existing studies, with the exception of several recent reports,^7,8 often involve relatively small patient numbers restricting conclusions regarding HRQOL. However, it is known that MPM patients often present with symptoms that can include dyspnea, coughing, nonspecific chest pains, weight loss, and night sweats.⁹

The disease is difficult to treat. Until recently, treatment options were limited, with no generally accepted standards.¹ Treatment intent is palliative and often recommended only for symptom control.¹⁰ Cisplatin is reported to be the most active (regarding response rates) chemotherapy regime available.¹¹ Recent evidence with newer antifolates, when combined with cisplatin, suggest this may be an important area for future research.¹² Given results from phase I/II clinical trials,^12-14 a phase III study was undertaken by the EORTC Lung Cancer Group and the National Cancer Institute (NCI) Canada to investigate whether the addition of raltitrexed to cisplatin would impact on HRQOL of MPM patients when compared to cisplatin alone. This article presents the symptoms and HRQOL findings.

	PATIENTS AND METHODS

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Study Design and Treatment
In this international, multicenter study (European Organisation for Research and Treatment of Cancer [EORTC] trial 08983 and the NCI Canada Clinical Trials Group BR17), the primary outcome was survival. Secondary outcomes included progression-free survival, safety, tumor-response rate, and HRQOL. Patients were randomly assigned to raltitrexed and cisplatin or cisplatin alone. Full details on the trial conduct and clinical outcome have been reported elsewhere.¹⁵ 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 Helsinki declaration. All patients provided written informed consent before being randomly assigned.

Procedures for HRQOL Data Collection
Two HRQOL measures were selected for the trial: the EORTC Quality of Life Questionnaire C30 (EORTC QLQ-C30, version 3)¹⁶ and the EORTC Lung Cancer 13 Module (EORTC QLQ-LC13).¹⁷ These tools have robust psychometric properties, and are the most frequently used HRQOL measures in lung cancer randomized clinical trials (RCTs).⁵ The EORTC QLQ-C30 is a core measure designed to be supplemented with disease-specific questionnaires.¹⁸ The EORTC QLQ-LC13 focus on symptoms and was developed and validated specifically for lung cancer patients. Both instruments were available in the native language of all participating patients.¹⁹

The EORTC QLQ-C30 measure comprises five functioning scales: physical, role, emotional, cognitive, and social; three symptom scales: fatigue, nausea/vomiting, and pain; six single item scales: dyspnoea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact; and the overall health/global QOL scale.

The EORTC QLQ-LC13 was designed for use with a wide range of lung cancer patients undergoing chemotherapy or radiotherapy.¹⁷ It includes 13 items which address key lung cancer symptoms (cough, hemoptysis, dyspnoea, and site specific pain), treatment-related adverse effect(s) (sore mouth, dysphagia, peripheral neuropathy, and alopecia) and pain medication. The dysphagia scale is multi-item; the remainders are single items scales.

The items on both measures were scaled and scored using the recommended EORTC procedures.²⁰ We excluded the financial impact of treatment scale from the analysis given this has limited value in an international clinical trial.

Protocol specified in the hypothesis that there would be no difference in the global HRQOL scale between treatment arms over the treatment period. The remaining HRQOL variables were then examined on an exploratory basis. The results of this study are presented in accordance with recent guidelines for reporting HRQOL.²¹

Given that statistical differences can occur when using large patient numbers and that these may not necessarily be clinically meaningful, we adopted a standard practice of interpretation of HRQOL scores using the minimal important difference approach. Differences of at least 10 points (on a 0 to 100 point scale) were classified as the minimum clinically meaningful change in a HRQOL parameters.²² Changes, 20 points were considered as large effects.

Assessments were performed at baseline–before start of therapy and not earlier than 14 days before randomization and before start of treatment, before the start of every cycle,^1-9 at the end of treatment, and then every six weeks until 12 months from randomization. EORTC guidelines for administering questionnaires were provided, ensuring standardization of HRQOL data by all personnel.²³ Compliance levels were monitored using standard EORTC procedures and calculated as the number of forms received out of the number expected at each assessment point.

Statistical Analysis
HRQOL was a secondary study end point. The sample size was based on the primary end point (survival). Randomization was undertaken in Brussels, at the EORTC Data Center, by telephone using a minimization technique independent from the investigators. Treatment comparison and score changes between baselines were performed using statistical analysis software (SAS Institute, Cary, NC), based on the intent-to-treat principle. A mixed-model approach estimated the HRQOL differences with a one-step autoregressive covariance structure. All patients with at least one valid HRQOL form were included in the analysis (n = 229). In order to correct for multiple comparisons, and to avoid type I errors, the level of statistical significance was set at P = .01.

Given that missing data is a common problem in HRQOL studies, sensitivity analyses were performed investigating the reasons for missing values (by drop-out) for various clinical factors on the probability of a missing HRQOL observation. The number of missing observations (generalized linear model for the Poisson process), the probability of any missing observations (logistic regression: completers v noncompleters) and time until drop-out (time-to-event analysis via Kaplan-Meier methodology, log-rank test) were used. Analysis of complete cases, or the last observation carried forward with missing observations (before death or progression), was conducted to check the robustness of the main results.

The group of patients having baseline and follow-up HRQOL data provided more than 95% power to detect a 10-point shift on the global HRQOL scale using a two-sided test at the 1% significance level. This posthoc estimation of the power is based on the average observed value and its SD (mean = 58.5, SD = 21.5).

	RESULTS

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Between March 2000 and January 2003, 250 patients were recruited into this trial. One hundred twenty-six patients received raltitrexed and cisplatin and 124 patients received cisplatin alone. The basic characteristics of those in each treatment group along with HRQOL assessments are presented in Table 1.

Compliance With HRQOL Measures
Table 2 summarizes compliance over the course of the study. Baseline questionnaires were available for 229 patients (91.6%) and all subsequent analyses were based on this sample. Overall compliance for the first seven cycles was over 83%, with no significant differences between arms overall (P = .10). Fisher's exact tests for compliance difference showed no significant difference from baseline over any treatment assessment time points at the P = .05 level (Bonferroni adjustment). Given the advanced and aggressive nature of MPM, patient attribution due to drop out or death (over treatment) led to a reduction in absolute numbers of patients available for inclusion in the analysis. For these reasons, the HRQOL analysis was restricted only on treatment up to, and including, cycle five.

View larger version (17K): [in this window] [in a new window]   Fig 1. Mean baseline scores for the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire C30 by treatment group and normative reference values. Functional scales: physical (PF), role (RF), emotional (EF), cognitive (CF), social (SF), and global quality of life (GL). Symptom scales/items: fatigue, (FA), nausea vomiting (NV), and pain (PA); six single item scales: dysponea (DY), sleep disturbance (SL), appetite loss (AP), constipation (CO), diarrhea (DI), and global quality of life (GL) scale.

Primary HRQOL End Point
Using the global HRQOL scale selected a priori, it is seen that at baseline HRQOL for both treatment groups is hindered, yet comparable (Fig 2). These differences represent a considerable decline in global HRQOL when compared to a normative population. During the subsequent assessments there was little change in global HRQOL, suggesting that in both arms, while being considerably impaired, additional treatment had limited impact on patient well-being, and as predicted, this was similar between both groups.

View larger version (9K): [in this window] [in a new window]   Fig 2. Primary health-related quality of life end point (global health status).

View larger version (45K): [in this window] [in a new window]   Fig 3. Other scales: (A)fatigue, (B) nausea/vomiting, (C) pain, (D) dyspnoea, (E) insomnia, (F) appetite loss, (G) constipation, (H) diarrhea, (I) LC dyspnoea, (J) LC coughing, (K) LC hemoptysis, (L) LC sore mouth, (M) LC dysphagia, (N) LC peripheral neuropathy, (O) LC alopecia, (P) LC pain in chest, (Q) LC pain in arm or shoulder, and (R) LC pain in other parts. LC, lung cancer module scales.

Levels of insomnia, appetite loss, constipation, diarrhea, lung cancer scale coughing, hemoptysis, sore mouth, dysphagia, alopecia, pain in the chest, and pain in the arm were all stable and without treatment effects over time.

Progression
Differences in baseline scores were examined between those patients who progressed and those without progression, stratified by treatment, over the end points. No statistically significant differences were found.

Drop Outs
The sensitivity analysis using both complete case and last observation carried forward shows comparable results, supporting the main findings. Modeling the time to drop-out showed no trends for several key factors, for example, age ( 50 v >50; P = .1120), treatment (P = .7412), histology (P = .1202), T stage (P = .0641), N stage (P = .9421), or M stage (P = .1067). However, a significant institution effect (P < .0138) is seen, indicating some institutes were better at obtaining completed patient HRQOL forms than others. Similar results were obtained when modeling the missing values. In addition, baseline scores were independent of the time of the drop out. Of the 229 patients with baseline questionnaires, 156 (68%) completed their questionnaires at all scheduled time points during the first five chemotherapy cycles before death or progression.

	DISCUSSION

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This study is one of a few large-scale randomized controlled trials investigating MPM patient survival times and also combining HRQOL outcomes. The primary objectives were to evaluate survival benefits, along with the important secondary end point of a detailed evaluation of HRQOL and symptom impact, during treatment, when comparing the standard cisplatin arm versus the cisplatin/raltitrexed experimental arm. While the survival results demonstrate a significant survival advantage of including raltitrexed, the findings related to the global HRQOL scale support our hypothesis of no difference between treatment arms.

Examining the baseline HRQOL scores, we noted similarities. However, while some statistical differences occurred on seven scales between the baseline scores for each group, these were not of clinical significance. Unlike many other disease sites, unfortunately, there exists no formal EORTC QLQ-C30 reference data for comparison with our population²⁵; however, given this is a rare disease this fact is understandable. From the results we are able to show that when compared to a normative population,²⁴ as expected, both groups had impaired HRQOL at baseline.

Taking the global HRQOL scale as our primary HRQOL end point, it was observed that, over the course of the five cycles of treatment, there were no differences between the two treatment arms. However, it is clear that both groups had impairment of global HRQOL scores, when compared to a normative general population. Importantly, in this disease population, this level did not deteriorate, remaining stable over treatment time.

The remaining scales were reported on an exploratory basis. There were relatively few HRQOL differences between treatment arms over the course of treatment. However, peripheral neuropathy did reveal differences with statistically significant increased problems in the cisplatin/raltitrexed arm at cycles three and five, but did not become clinically meaningful.

Both treatments also led to a significant improvement, over time, in dyspnoea (as noted in the dyspnoea scale of the EORTC QLQ-C30). This effect represents, clinically, a meaningful reduction from baseline in the cisplatin/raltitrexed arm. A similar pattern was also seen in the EORTC QLQ-LC13 dyspnoea scale. Clearly, dyspnoea is a major symptomatic problem for patients. Therefore, any reduction of this problem is of importance to patient care.²⁶

Fatigue was seen to steadily worsen in both arms to a statistically significant increase over time, to a near, but not clinically meaningful difference at the fifth cycle compared to baseline. Given it is well known that use of cisplatin is related to increased fatigue this finding is not unexpected.²⁷ In addition, nausea and vomiting increased over time, in both groups, showing a statistically and clinically meaningful increase from baseline from cycle two onwards. This again is a common problem for patients undergoing cisplatin chemotherapy treatment²⁸ and is also seen in the clinical-reported toxicity data.¹⁵

However, pain levels remained fairly constant in both arms over treatment. Stabilization of HRQOL and symptoms were also seen for insomnia. Appetite loss, constipation, diarrhea, lung cancer scale coughing, hemoptysis, sore mouth, dysphagia, alopecia, pain in the arm, and pain in the chest were also evident. All these HRQOL issues were constant with no deterioration over time. Cognitive functioning was unimpaired in our patients and comparable with a normative reference population. While there is growing evidence that cognitive functioning is influenced by chemotherapy^29,30 our study found no evidence for this in either treatment arm. However, given that our study did not assess long-term HRQOL this could be an explanation together with the fact that the EORTC cognitive functioning scale is relatively brief. As with other self-assessment cognitive functioning scales, the scales used may not correlate well with more objective cognitive testing.^31,32,33

We are aware of only one other large randomized study, whose HRQOL data has only been published in abstract form.³⁵ Vogelzang et al³⁴ reports examining a novel antifolates (pemetrexed) with cisplatin (n = 226) compared to cisplatin alone (n = 222). The survival rate reported is significantly superior in the combined arm (12.1 months v 9.3 months, P = .020). These HRQOL experiences were assessed using a modified lung cancer measure⁷ and reveal that both treatment arms also experienced increased fatigue; by cycle six significantly worse dyspnoea was seen in the cisplatin arm. The initial three cycles led to a reduction in global HRQOL and stabilized at subsequent assessments. From these general findings, while not directly comparable given different HRQOL measures were used in each trial, it is still possible to see that these results are not dissimilar to those presented here.

Some limitations apply to our study. For example, while we had a high baseline compliance of 91% from a reasonable sample size (n = 250) suffering a rare disease, due to rapid patient attrition, we were unable to focus on results after the fifth treatment cycle. Patient numbers simply become too few to make conclusions from this point. Therefore, our results are only representative of patients under treatment, a not uncommon problem in such an advanced aggressive disease.⁵ However, we conducted a sensitivity analysis, and this revealed no major bias, with the exception of an institutional effect, suggesting that certain institutions had better success at collecting data (eg, more resources) over the five cycles of treatment. In the future, the EORTC will explore key factors with institutions to help improve QOL compliance in new clinical trials.

Another concern may relate to the use of the measures, in particular the EORTC QLQ-LC13, which while heavily symptom based, is not specifically developed for use in MPM patients. However, research reported by Nowak et al⁸ confirms the feasibility and validity of both measures for MPM patients. Furthermore, when Muers et al¹⁰ compared the EORTC QLQ-C30 plus the EORTC QLQ- LC13 against the commonly used Functional Assessment to Cancer Therapy Lung (FACT-L) measure³⁶ in MPM patients, the majority who expressed a preference, preferred the EORTC measures. Therefore, the general conclusion is that these EORTC measures are robust and valid for use in this disease.

These findings also highlight the importance of using symptom scales to identify disease or treatment-related problems in such a disease setting. For example, while the global HRQOL scale provides an important index of the patients overall well-being, symptom scales also add greater insights. In future trials of MPM patients, rather than using the global HRQOL scale, it may also be useful to focus on symptom related problems which can be influenced by the disease and treatment, and which then can be targeted with any appropriate interventions.

In conclusion, this study suggests that there were no significant differences in the global HRQOL scale between groups over the course of the treatment representing a stabilization of global HRQOL. In palliative situations where a disease, such as MPM, is rapidly fatal, this should be regarded as an important outcome.^2,37 Over treatment, both arms experienced increases in fatigue, nausea and vomiting, all common problems with cisplatin based regimes. Patients in the cisplatin/raltitrexed arm had significant clinically meaningful improvements of dyspnoea during treatment from cycle two onwards compared to baseline scores. Given that survival was increased significantly in the cisplatin/raltitrexed arm, and that there was stabilization on global HRQOL, these findings provide useful insights to help treat symptoms and understand the impact of cisplatin/raltitrexed in selected MPM patients.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Mark Vincent AstraZeneca (A) AstraZeneca (B); AstraZeneca (A) Giuseppe Giaccone AstraZeneca (A) AstraZeneca (A) AstraZeneca (B) Jan Van Meerbeeck AstraZeneca (A) AstraZeneca (A)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

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Conception and design: Andrew Bottomley, Christian Manegold, Sjaak Burgers, Catherine Legrand, Mark Vincent, Giuseppe Giaccone, Jan Van Meerbeeck Administrative support: Andrew Bottomley, Rabab Gaafar, Christian Manegold, Sjaak Burgers, Catherine Legrand, Mark Vincent, Giuseppe Giaccone, Jan Van Meerbeeck Provision of study materials or patients: Rabab Gaafar, Christian Manegold, Sjaak Burgers, Mark Vincent, Giuseppe Giaccone, Jan Van Meerbeeck Collection and assembly of data: Andrew Bottomley, Rabab Gaafar, Christian Manegold, Sjaak Burgers, Corneel Coens, Mark Vincent, Giuseppe Giaccone, Jan Van Meerbeeck Data analysis and interpretation: Andrew Bottomley, Corneel Coens, Catherine Legrand, Jan Van Meerbeeck Manuscript writing: Andrew Bottomley, Rabab Gaafar, Christian Manegold, Sjaak Burgers, Corneel Coens, Catherine Legrand, Mark Vincent, Giuseppe Giaccone, Jan Van Meerbeeck Final approval of manuscript: Andrew Bottomley, Rabab Gaafar, Christian Manegold, Sjaak Burgers, Corneel Coens, Catherine Legrand, Mark Vincent, Giuseppe Giaccone, Jan Van Meerbeeck

 

	Acknowledgment

 
We thank Annelore Dehoorne and Sonia Dussenne for the data management.

	NOTES

 
This study was conducted by the European Organisation for Research and Treatment of Cancer and the National Cancer Institute of Canada Clinical Trials Group.

Supported by an educational Grant from AstraZeneca, and in part by Grants No. 5U10CA11488-30, 5U10CA11488-31, 5U10CA11488-32, 5U10CA11488-33, and 5U10CA11488-34 from the National Cancer Institute, Bethesda, MD.

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

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Submitted July 19, 2005; accepted November 16, 2005.

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