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Assessing Quality of Life During Chemotherapy for Pleural Mesothelioma: Feasibility, Validity, and Results of Using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire and Lung Cancer Module

From the National Health and Medical Research Council Clinical Trials Centre, University of Sydney; Sydney Cancer Centre–Royal Prince Alfred and Concord Hospitals, Sydney; and Sir Charles Gairdner Hospital, Perth, Australia

Address reprint requests to Anna Nowak, MD, NHRMC, Clinical Trial Centre, Locked Bag 77, Camperdown NSW 1450 Australia; e-mail: annan{at}ctc.usyd.edu.au

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: To assess the feasibility and validity of using the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and Lung Cancer Module (QLQ-LC13) to describe health-related quality of life (HRQL) in patients with pleural mesothelioma undergoing combination chemotherapy, to identify the most impaired aspects of HRQL, and to assess the impact of chemotherapy on HRQL.

PATIENTS AND METHODS: Fifty-three patients received cisplatin on day 1 and gemcitabine on days 1, 8, and 15 of a 28-day cycle for a maximum of six cycles. HRQL was assessed using the EORTC QLQ-C30 and QLQ-LC13.

RESULTS: Compliance was 100% at baseline but subsequently decreased. At baseline, role function and social function were the most impaired domains, and the worst-rated symptoms were fatigue, dyspnea, pain, insomnia, appetite loss, and cough. Dyspnea, pain, insomnia, and cough improved with chemotherapy, although functional domains and chemotherapy-related symptoms deteriorated. Fatigue remained unchanged. Few patients reported hemoptysis. Functional domains and symptoms scales from the QLQ-C30 demonstrated predictive validity for survival. The predictive value of QLQ-LC13 pain scores was improved by combining three pain items into a single score. Dyspnea scores were correlated strongly with lung function as measured by forced vital capacity.

CONCLUSION: This study supports the validity of the EORTC QLQ-C30 and LC13 as outcome measures for trials of chemotherapy in mesothelioma. Although the most prominent symptoms reported were concordant with clinical experience, impairments in role and social function and insomnia were worse than expected. Future research should focus on how best to apply, analyze, and interpret existing, validated HRQL instruments in mesothelioma research and practice, not on the development of new ones.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Pleural malignant mesothelioma usually presents as advanced disease and is difficult to treat using conventional means.^1,2 Patients commonly report dyspnea, fatigue, chest pain, and weight loss at diagnosis, but the nature and severity of self-reported symptoms have not been assessed using validated measures of health-related quality of life (HRQL), nor has the effect of mesothelioma on social, emotional, or functional domains been studied. There are no mesothelioma-specific HRQL instruments available, and although validated tools are available for assessment of HRQL in lung cancer,^3-6 the validity and feasibility of their use in mesothelioma has not been studied.

HRQL may be measured in phase II trials to gain information on the symptoms and functions that are important to patients and to confirm that data collection is feasible and the chosen instrument is valid. Furthermore, if the aim of the study treatment is to improve aspects of HRQL, then HRQL data can provide preliminary information about its activity. Assessing HRQL in the phase II setting helps ensure that optimal methods are used in subsequent phase III trials.

Approximately one third of patients with pleural mesothelioma respond to combination chemotherapy. Symptomatic benefit and improved HRQL^7-9 usually accompany responses. However, the effects of mesothelioma and cytotoxic treatment on HRQL have been formally assessed in only three studies. In each, a different assessment instrument was used, none of which has been validated in this disease. We previously reported the results of a phase II study of cisplatin and gemcitabine in advanced mesothelioma⁷ in which HRQL was assessed with the European Organization for the Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30)¹⁰ and Lung Cancer Module (QLQ-LC13).⁶ The EORTC QLQ-C30 is reliable and valid in populations that include lung cancer patients.^10,11 The QLQ-LC13 is a lung cancer–specific questionnaire designed as a modular supplement to the QLQ-C30; the QLQ-LC13 is reliable and valid in lung cancer but untested in mesothelioma.⁶ Here, we report the HRQL analysis in more detail, focusing on the spectrum of HRQL impairment at baseline, the feasibility of collecting HRQL data in these patients, and the impact of treatment on HRQL. In addition, aspects of the validity of the use of this tool in mesothelioma are assessed.

	PATIENTS AND METHODS

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Eligibility Criteria
Patients were accrued from six tertiary referral centers. Eligible patients had confirmed malignant pleural mesothelioma, were aged 75 years, had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, life expectancy greater than 12 weeks, and measurable disease. The ethics committee of each center approved the protocol. Written informed consent was obtained from patients before study entry.

Treatment
Patients received cisplatin 100 mg/m² intravenously on day 1 and gemcitabine 1,000 mg/m² on days 1, 8, and 15 of a 28-day cycle to a maximum of six cycles. Treatment ceased in the event of disease progression, unacceptable toxicity, or patient request.

End Point Assessment
The primary end point of the trial was tumor response. Secondary end points were time to progression, overall survival, duration of response, toxicity, and HRQL. HRQL was assessed with the EORTC QLQ-C30 version 3.0¹⁰ and QLQ-LC13⁶ at baseline and on day 1 of cycles 2, 4, and 6, after cycle 6, and 8 weekly thereafter until disease progression. Patients who had experienced disease progression or were no longer on treatment were not required to complete HRQL forms. The QLQ-C30 is a validated, patient-rated core questionnaire for cancer patients in clinical trials and covers the domains of global health and physical, emotional, role, social, and cognitive function. Symptoms of fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties are also assessed. The QLQ-LC13 is a 13-item lung cancer–specific questionnaire that includes multi-item and single-item measures of lung cancer symptoms and treatment-associated toxicities.⁶

Compliance
Compliance at each assessment was calculated by dividing the number of forms completed by the number of patients expected to complete the forms at that time point. For individual items, compliance was calculated by dividing the number of times the item was completed by the number of times the form was completed.

Baseline HRQL
The functional domain and symptom scores were calculated for each patient following the EORTC scoring guidelines.¹² The mean score for all patients was then calculated for each domain and symptom.

Change in HRQL During Treatment
Each patient's experience of each domain on treatment was summarized by their mean change score, calculated by subtracting their baseline score from the mean of their scores on treatment. This approach was used to minimize the likelihood that systematically missing data from progressing patients would bias the results. The group's experience of treatment was summarized by the average of all patients' mean change scores and compared with a mean change of zero using one-sample Student's t tests. A priori hypotheses were that pain and dyspnea would improve and that fatigue, alopecia, and nausea and vomiting would deteriorate during treatment.

Comparison With Reference Values
HRQL reference data were obtained from the EORTC QLQ-C30 reference values for a normal Norwegian adult population¹³ and a population of stage I to IV non–small-cell lung cancer (NSCLC) patients.¹⁴ Reference data were not available for the LC13.

Floor and Ceiling Effects
Floor and ceiling effects reflect the extent to which scores cluster at the top or bottom of the scale range. These effects were determined using the percentage of the sample scoring the minimum (floor, best for symptoms) or maximum (ceiling, best for functions) possible scores at baseline.

Internal Consistency Reliability
The internal consistency of the multi-item scales was assessed using Cronbach's alpha coefficient. Cronbach's greater than .70 was considered desirable.

Discriminative Validity
Discriminative validity is present when the instrument can detect expected differences in HRQL between groups classified by independent criteria. We generated a priori hypotheses about the effect of ECOG PS, hemoglobin, and forced vital capacity (FVC) on HRQL domains and symptoms, specifically that patients with ECOG PS 0 to 1 would have significantly better scores for physical function, global health status, and fatigue than patients with ECOG PS 2; that baseline hemoglobin concentration would be correlated with fatigue, global health status, and physical function; and that FVC would be correlated with the dyspnea scales from both tools. Data were analyzed using Spearman's rank correlation.

Predictive Validity
Predictive validity refers to the ability of the HRQL tool to predict patient outcomes. We assessed associations between baseline HRQL and survival. For each domain, patients were divided into groups scoring above and below the median. Survival distributions of the groups were compared with the log-rank test, using the P value to summarize the strength of association between aspects of HRQL and survival. This analysis was not done for consistently low-scoring symptoms. Multivariable relationships were assessed with Cox regression models. First, we added each HRQL domain in turn to a model that included established prognostic factors: sex, anemia, WBC count, performance status, and nonepithelioid histology.¹⁵ This analysis shows the prognostic information HRQL domains provide in addition to established factors. Second, we used forward and backward selection methods to determine the best subset of independent prognostic factors from among all those that were significant in univariate analysis.

Derivation of a Composite Pain Score
A composite pain score was derived for the LC13 by combining the three items for chest pain, arm pain, and pain elsewhere, using a similar calculation to other composite scores in the QLQ-C30 and LC13. Raw score = (Item 1 + Item 2 + Item 3)/3, Transformed Score = {(Raw score –1)/range} x100

	RESULTS

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Patient Characteristics
All analyses are based on the 53 eligible patients whose baseline characteristics are listed in Table 1. Two patients were ineligible: one with peritoneal mesothelioma and another with adenocarcinoma on pathology review. Most patients had tumor-node-metastasis system stage III or IV disease (87%) and an ECOG PS of 0 or 1 (91%).

Baseline HRQL
For functional domains, a high score denotes better functioning. Role, social, and emotional functions were the most impaired at baseline, with mean scores of 57, 67, and 76, respectively (Fig 1A). Although 87% of patients had stage III or IV disease, physical function was the least impaired with a mean score of 90, and the mean score for cognitive function was 84. Global health status was scored as markedly impaired, with a mean score of 55.

View larger version (29K): [in this window] [in a new window]   Fig 1. Mean baseline health-related quality-of-life scores for (A) functional domains of the European Organization for Research and Research of Cancer Core Quality of Life Questionnaire (QLQ-C30) and (B) symptom domains of the QLQ-C30 and Lung Cancer Module (LC13). Mean change scores on treatment for (C) functional domains of the QLQ-C30 and (D) symptom domains of the QLQ-C30 and LC13. (* = P < .05).

Change in HRQL During Treatment
Patients' functional scale scores, on average, did not improve during chemotherapy (Fig 1C). There were no statistically significant changes in emotional, physical, or role function or in global health status, although all these functions showed a trend to deterioration. There were moderate decreases in cognitive function (–11; P < .01) and social function (–9; P = .05). There were, however, improvements (lower scores) in some of the worst-rated symptoms (Fig 1D); namely, cough (–9; P = .02), arm pain (–8; P = .05), and other pain (–11, P = .05) improved significantly. Symptoms related to chemotherapy that deteriorated significantly during treatment (higher scores) were alopecia (26; P < .01), peripheral neuropathy (8; P = .01), and nausea and vomiting (13; P = .03).

Comparison With Reference Data
Figure 2 shows a comparison of scores on the QLQ-C30 from our mesothelioma patients to reference scores from a normal population and a population of NSCLC patients of all disease stages.^13,14,16 The aim of this comparison is to aid interpretation rather than to test hypotheses, so no formal statistical tests were done. The population demographics are listed in Table 2. The mean score for role function from mesothelioma patients was approximately 15 points lower than the NSCLC patients and 25 points lower than the normal population, and the mean score for social functioning in mesothelioma patients was approximately 10 and 20 points lower, respectively. The mesothelioma group had emotional function scores between the two reference groups, and all groups scored similarly for cognitive function. Physical function scores were similar for the mesothelioma patients and the normal group, approximately 25 points higher than for the NSCLC group. For global health status, both the mesothelioma patients and the NSCLC group scored 15 to 20 points lower than the normal population.

View larger version (28K): [in this window] [in a new window]   Fig 2. Mean baseline health-related quality-of-life (HRQL) scores for functional and symptom domains of the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30) for the mesothelioma study patients, compared with a normal reference population and a population of lung cancer patients of all stages.

Floor and Ceiling Effects
Few patients scored 0 or 100 for the global health status domain. Few patients scored 0 for the other functional domains; however, ceiling effects were prominent for social, cognitive, and physical function, with many patients scoring 100. Several symptoms were absent in many patients at baseline (ceiling effect); some were related to treatment toxicity (alopecia, nausea, and constipation), and others are more frequent in lung cancer than in mesothelioma (hemoptysis, arm pain, and pain elsewhere). There were no prominent floor effects for any symptoms.

Internal Consistency Reliability
Cronbach's alpha coefficient for the multi-item scales of the QLQ-C30 and LC13 exceeded 0.70 for social, emotional, and role function; global quality of life; nausea and vomiting; fatigue; pain; and dyspnea. Cognitive function (0.51) and physical function (0.52) had lower coefficients, as expected, because of the nature of the items in these scales.¹⁰

Discriminative Validity
Discriminative validity was assessed by looking for expected differences in HRQL between groups defined by independent criteria. We have previously shown that patients with an objective response have a significant improvement in FVC when compared with nonresponders⁷ and that increase in FVC is correlated with tumor response.¹⁷ Baseline FVC (as a percentage of predicted) was strongly correlated with dyspnea as measured by the QLQ-C30 (r = –0.65; P < .0001) and the LC13 (r = –0.42; P = .002). ECOG PS scores were not correlated with global health status (r = –0.19; P = .2), physical function (r = –0.14; P = .3), or fatigue (r = 0.10; P = .5), but were correlated with appetite loss (r = 0.34; P = .03) and cough (r = 0.30; P = .01). Hemoglobin concentrations at baseline were not correlated with physical function (r = 0.21; P = .14), global health status (r = 0.18; P = .2), or fatigue (r = –0.13; P = .34). At day 1 of cycle 5, hemoglobin concentration was substantially correlated with global health status (r = 0.47; P = .01) but not with physical function (r = 0.29; P = .14) or fatigue (r = –0.15; P = .4).

Predictive Validity
Baseline scores for functions (role, cognitive, emotional, and physical) and symptoms (fatigue, dyspnea, and pain) were significant predictors of survival (P < .05; Fig 3). Fatigue and physical function were the strongest predictors. Prominent symptoms that were not associated with survival time included dyspnea, pain (LC13), appetite loss, insomnia, cough, and constipation. Physical function, role function, fatigue, and three of the pain domains (chest pain from the LC13, pain from the QLQ-C30, and the novel composite pain score from the LC13) were independently significant in a model already accounting for the effects of performance status, sex, nonepithelioid histology, WBC count, and hemoglobin (Table 3). Both multivariable selection methods gave models that included HRQL and a traditional factor; however, the individual models were different: sex and pain were significant using backward selection, whereas hemoglobin and fatigue were significant using forward selection.

View larger version (25K): [in this window] [in a new window]   Fig 3. Kaplan-Meier estimates of overall survival time for patients, divided into groups scoring above and below the median for each of nine health-related quality-of-life (HRQL) domains. (A) Global health status; (B) physical function; (C) role function; (D) cognitive function; (E) emotional function; (F) fatigue; (G) insomnia; (H) pain (QLQ-C30); (I) dyspnea (QLQ-C30). Survival was compared between groups using the log-rank test, with P values shown above. Dashed line represents patients with HRQL better than median score for that domain; solid line represents patients with HRQL worse than median score for that domain. QLQ-C30, European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire.

View larger version (10K): [in this window] [in a new window]   Fig 4. Kaplan-Meier estimates of overall survival time for patients, divided into groups scoring above and below the median for three pain items from the Lung Cancer Module (LC13) and a composite score derived from these three items. Dashed line represents patients with health-related quality of life (HRQL) better than median score for that domain; solid line represents patients with HRQL worse than median score for that domian. (A) LC13 composite pain score; (B) chest pain; (C) arm pain; (D) pain elsewhere. Survival was compared between groups using the log-rank test, with P values shown above.

	DISCUSSION

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The third trial including HRQL analysis is presented here. At the inception of the study, a primary objective was to document HRQL changes in treated patients. In the absence of a validated tool for measuring HRQL in mesothelioma, the QLQ-C30 and LC13 were chosen because of substantial data supporting their validity in lung cancer and other settings.^6,10-14,16

In this trial, compliance levels were initially high but decreased over time, with the majority of missing forms being attributed to data management staff omission rather than patient noncompliance. Compliance compared favorably with other studies collecting HRQL data in patients with advanced cancer (reviewed in Bottomley¹⁹), which supports the feasibility of using these questionnaires in this setting; however, communication with data management staff is important to optimize data collection.

Although patients were selected for the diagnosis of a physical illness, it is interesting that the worst-rated functional domains were role, social, and emotional function. Physical function was rated least impaired. The high physical function scores are surprising given the frequency of fatigue and dyspnea. However, the questions comprising this domain ask about difficulty walking, the need to stay in a bed or chair during the day, assistance with self-care, and trouble doing strenuous activities. The inclusion criteria for this trial specified an ECOG PS of 0 to 2, excluding most patients with impairment in these activities. Baseline scores are difficult to interpret without a comparator, and scores from different domains are not directly comparable.

The symptoms rated worst at baseline concur with clinical experience. Fatigue, dyspnea, pain, appetite loss, cough, and constipation were prominent. Insomnia was rated as severe as pain and is possibly underrecognized in clinical practice. The high score for pain elsewhere and the high proportion of these patients reporting back pain suggests that answers to this item may be related to the disease process. Patients may consider chest pain to be anterior and describe posterior thoracic pain as back pain. An item that examines back pain or posterior thoracic pain may be a more specific addition to the questionnaire for mesothelioma. Alternatively, as little additional information is gained by separating pain sites in the LC13, the composite pain score combining all three might provide a better index of pain.

Some of the mesothelioma-related symptoms rated worst at baseline, such as pain and cough, improved with chemotherapy. These symptoms would be expected to worsen in people with untreated mesothelioma. The changes we observed reflect small to medium effects according to the criteria of Kazis (4 to 10 points equates to an effect size of 0.2 to 0.5 standard deviations), suggesting that these improvements are likely to be clinically significant.²⁰ Although fatigue and appetite loss were prominent at baseline, they did not improve with chemotherapy; however, these are common side effects of cisplatin and gemcitabine. Other symptoms of chemotherapy toxicity increased during treatment, again with small to medium effect sizes, suggesting that these changes are clinically significant.

The impact of nausea and vomiting was less than expected based on clinician ratings using the National Cancer Institute Common Toxicity Criteria.⁷ Questionnaires were administered on day 1 of each cycle, at least 4 weeks after their last dose of the most emetogenic chemotherapy. Because the EORTC questionnaires ask about the previous week, they need to be administered on day 8 to detect early transient side effects of chemotherapy.

Moderate declines in scores for cognitive and social function suggest that chemotherapy had a negative effect on these domains. However, this may be partly explained by prominent ceiling effects for these domains, with baseline scores for many patients already at a maximum and only able to deteriorate with treatment. Impairment in cognitive function may reflect the effects of chemotherapy, antiemetics, or corticosteroids.

The important question of whether these patients experienced HRQL benefits from this palliative regimen is difficult to answer without an untreated control group. The changes seen during treatment support the activity of cisplatin and gemcitabine in palliating some of the worst-rated symptoms of mesothelioma. Although two other studies have shown some HRQL benefits from palliative chemotherapy,^9,18 it is difficult to compare HRQL data from these trials because of differences in measurement tools, treatment regimens, and patient selection. Nevertheless, all three trials reported improvements in some symptoms, functions, and global perceptions.

Comparisons of our mesothelioma patients with the reference populations is interesting, despite the obvious limitations of comparing data from three unrelated studies. The reference normal population was obtained by surveying healthy Norwegians, whereas the reference NSCLC population has demographics more similar to those of our mesothelioma patients. Role and social function were scored more than 20 points lower in mesothelioma patients than in the normal population and more than 10 points lower than in the NSCLC population. Previous work has shown that patients regard a change of 20 points as "very much worse" and 10 to 20 points as "moderately worse."²¹ Hence the data suggest that these patients with mesothelioma reported substantial impairments in role and social function compared with a normal population and moderate impairments compared with a heterogeneous group of NSCLC patients. The similarity of the physical function scores in the normal and mesothelioma populations is surprising but reflects ceiling effects and the good PS of our study patients. Global health status was more than 20 points lower in mesothelioma patients than in the normal population, a large difference according to King et al.²² The mesothelioma patients, as expected, rated many symptoms as substantially worse than the normal population, whereas the similar symptom scores of the lung cancer and mesothelioma populations would be expected from clinical experience.

This study supports many aspects of the validity of the QLQ-C30 and LC13 in good PS patients with measurable pleural mesothelioma in a clinical trial of chemotherapy. Most functions and symptoms were relevant at baseline, and some symptoms improved with treatment. The ceiling effect for physical function probably reflects the good PS of these patients and may not be present in an unselected group with mesothelioma. However, it remains possible that the tool cannot distinguish small degrees of physical function impairment in this group. Hemoptysis and arm pain were infrequent and could be excluded from a mesothelioma-specific instrument. Tests of internal consistency supported the validity of the scales in this population. Cognitive function is a two-item scale and thus more likely to show poor internal consistency. The lower Cronbach's alpha coefficient of the physical function domain reflects the study entry criteria, with few very poor PS patients in this group.

The predictive validity of the QLQ-C30 in this population was supported by significant associations between survival and all but one functional domain item, as well as fatigue, dyspnea, and pain. The lack of association between global health status and survival is surprising and may simply reflect the small sample size, although the trend was in the expected direction. Individual items from the LC13 module were not strongly associated with survival, although all showed trends in the expected direction, and the novel composite pain score did show a strong association. The importance of these HRQL domains as independent prognostic factors was supported by multivariable regression. The small number of patients and their homogeneity as a result of the trial inclusion criteria limited our ability to assess discriminative validity, as there was little variation in hemoglobin and ECOG PS in this group. Physician ratings of PS are commonly used to validate HRQL measures in cancer^3,6,10,23; however, most patients in this study had ECOG 0 (32%) or 1 (59%) PS. The same explanation applies to the lack of associations between hemoglobin levels and fatigue, physical function, or global health status. The lack of association between hemoglobin and HRQL after four cycles of chemotherapy when there was more variation in hemoglobin levels suggests that fatigue is multifactorial in this setting. The validity of the dyspnea scales was supported by strong associations with FVC. We have previously shown that FVC improves with objective tumor response⁷ and is correlated strongly with tumor measurements.¹⁷ This finding suggests that changes in FVC are also reflected in patients' perceptions of dyspnea in mesothelioma.

This study supports the validity of the QLQ-C30 and LC13 as outcome measures for trials of chemotherapy in malignant mesothelioma. Although the most prominent symptoms reported were concordant with clinical experience, impairments in role and social function and insomnia were worse than expected and are probably underrecognized in practice. The LC13 item for hemoptysis contributed little, and its three items for pain are probably better combined into a composite score. Our study design did not allow us to assess test-retest reliability, convergent and divergent validity, and responsiveness. Future research should focus on how best to apply, analyze, and interpret existing, validated HRQL instruments in mesothelioma research and practice, not on the development of new ones.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Supported in part by a grant from Eli Lilly (Indianapolis, IN) for data management; an Eva K.A. Nelson scholarship from the University of Western Australia, a Medical Oncology Group of Australia/Novartis Clinical Research Fellowship, and a John Nott Traveling Fellowship (A.K.N.).

Some data from this study have been previously published.⁷

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

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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Submitted September 29, 2003; accepted April 30, 2004.

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