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Originally published as JCO Early Release 10.1200/JCO.2005.01.003 on February 14 2005

Journal of Clinical Oncology, Vol 23, No 10 (April 1), 2005: pp. 2136-2144
© 2005 American Society of Clinical Oncology.
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Randomized Phase II Study of Two Gemcitabine Schedules for Patients With Impaired Performance Status (Karnofsky performance status ≤ 70) and Advanced Non–Small-Cell Lung Cancer

S. Baka, L. Ashcroft, H. Anderson, M. Lind, P. Burt, R. Stout, I. Dowd, D. Smith, P. Lorigan, N. Thatcher

From the Christie Hospital and Wythenshawe Hospital, Manchester, Princess Royal Hospital, Hull, United Kingdom

Address reprint requests to Sofia Baka, MD, Christie Hospital, Wilmslow Rd, Withington, Manchester M20 4BX, United Kingdom; e-mail: bakasofia{at}hotmail.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
PURPOSE: This randomized phase II study compared two treatment schedules of gemcitabine in patients with non–small-cell lung cancer (NSCLC) and impaired Karnofsky performance status (KP). Primary objectives were to record changes from baseline KP and to assess symptom palliation. Secondary objectives were overall survival, tumor response, and toxicity.

PATIENTS AND METHODS: Patients with stage IIIb and IV NSCLC and KP ≤ 70 were randomly assigned to receive gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of each 28-day cycle (3w4) or gemcitabine 1,500 mg/m2 on days 1 and 8 of each 21-day cycle (2w3), both for up to six cycles. KP, toxicity, and SS14 lung cancer specific questions were recorded before each cycle of treatment. Response was evaluated 4 weeks after the last cycle.

RESULTS: One hundred seventy-four patients were enrolled. There was significant early attrition due to disease progression; only 61.5% of patients were alive at 2 months. There was a significant improvement in KP from baseline to pre–cycle 3 in both arms, with a trend in favor of the 3w4 regimen for duration and faster onset of improvement. Eight of the 17 quality-of-life (QOL) variables assessed showed an improvement of more than 10% between baseline and the start of the third cycle of treatment. Response rate, survival, and duration were similar in both arms.

CONCLUSION: There was no significant difference between the two schedules examined in terms of improvement in KP or QOL, but there seemed to be a trend in favor of the 3w4 schedule.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Chemotherapy for advanced non–small-cell lung cancer (NSCLC) patients has demonstrated significant advantages over supportive care. Platinum-based chemotherapy can prolong survival, improve quality of life (QOL), and reduce tumor-related symptoms.1-4 More recent trials following the meta-analysis have confirmed the benefit with platinum regimens and with newer agents (eg, gemcitabine).5,6 However, the evidence base is largely restricted to fitter patients, with scant data on the efficacy of chemotherapy for more impaired performance status (PS) patients and with no randomized trials specifically targeted to the PS 2/3 or Karnofsky equivalent (KP) patient populations.4,7-9 Available information is based on subgroup analyses from trials in which patients with a PS of 2 (PS 2 patients) were a minority. Indeed, some of the larger trials have not recruited PS 2 patients at all, and others have discontinued recruitment after toxicity issues.7 Nevertheless, the proportion of PS 2 patients in population-based studies is considerably higher than that reported in the majority of clinical trials.9,10 Given that the median survival of PS 2 patients rarely exceeds 5 months, with a 1-year survival rate less than 20%, an important aim is palliation.5,11,12 There is the view that unfit patients are at higher risk for severe toxicity. This perception stopped accrual of PS 2 patients in the recent, large, Eastern Cooperative Oncology Group (ECOG) E1594 study.7 Later, a detailed subgroup analysis described an increased incidence of toxicity in these patients; this was not significantly greater than that seen for those patients with a better PS. Furthermore of the five deaths on study, only two (3%) were attributed to drug toxicity12; the poor outcome in this group of patients was due to disease rather than to treatment-related toxicity. Moreover, the importance of QOL with other assessments has been increasingly highlighted and is especially important in choosing between treatments among which there is no major survival difference.13,14

Gemcitabine is a newer-generation nucleoside analog that is now well established in the treatment of NSCLC.4,6,7,15 Gemcitabine as a single agent is known to provide symptom palliation and improvement in QOL, with a favorable toxicity profile. The symptom benefit was two- to three-fold greater than that expected from the objective response rate.6,16,17 In a randomized study of gemcitabine plus best supportive care versus best supportive care alone, where QOL was the primary end point, there was overall improvement in the QOL in the gemcitabine-treated patients. This trial had a high proportion of patients with impaired PS (KP 60, 36%; KP 70, 35%).6 There were also fewer hospital admissions and a reduced requirement for palliative radiotherapy in the chemotherapy arm. Gemcitabine was therefore chosen for further evaluation in impaired-PS patients. A previous study using gemcitabine 1,000 mg/m2/wk on days 1, 8, and 15 reported a 20% increase in KP score from baseline.6 The hypothesis was that the shorter 2w3 regimen with the same total dose 1,500 mg/m2/wk would improve the PS to a greater extent. At the time of study design, there were no data on a days 1 and 8 single-agent gemcitabine regimen,18 and it was thought reasonable in the trial to keep the total dose per cycle (3,000 mg/m2) constant. The primary objective of this randomized phase II study was to compare changes in PS between two treatment schedules of gemcitabine that are commonly used.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Eligibility Criteria
Patients with histologically or cytologically confirmed, locally advanced, stage III or IV NSCLC who had not received prior chemotherapy were eligible for the study. Criteria for entry into the trial also included KP greater than 30 and less than 80, disease not amenable to curative surgery or radical radiation, a life expectancy of at least 4 weeks, male or female sex, age at least 18 years of age, and adequate bone marrow reserve: WBC count ≥ 3.5 x 109/L, platelets ≥ 100 x 109/L, and hemoglobin ≥ 100 g/L. The ethical committees of the participating hospitals approved the trial, and all patients gave their informed consent to participate in the study.

Medical history and physical examination, determination of PS, CBC, biochemistry, chest x-ray, and computed tomography scan of the thorax and upper abdomen were obtained before treatment. Health-related QOL (HRQoL) was assessed with patient self-administered SS14 lung cancer–specific questions, based on the Rotterdam Symptom Checklist, derived from the European Organisation for Research and Treatment of Cancer QLQ-C30 and LC-13 questionnaires plus three additional questions relating to gemcitabine.6 The clinical staff also assessed the baseline prechemotherapy symptoms at the same visit.

Treatment
Patients were randomly assigned to receive gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of each 28-day cycle (3w4) plus best supportive care (BSC) or gemcitabine (same total dose) 1,500 mg/m2 on days 1 and 8 of each 21-day cycle (2w3), plus BSC for up to six cycles.

Patients were seen every week during treatment, and a CBC was performed. Dose adjustment was made based on the toxicity grading. If grade 3/4 hematologic toxicity or no hematologic toxicity was present at the time of planned drug administration, the dose was omitted (eg, pulmonary, neurological) or reduced by half. Patients could also be offered any palliative treatment other than a different chemotherapy, including palliative surgical procedures and radiation therapy.

Patient Evaluation and Statistical Methods
The primary objective of the study was to assess the change in Karnofsky performance status from baseline to the time the third chemotherapy was due. Other secondary objectives were to determine the change in symptom palliation using the SS14 symptom scale plus three additional questions to assess potential gemcitabine toxicity, overall patient survival, toxicity assessment and tumor response. A comparison of symptoms recorded by the patient and the physician separately before chemotherapy was also performed.

Performance status was documented, and the SS14 questionnaires were administered before each cycle. Toxicity was recorded after each cycle of treatment using the WHO criteria, and tumor response was evaluated in patients receiving at least one cycle of chemotherapy, at 4 weeks after the last cycle of chemotherapy.

The study was designed to recruit 174 patients with 87 patients in each arm, using Donnar's formula for proportions. The sample size (allowing for 6% of patients being not assessable) was based on a two-tailed test with 80% probability of detecting a change in the numbers of patients having improved KP from baseline to just before the third chemotherapy cycle, from 20% in the 3w4 patients to 40% in the 2w3 patients. Within-arm comparisons were made using the Wilcoxon matched-pairs test, and between-arm comparisons were made using Mann-Whitney U tests for non-normally distributed data and two sample t tests for normally distributed data. Categorical data were compared using Pearson's {chi}2 test. Overall survival curves were compared using the log-rank test. Baseline QOL forms were only included if completed on or before random assignment, but an acceptable time window of ± 1 week was permitted around other assessment points.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Patient Characteristics
From April 1998 to June 2002, 174 chemotherapy-naive patients with NSCLC (87 in each arm) were enrolled. One patient in each arm did not receive chemotherapy: one patient's condition had deteriorated before treatment, and the other had already mistakenly been randomly assigned to another study. The patient characteristics were balanced, with no statistically significant differences (Table 1). The 10 stage IIIA patients had large-volume disease that was considered beyond radical radiotherapy. For nine patients, it was not possible to reliably allocate them to either stage IIIB or IV. Seventy-six percent of patients in the 3w4 arm and 71% in 2w3 arm had a KP ≤ 60.


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  		Table 1. Patient Characteristics

 
Baseline symptoms that were described as moderate or severe in the greatest number of patients were cough, chest pain, dyspnoea and lethargy, and fatigue. These were of similar frequency in each arm. There was considerable underreporting of baseline symptoms on the physician assessment compared with the patient assessment (Table 2).


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  		Table 2. Baseline Symptoms

 
Twelve patients had radiotherapy after completion of chemotherapy, and three had second-line chemotherapy. There was no significant difference in the number of chemotherapy cycles, with 220 cycles given four weekly (3w4) and 233 cycles given three weekly (2w3; Table 3). Dose omissions and reductions on day 8 were almost identical, being 12% and 13%, respectively, for the two schedules. Twenty-six percent of day-15 treatments were omitted in the 3w4 arm due to toxicity.


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  		Table 3. No. of Cycles Given

 
PS (KP)
One hundred seven (61.5%) of the patients randomized (51 of the 3w4 arm and 56 of the 2w3 arm) were alive at 2 months. Completion of both assessments at baseline and pre–cycle 3 was obtained for 67 (63%) of these patients (33 from the 3w4 arm and 34 from the 2w3 arm).

When the baseline KP score was compared with that recorded at the start of cycle 3, there was a significant improvement in KP score in both arms (Table 4) . In the 3w4 arm, a significant improvement in KP became apparent by the start of cycle 2 (day 28) and continued until after cycle 6 (day 168). The 2w3 arm took longer to show a significant improvement (ie, start of cycle 3 [day 63] and continuing until the start of cycle 6 [day 105]) Figure 1. There was a trend toward an improvement in duration of improvement in KP for the 3w4 arm.


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  		Table 4. Between-Cycle KP Scores

 


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  		Fig 1. Prechemotherapy Karnofsky performance status (KPS) scores. 3w4, gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of each 28-day cycle; 2w3, gemcitabine 1,500 mg/m2 on days 1 and 8 of each 21-day cycle; Pt No, number of patients.

 
Symptom Palliation
Individual SS14 items. QOL assessment forms were completed by 38 of the 107 alive at the end of cycle 2 (21 in arm 3w4 and 17 in arm 2w3, Tables 5 and 6) . All items on the SS14 were scored in the same direction, with higher scores representing higher symptom burden.6 On the 3w4 arm, the symptoms with significantly worse scores (P < .05) were tiredness, rash, and ankle swelling post–cycle 1. Significantly better scores were for worry post–cycle 2, other pain and sleeping post–cycle 3, and appetite and constipation post–cycle 4. On the 2w3 arm, significantly worse scores were reported for ankle swelling post–cycle 1 and tiredness post–cycle 2. There was no significant improvement reported on this arm for QOL symptoms (Tables 5 and 6).


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  		Table 5. SS14 Symptom Scale (subset of European Organisation for Research and Treatment of Cancer QLQ-C30 and LC13)

 

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  		Table 6. SS14 Items With Statistically Significant Differences Over Treatment Cycles Compared With Baseline

 
Since small differences were unlikely to reflect clinical benefit, interest was focused on those subscale items that showed a ≥ 10% between-treatment difference in the number of patients who improved or deteriorated. Scores for questions 1 to 7 and 17 (Table 5) did not have a ≥ 10% between-treatment difference in the proportion of patients reporting improvement or deterioration from baseline to post–cycle 2. The only statistical difference between the arms was for weakness (P = .005), where the 2w3-arm score difference from pretreatment to post–cycle 2 was worse. At the start of cycle 3, of the 17 variables analyzed, eight showed between-treatment differences in improvements that were ≥ 10% (Fig 2A): five of the improvements were greater for the 3w4 arm (ankle swelling, weakness, chest pain, shortness of breath, and coughing blood). Ankle swelling was not a problem for any of the 2w3 patients pretreatment; therefore, improvement was not possible, whereas three variables were better for the 2w3 arm (rash, appetite, and pain in arms/shoulders; Fig 2A). At the same time point, seven variables showed between-treatment differences in deterioration that were ≥ 10% (Fig 2B): one of the deteriorations was greater in the 3w4 arm (ankle swelling), whereas six were greater for 2w3 (Fig 2B).



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  		Fig 2. SS14 items that showed a ≥ 0% between-treatment difference in the proportion of patients reporting improvement (A) or deterioration (B) from baseline to post–cycle 2. 3w4, gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of each 28-day cycle; 2w3, gemcitabine 1,500 mg/m2 on days 1 and 8 of each 21-day cycle; pts, patients; a/s, arm/shoulders.

 
Total SS14 score (questions 1 to 14). The total SS14 score (Table 5) from baseline to the start of cycle 3 was significantly reduced for the 3w4 arm (P = .02; 95% CI, 0.41 to 4.35), reflecting an improvement in symptoms. There was no change in the 2w3 arm (P = .929; 95% CI, –3.94 to 4.30) and no difference between the arms. The SS14 scores are summarized in Table 7. Questions 15 to 17 were relevant to gemcitabine treatment and showed an initial increase for these symptoms in the 3w4 arm from baseline to post–cycle 1 score (P = .004), but this was not sustained, and by the start of cycle 3 was no longer significantly different from the baseline score (P = .313). There was no difference in the 2w3 arm within cycles or any difference between arms.


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  		Table 7. SS14 Quality of Life Total Scores (questions 1 to 14)

 
Tumor Response and Survival
Seventy-two patients in the 3w4 arm and 71 in the 2w3 arm were assessable for response. The overall objective response was 7.6%, with stable disease in a further 16% of patients. There was no significant difference in response rate between the two regimens (Table 8). One patient died from neutropenic sepsis between chemotherapy courses, and one died from heart disease. The median survival in the 3w4 arm was 83 days (95% CI, 59 to 107) and 65 days (95% CI, 45 to 85) in arm 2w3 (P = .81). The 1-year survival was 9% for the 3w4 arm and 13% for the 2w3 arm.


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  		Table 8. Response to Treatment (patients who have received at least 3,000 mg/m2 of gemcitabine)

 
Toxicity
A summary of toxicity is presented in Table 9. Grade 3 and 4 anemia was numerically slightly more common in the 3w4 arm (P = .07). There were three and two patients with grade 3 leucopenia in each arm, respectively, one per arm requiring one course of intravenous antibiotics each. Five and six patients were reported with grade 3 and 4 thrombocytopenia, respectively.


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  		Table 9. Maximum Grade Hematologic/Nonhematologic Toxicities

 
Considering clinically relevant toxicity, the total numbers of patients requiring blood transfusions were similar: 24 in the 3w4 arm and 19 in the 2w3 arm (P = .26). The 24 patients in the 3w4 arm required a total of 109 units of blood, though three of the 24 patients accounted for 32 of these units. The 19 patients in the 2w3 arm required 46 units. Two patients in each arm required between two and eight units of platelets. Twenty-four patients in each arm received intravenous antibiotics during chemotherapy; only five of these episodes were associated with grade 3/4 infections and/or fever. Forty-two patients on the 3w4 arm and 39 patients on the 2w3 arm required oral antibiotics.

Between 50% and 60% of patients in each arm experienced grade 1/2 toxicities—the most common of these were anemia, raised alkaline phosphatase, nausea, and vomiting. There was no significant difference in any of the other nonhematologic toxicities between the arms.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Authors' Disclosures of...
 REFERENCES
 
The outcome for patients with inoperable NSCLC and impaired PS remains poor, with a median survival of approximately 4 to 6 months, and 1-year survival of 20%.19-22 The treatment intent in these patients is palliative (ie, control of symptoms, improvement in QOL, least treatment toxicity, and increased duration of survival). There is no definite advantage in terms of survival for combination chemotherapy in these patients. One subgroup analysis suggested a benefit with the addition of carboplatin to paclitaxel. However, the main bulk of data supports single-agent therapy.23-25

Gemcitabine has been evaluated as a single-agent therapy in advanced NSCLC.6,13,16,17 Gemcitabine improves both tumor-related symptoms and PS in approximately one third of patients.6,13,17 A study randomly assigning patients with impaired PS (KP ≤ 70) to either chemotherapy or BSC demonstrated an improvement in QOL in those patients receiving chemotherapy.6 Gemcitabine can be administered on either a 3- or 4-weekly cycle; there is no clear advantage in terms of response rate or overall survival for either regimen.26

The majority of patients in this study had stage IV disease (64%) and all had an impaired PS (KP ≤ 70). The small number of stage III patients had bulky mediastinal disease and poor PS, which excluded more intensive treatment. The KP and ECOG PS are strongly correlated.9 A three-point conversion demonstrated a best fit for KP 70/60 and PS 2, and KP less than 60 and PS 3/4, which agrees with a previous assessment.27 A recent study found that, with few exceptions, patients and oncologists assessed PS similarly.28 However, QOL measured by patients and physicians differed in some studies, but not to a great extent in others.29,30 The attrition rate during the first two cycles of treatment was high (38.5%), exceeding the expected 6% allowed for in the study design. Future studies should make greater allowance for attrition and missing data. Furthermore, only 63% of the 107 patients alive completed the 2-month assessment. The high proportion of poor-PS patients in this group can explain the disproportionately low number of patients completing the 2-month evaluations as compared to those previously published. However, the attrition rate makes interpretation of the results difficult and raises the risk of bias owing to ill patients being unable to complete QOL forms or staff being unwilling to approach them.31 Another problem in the current study was that some patients attended different clinics with staff not familiar with the need to record the KP and so on. Furthermore, "positive" results may be hidden (eg, The SS14 total score improved in the 3w4 arm, but there was no change in the 2w3 arm), possibly due to small patient numbers (ie, 21 v 17 led to no statistically significant difference). For this reason, interpretation of the magnitude of improvement in disease-related symptoms or PS should be cautious. However, as both treatment arms were well balanced for prognostic factors and numbers of cycles of treatments administered, it is reasonable to make comparisons between the two arms.

It was interesting to note the significant under reporting of symptoms by physicians as compared with patients. In particular fatigue, and lethargy are lung cancer symptoms reported frequently by patients, but that are under-recognized by physicians.16,32 This demonstrates the absolute requirement to use patient-assessed QOL and symptom control in studies in which evaluation of symptoms is a major end point.

There was a significant improvement in KP in both arms after two cycles of treatment when compared with the baseline score. This improvement seemed to start earlier in the 3w4 arm than the 2w3 arm and seemed to last for longer (140 days v 42 days) and was statistically significant. When we considered a greater than 10% change in any of the 14 questions asked by the SS14 questionnaire and the additional three questions regarding gemcitabine toxicity, there seems to be a trend in favor of the 3w4 arm. When one further compared the total SS14 score, there was a significant improvement in the 3w4 arm but no improvement in the 2w3 arm; however, the difference between the two arms was not significant.

For both groups, the objective response rate was 7.6%, and 16% of all patients had stable disease. This study illustrates greater clinical benefit for patients in terms of PS and disease-related symptoms, despite the low objective response rates. Clinically significant toxicity was similar in both arms, even in the "dose intensified" 2w3 arm. There seemed to be more clinically significant anemia, though it was not statistically significant in patients receiving 3w4 treatments. Patients were treated with RBC transfusions. However, it is possible that adequate hemoglobin levels could be better maintained in these patients with the appropriate use of erythropoietin, with a further improvement in their QOL. Antibiotics were given prophylactically with neutropenia less than 1 x 109/L, but use was not significantly different between the two regimens.

Twenty-six percent of the day-15 chemotherapy doses were cancelled. But patients attended anyway for review. However, we did not record all the hospital visits in this study of patients.

Comorbidity data were not collected in this study, but for lung cancer patients, are reported as being two-fold greater than in a general population.33 Comorbidity will impact PS and can influence treatment choice.33 Recording comorbidity would be helpful in future studies, together with an assessment of the duration of the pretreatment impaired PS. It would then be possible to distinguish between an "acute" deterioration in PS due to tumor and so on, and a more chronic impaired PS due to long-standing comorbidity. These two scenarios may exert a different influence on treatment effect.

Both treatment schedules were well tolerated, and there was no clear difference between them in terms of the primary or secondary end points. There was, however, a trend toward a more improved PS and relief of disease-related symptoms in the 3w4 arm. The higher attrition rate in the first 2 months of treatment illustrates the poor prognosis for this group of patients and reinforces the absolute need to include appropriate QOL monitoring in further studies. Single-agent gemcitabine can be considered for this group of patients and would be a reasonable comparator in future trials.


   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
REFERENCES
 
The following authors or their immediate family members have 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. Consultant/Advisory Role: N. Thatcher, Eli Lilly; M. Lind, Eli Lilly. Honoraria: N. Thatcher, Eli Lilly; H. Anderson, Eli Lilly; M. Lind, Eli Lilly. Research Funding: N. Thatcher, Eli Lilly. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration form and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.


   Acknowledgment
 
We thank Eli Lilly Company for the support of the study.


   NOTES
 
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 January 6, 2004; accepted September 2, 2004.


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