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The Oncologist, Vol. 9, No. 2, 173–181, April 2004
© 2004 AlphaMed Press

ORIGINAL PAPER
Lung Cancer

Topotecan in the Treatment of Relapsed Small Cell Lung Cancer Patients with Poor Performance Status

Joseph Treata, Chao Hui Huanga, Stephen R. Laneb, Jeremey Levinb

a Fox Chase-Temple University Cancer Center, Philadelphia, Pennsylvania, USA; b GlaxoSmithKline, Philadelphia, Pennsylvania, USA

Correspondence: Joseph Treat, M.D., Fox Chase-Temple University Cancer Center, 3322 North Broad Street, Philadelphia, Pennsylvania 19140, USA. Telephone: 215-707-2777; Fax: 215-707-8092; e-mail: treatja{at}tuhs.temple.edu


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
After completing this course, the reader will be able to:

  1. Describe the hematologic safety profile of topotecan in patients with relapsed small cell lung cancer.
  2. Identify the risk factors for poorer performance status.
  3. Discuss the role of topotecan in the management of poor performance status patients with relapsed small cell lung cancer.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
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 Learning Objectives
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
Topotecan is the only single-agent therapy approved by the U.S. Food and Drug Administration for the treatment of patients with recurrent small cell lung cancer (SCLC). Poor performance status (PS) at the time of relapse can hinder the ability of a patient to tolerate second-line chemotherapy. To investigate the feasibility of topotecan in the treatment of relapsed SCLC patients with PS 2 scores, we retrospectively analyzed data from five clinical trials that included 479 patients who were treated with single-agent topotecan at a dose of 1.5 mg/m2/day on days 1–5 of a 21-day course. Of these patients, 381 had a PS 0 or 1 and 98 had a PS 2. Topotecan was well tolerated by both patient groups. Hematologic toxicities were generally manageable, and neutropenia was noncumulative. With the exception of grade 3/4 anemia, the incidences of severe hematologic toxicities were not statistically different between the two groups. The nonhematologic toxicity profiles were also similar in the two patient groups. Treatment provided similar benefits, including antitumor response rates and symptom palliation, in PS 0/1 and PS 2 patients. As expected, the median overall survival time was shorter in patients with worse PS scores; the median overall survival times were 36.3 weeks, 25.4 weeks, and 16 weeks for PS 0, PS 1, and PS 2 patients, respectively. In conclusion, treatment with topotecan is feasible and well tolerated in patients with relapsed SCLC with suboptimal PS scores.

Key Words. Lung neoplasms • Palliative care • Salvage therapy • Topotecan


   INTRODUCTION
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 Learning Objectives
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
Lung cancer is the leading cause of cancer-related death in the U.S., accounting for an estimated 31% and 25% of cancer deaths in men and women, respectively [1]. It was estimated that 171,900 new cases of lung cancer would be diagnosed in 2003 and that 157,200 people would die of the disease. Of these lung cancer cases, approximately 14%–18% are small cell lung cancer (SCLC), an aggressive and lethal cancer with a median survival of only 8 months in patients with advanced disease [2–5]. Unfortunately, the vast majority of patients die within 2 years of diagnosis.

SCLC is highly responsive to chemotherapy and radiation, and in the U.S., the current standard of care for first-line chemotherapy in patients with limited or extensive disease is etoposide combined with either carboplatin or cisplatin [3, 6, 7]. Despite high rates of response to first-line therapy, most patients with SCLC eventually experience disease recurrence or progression and die from their disease [6–11]. Options for treatment at relapse depend on the performance status (PS) of the patient, choice of first-line chemotherapy, response to first-line treatment, treatment-free interval, and recovery time from any toxicities associated with first-line therapy.

PS often reflects the extent of disease and is a powerful predictor of overall survival in patients with SCLC. Several multivariate and retrospective analyses have demonstrated that patients with poorer PS scores have shorter survival durations [12–14]. In a Cancer and Leukemia Group B multivariate analysis of more than 1,500 patients, Spiegelman et al. [12] reported higher response rates in SCLC patients with PS scores <=0/1 than in patients with PS scores >1; however, this difference was only statistically significant in patients with limited disease (p = 0.04). In addition, patients with limited or extensive SCLC and a PS score of 0/1 had significantly longer survival times than patients with poorer PS scores (p < 0.001). Likewise, Osterlind and Anderson [14] reported that a poor PS was significantly associated with a shorter duration of survival.

PS can also predict a patient’s ability to tolerate chemotherapy. Because patients with poorer PS scores are unable to tolerate intense chemotherapy, many receive subtherapeutic doses of chemotherapy or supportive care alone. Therefore, there is a need for treatments that provide palliation of symptoms and improvements in quality of life in SCLC patients with PS scores >=2.

Topotecan (Hycamtin®; GlaxoSmithKline; Philadelphia, PA), a topoisomerase-I inhibitor with broad antitumor activity, is the only drug approved by the U.S. Food and Drug Administration for the single-agent treatment of patients with relapsed SCLC. The efficacy of topotecan was established in patients with recurrent SCLC, with overall response rates ranging from 2%–14% in chemotherapy-refractory patients and 14%–38% in chemotherapy-sensitive patients [15–19]. In addition, single-agent topotecan has been shown to provide symptom palliation in SCLC patients. Compated with baseline, patients treated with topotecan experienced imporvements in dyspnea, anorexia, hoarseness, fatigue, and interference with daily activities [18]. In this integrated report of five large trials, we retrospectively evaluated the effect of PS on outcome in patients with recurrent SCLC treated with topotecan at the standard dose and schedule.


   MATERIALS AND METHODS
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 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusions
 References
 
Integrated Analysis and Study Population
The current report is a retrospective analysis of patient data integrated from five large topotecan registration trials conducted in patients with chemotherapy-sensitive recurrent SCLC [15–19]. The studies, sumarized in Table 1Go [15–19], included three multicenter, single-arm phase II studies (014,053, and 092) and one comparative phase II study (065) of i.v. versus oral topotecan. In addition, a randomized, controlled, phase III study (090) compared single-agent topotecan with CAV (cyclophosphamide, 1,000 mg/m2, doxorubicin, 45 mg/m2, and vincristine, 2 mg, infused on day 1 every 21 days).


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  		Table 1. Topotecana SCLC trials included in the integrated analysis
 
In all studies, patients were required to have histologically confirmed limited or extensive-disease SCLC with documented progressive disease after one prior chemotherapy regimen. Patients had to have bidimensionally measurable disease and a life expectancy >3 months. Patients were also required to have an Eastern Cooperative Oncology Group (ECOG) or World Health Organization (WHO) PS <=2. At study entry, patients were required to have adequate hematologic, renal, and hepatic functions as defined by the following: WBC >= 3.5 x 109/l, absolute neutrophil count (ANC) >= 1.5 x 109/l, platelet count >= 100 x 109/l, hemoglobin level >= 9.0 g/dl, total bilirubin level <=1.5–2.0 mg/dl, alanine aminotransferase and aspartate aminotransferase levels <=2 times the upper limit of normal in the absence of liver metastases or <=3–5 times the upper limit of normal in the presence of liver metastases, and creatinine level <=1.5–1.6 mg/dl or creatinine clearance >=60 ml/minute. Patients previously treated with topotecan were ineligible for the studies, as were patients with symptomatic brain metastases. Written informed consent was obtained from each patient before his or her entry into any of the studies.

Treatment
Patients included in the integrated analysis were treated with topotecan at a starting dose of 1.5 mg/m2/day administered via 30-minute i.v. infusions on days 1–5 of a 21-day course. Treatment cycles were repeated every 3 weeks if complete hematologic recovery (WBC > 3.5 x 109/l, ANC >= 1.0–1.5 x 109/l, platelet count > 100 x 109/l, hemoglobin >= 9.0 g/dl) and nonhematologic recovery (to <= grade 1) had occurred. Treatment delays of 1–2 weeks were allowed if complete hematologic recovery had not occurred before the start of the next course, and patients were withdrawn if a treatment delay due to toxicity at the minimum dose (1.0 mg/m2) persisted for more than 2 weeks. G-CSF support was permitted for therapeutic intervention and prophylaxis at the discretion of the investigator in studies 065 and 090 and for therapeutic intervention in study 014.

Topotecan dose reductions in increments of 0.25 mg/m2 were implemented for grade 4 neutropenia complicated by fever or infection or lasting >= 7 days, grade 3 neutropenia lasting beyond day 21 of the treatment cycle, and grade 4 thrombocytopenia or grade 3 thrombocytopenia associated with bleeding or lasting 7–14 days. In addition, similar dose reductions were implemented for grade 2 nonhematologic toxicities (except for nausea, vomiting, and alopecia) in study 014, grade 3/4 nonhematologic toxicities (excluding grade 3 nausea) in study 090, and grade 3/4 nonhematologic toxicities (excluding grade 3 nausea and grade 3/4 vomiting) in study 065. Topotecan dose escalations to a maximum of 2.0 mg/m2 were allowed in the absence of grade 2 or higher toxicities in studies 053, 065, and 090.

Patient Assessments

Safety and Tolerability
Before the start of treatment, each patient underwent a complete physical examination with medical history and assessments of CBC, blood chemistry, and urinalysis. During treatment, a CBC was repeated on a weekly basis (days 8 and 15) and a blood chemistry analysis was performed on day 15 of each course. In study 014, a CBC was repeated twice per week during the first course and weekly in subsequent courses. Quantitative hematologic and nonhematologic toxicities were assessed according to the National Cancer Institute Common Toxicity Criteria, and all toxicities >= grade 3 were considered severe. When assessed, symptoms of disease were rated based on a 4-point ordinal scale describing the degree to which a patient was bothered by an individual symptom (from "not at all" to "very much"). Improvement was declared for a given symptom if a patient recorded two consecutive post-baseline assessments that were lower (i.e., better) than the baseline assessment for that symptom.

Response and Survival
Lesions were measured by computed tomography, magnetic resonance imaging, x-ray, or physical examination. Response was evaluated according to the WHO criteria [20]. All responses in the randomized trials were confirmed by an independent radiologist blinded to treatment, and all patients who received at least one cycle of therapy were eligible for response, time to disease progression, and survival evaluations. Time to progression and survival were measured from the time of first topotecan dose to the time of documented disease progression or death, respectively. For patients not experiencing an event at the time of the analysis, the last known date of contact was used as a censoring point.

Statistical Measurements
Specific baseline, medical history, toxicity, and response data were pooled across the five clinical studies and retrospectively grouped according to baseline PS. The data in the analysis included demographic information, patient disposition, medical history, treatment exposure, hematologic and nonhematologic toxicity data, and response data.

Summary statistics were used for general descriptions of the patients studied and an overview of the safety and efficacy results. Estimates for survival and time to progression were derived using Kaplan-Meier methods. In addition, time-to-event data (survival and time to progression) were analyzed using proportional hazards (Cox) regression models, which included PS and other important baseline characteristics thought to be prognostic factors (baseline brain and/or liver metastases, age, time to progression from previous treatment). Differences between PS categories in the incidence of grade 3/4 toxicity were tested using chi-square tests. All analyses were performed using SAS® (SAS Institute Inc.; Cary, NC) statistical software.


   RESULTS
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 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusions
 References
 
Patients
A total of 480 patients were enrolled in the five pooled studies. The PS for one patient was unknown; therefore, 479 patients are included in this analysis. The patient demographics and baseline characteristics are summarized in Table 2Go. The majority of patients were older than 40 years of age, Caucasian, and had received only one prior treatment regimen. Nine patients, all PS = 0/1, had received more than one prior treatment. Of the 479 patients, 114 had PS = 0, 267 had PS = 1, and 98 had PS = 2.


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  		Table 2. Patient demographics and baseline disease characteristics by PS of patients enrolled in the pooled trials
 
Dosing
There were 1,874 courses of chemotherapy administered, including 1,533 courses in PS 0/1 patients and 341 courses in PS 2 patients. The median number of courses administered was 4 (range 1–22 courses) in PS 0/1 patients and 2 (range 1–14 courses) in PS 2 patients. In 1,152 courses given to PS 0/1 patients, there were 470 (41%) treatment delays and 147 (13%) dose reductions, whereas in 243 courses administered to PS 2 patients, there were 105 (43%) treatment delays and 36 (15%) dose reductions. Treatment discontinuations due to adverse events occurred in 56 of 381 (15%) PS 0/1 patients and in 18 of 98 (18%) PS 2 patients. Thirteen PS 0/1 patients had their dose escalated as did four PS 2 patients.

Safety and Tolerability
The incidences of grade 3/4 hematologic toxicities by baseline PS are provided in Table 3Go. Grade 3/4 leukopenia, neutropenia, and thrombocytopenia occurred in similar proportions of PS 0/1 patients and PS 2 patients. PS 2 patients experienced a higher incidence of anemia than PS 0/1 patients (p = 0.009). The proportions of patients experiencing febrile neutropenia were similar in the two patient groups (3% of PS 0/1 patients versus 4% of PS 2 patients). The median onsets and median durations of hematologic toxicities were similar in both patient groups over approximately 1,400 courses in PS 0/1 patients and over approximately 300 courses in PS 2 patients. For grade 3/4 anemia, PS 0/1 patients experienced a median onset of 13 days with a median duration of 5 days and PS 2 patients experienced a median onset of 12 days with a median duration of 7 days. The median onsets of thrombocytopenia were 15 days for both PS 0/1 and PS 2 patients, whereas the median durations of thrombocytopenia were 4 days for PS 0/1 patients and 7 days for PS 2 patients. The median onsets of neutropenia were 10 days (PS 0/1) and 9 days (PS 2), and the median durations were 7 days in both groups. As shown in Figure 1Go, hematologic toxicities did not appear to be cumulative, and the incidences of grade 3/4 hematologic toxicities with increasing course number remained similar in the two patient groups. There were no statistical differences in the use of growth factor or blood product support between patient groups. Eight percent of PS 0/1 patients and 11% of PS 2 patients received G-CSF support, with only 2% of patients in each group receiving prophylactic G-CSF support at the discretion of the investigator. Likewise, erythropoietin was administered to 3% of PS 0/1 patients and to 1% of PS 2 patients. RBC and platelet transfusions were administered to 45% and 16% of PS 0/1 patients, respectively, and 59% and 26% of PS 2 patients, respectively.


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  		Table 3. Incidence of grade 3 or 4 hematologic toxicity by PS
 


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  		Figure 1. Grade 3/4 hematologic toxicity by course. The incidences of grade 3/4 leukopenia, neutropenia, thrombocytopenia, and anemia for PS 0/1 patients (gray bars) and PS 2 patients (white bars) are plotted as the percent of total courses.

 
The incidences of grade 3/4 nonhematologic toxicities (regardless of relationship to study treatment) by baseline PS are provided in Table 4Go. Overall, the incidences of nonhematologic toxicities in PS 2 patients were similar to those reported in PS 0/1 patients. The most common grade 3/4 nonhematologic toxicities in both groups were dyspnea, asthenia, nausea, and vomiting. The incidences of dyspnea, pain, respiratory insufficiency, vomiting, and alkaline phosphatase increase were significantly higher in PS 2 patients than in PS 0/1 patients (p < 0.05). Of the 480 patients enrolled in the five pooled studies, 201 (42%) had serious adverse experiences; approximately 75% were due to hematologic toxicities. Death considered by the investigator to be possibly related to study treatment occurred in 12 (3%) PS 0/1 patients and in five (5%) PS 2 patients. Patients whose cause of death was unknown were considered to have died due to causes possibly related to the study treatment.


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  		Table 4. Grade 3 or 4 nonhematologic adverse events with an incidence >= 3% by PS
 
Antitumor Response and Survival
The antitumor activity of topotecan in the intent-to treat population by baseline PS and chemosensitivity is provided in Table 5Go. The overall response rate was 14% in PS 0/1 patients, including 11 complete responses and 42 partial responses. Similarly, PS 2 patients experienced an overall response rate of 17%, with three complete responses and 14 partial responses. The proportions of patients who experienced responses to topotecan were similar in chemosensitive PS 0/1 patients and PS 2 patients (18% versus 24%). Patients with chemoresistant or refractory disease demonstrated a lower response rate regardless of PS (4% in PS 0/1 patients versus 3% in PS 2 patients).


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  		Table 5. Antitumor response by PS in the intent-to-treat population
 
The time to progression by PS is illustrated in Figure 2Go. The median times to progression for PS 0 and PS 1 patients were 12.6 weeks (95% confidence interval [CI] = 11.1–15.3) and 11.3 weeks (95% CI = 9.1–12.1), respectively. In contrast, the median time to progression for PS 2 patients was of a shorter duration at 8.7 weeks (95% CI = 7.3–12.4). After accounting for the effects of baseline brain and liver metastases, age, time to progression from the previous treatment, and individual study effect, the time to progression was significantly shorter in PS 2 patients than in PS 0/1 patients (p = 0.046).



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  		Figure 2. Estimates of time to progression by PS. The Kaplan-Meier method was used to estimate the time to progression in topotecan-treated relapsed SCLC patients rated PS = 0 (solid line), PS = 1 (dotted line), and PS = 2 (dashed line).

 
The median overall survival by PS is illustrated in Figure 3Go. As expected, the overall survival for PS 2 patients was shorter, at 16.0 weeks (95% CI = 13.3–19.9), than the overall survival times of 36.3 weeks (95% CI = 31.7–42.7) and 25.4 weeks (95% CI = 22.4–27.6) in PS 0 and PS 1 patients, respectively. Furthermore, after accounting for the effects of baseline brain and liver metastases, age, time to progression from the previous treatment, and individual study effect, the overall survival time of PS 0/1 patients was significantly longer than that of PS 2 patients (p < 0.001).



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  		Figure 3. Estimates of overall survival by PS. The Kaplan-Meier method was used to estimate the overall survival in topotecan-treated relapsed SCLC patients rated PS = 0 (solid line), PS = 1 (dotted line), and PS = 2 (dashed line).

 
Symptom Palliation
Symptom palliation was assessed in patients from studies 053, 065, and 090. Totals of 202 PS 0/1 patients and 58 PS 2 patients were eligible for the assessment (Table 6Go). Patients within each PS group experienced improvements in dyspnea, cough, chest pain, anorexia, insomnia, hoarseness, fatigue, interference with daily activities, and hemoptysis. There were similar levels of symptom improvement in PS 0/1 patients and PS 2 patients.


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  		Table 6. Symptom improvement in patients treated with topotecan in studies 053, 065, and 090 by PS
 

   DISCUSSION
Top
 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusions
 References
 
PS is a good predictor of overall survival in patients with SCLC and correlates with quality of life [12–14, 21, 22]. Patients may have poorer PS scores because of tumor burdens, comorbidities, and persistent toxicities from prior chemotherapy. Most clinical trials require patients to have an ECOG or WHO PS score <=2, and some cooperative group lung cancer trials now exclude PS 2 patients. Patients with poor PS often do not tolerate chemotherapy because of comorbid conditions and impaired organ function. As a result, several studies have halted accrual of patients with PS scores >=2 because of possible greater toxicities and a higher risk of death due to treatment-related adverse events compared with PS 0/1 patients [5, 23]. Sweeney et al. [24] reported that, in an ECOG study comparing four chemotherapy regimens in patients with non-small cell lung cancer, PS 2 patients experienced a greater number of adverse events and a lower overall survival rate than did PS 0/1 patients. In a Cancer and Leukemia Group B study comparing a two-drug regimen with a three-drug regimen in patients with extensive-disease SCLC, accrual of PS 2 patients was halted due to toxicities [25]. In addition, there is little evidence to suggest that patients with PS scores >2 will benefit from treatment [5, 23, 26]. However, because prolonging survival and palliating

symptoms are the ultimate goals in treating extensive-disease SCLC, the potential for such benefits must be considered when managing the treatment of patients with higher PS scores [27].

Topotecan is the first single-agent therapy to demonstrate symptom palliation in patients with relapsed SCLC [18]. In the current analysis, we investigated the feasibility of topotecan treatment in patients with relapsed SCLC who had a PS 2 and found that the treatment was generally well tolerated. For the majority of the reported nonhematologic toxicities, PS 2 patients experienced an incidence similar to that of PS 0/1 patients. Exceptions include grade 3/4 dyspnea, vomiting, respiratory insufficiency, and alkaline phosphatase increase. Most of these did not appear to be treatment related. Hematologic toxicities were also similar in the two patient groups, with the exception of anemia, which was more frequent in PS 2 patients. This is not surprising given the greater likelihood of comorbidity and bone marrow involvement occurring in patients with poor PS scores. Overall, a high percentage (48%) of patients treated in the studies that composed this analysis received RBC transfusions. A higher proportion of PS 2 patients was transfused compared with PS 0/1 patients (59% versus 45%), but the difference was not statistically significant. Eligibility requirements varied slightly among the different studies, but, in general, patients were required to have baseline hemoglobin levels >= 9 g/dl and treatment with erythropoietin was permitted at the investigator’s discretion. As the studies were performed at a time when prophylactic use of erythropoietin was less common, only 3% of patients received erythropoietin. Based on the results of this analysis, it seems reasonable to recommend routine administration of erythropoietin to patients receiving topotecan in this setting. Similar to what was observed in PS 0/1 patients, hematologic toxicities in PS 2 patients were generally manageable and neutropenia was noncumulative. Often, because of hematologic toxicity, the dose of topotecan is reduced or treatment is delayed when using the approved dosing regimen. In the current study, the number of dose reductions and treatment delays were similar in PS 0/1 and PS 2 patients. The optimal dosing schedule for topotecan has not been determined, and several alternative treatment schedules that appear to cause less myelosuppression are currently being investigated. Overall, the data from this analysis suggest that topotecan was generally well tolerated in PS 2 patients, and that patients in this group were able to tolerate systemic chemotherapy as well as those patients who entered the trials with better PS scores.

Antitumor responses were also similar in the two patient groups, with overall response rates of 14% and 17% in PS 0/1 and PS 2 patients, respectively. In addition, stable disease was achieved in 22% of PS 0/1 patients and in 14% of PS 2 patients. In patients with chemoresistant or refractory disease, response rates were lower (4% in PS 0/1 and 3% in PS 2 patients). The proportion of PS 2 patients experiencing responses, compared with PS 0/1 patients, did not appear to be dependent on the chemosensitivity of disease. Because topotecan was well tolerated and demonstrated antitumor activity in PS 2 patients, it should be considered as a treatment alternative to best supportive care in PS 2 patients with chemosensitive disease. As expected, the time to progression and overall survival were shorter for PS 2 patients than for PS 0/1 patients; however, PS 2 patients still experienced benefits from treatment, including symptom improvements and tumor shrinkage.

In a previous study (090), topotecan provided improvements in dyspnea, anorexia, hoarseness, fatigue, and interference with daily activities in patients with relapsed SCLC and a PS score <=2 [18]. The current retrospective analysis suggests that PS 2 patients experience symptom palliation and benefits with topotecan treatment comparable with those of PS 0/1 patients. Although additional randomized prospective studies are required to fully characterize the role of chemotherapy in SCLC patients with PS scores >1, results from this analysis suggest that topotecan can provide symptom palliation and clinical benefit in patients with suboptimal PS scores.


   CONCLUSIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
References
 
Oncologists are often faced with the difficult decision of whether or not to treat poor PS patients with chemotherapy. This retrospective analysis suggests that topotecan is well tolerated and provides clinical benefit to PS 2 patients with relapsed chemotherapy-sensitive SCLC. Therefore, this treatment should be considered for these patients. Prospective, randomized, and stratified (according to PS) studies are needed to fully characterize the use of topotecan and other chemotherapeutic agents in poor PS patients.


   ACKNOWLEDGMENT
Top
 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
The authors thank the patients for their participation and the study coordinators and physicians for their assistance in the five clinical trials included in this meta-analysis. GlaxoSmithKline has provided collaborative support and assistance to the authors for the analysis, writing, and preparation of this article.


   REFERENCES
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 Learning Objectives
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 

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Received October 20, 2003; accepted for publication February 6, 2004.




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