1 Medizinische Klinik mit Schwerpunkt Onkologie und Hämatologie, Charité Campus Mitte, Humboldt Universität zu Berlin, Berlin; 2 Frauenklinik, Oskar-Ziethen-Krankenhaus, Berlin; 3 Frauenklinik, Universitätsklinikum Ulm, Ulm; 4 Klinik für Gynäkologie und Geburtshilfe, Charité Campus Mitte, Humboldt Universität zu Berlin, Berlin; 5 Department for Intelligent Systems, University of Bremen, Bremen; 6 Department of Pathology, University of Halle, Halle, Germany
* Correspondence to: Dr P. Schmid, Department of Oncology and Hematology, Charité Campus Mitte, Humboldt University Berlin, Schumannstr. 20/21, 10117 Berlin, Germany. Tel: +49-30-450-613005; Fax: +49-30-450-513952; E-mail: peter.schmid{at}charite.de
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Abstract |
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Patients and methods: Forty-four patients with histologically confirmed stage II or III breast cancer were treated with NPLD (60 mg/m2) and docetaxel (75 mg/m2) on day 1 and gemcitabine as 4-h infusion (350 mg/m2) on day 4. Treatment was repeated every 3 weeks for a maximum of six cycles. All patients received prophylactically recombinant granulocyte colony-stimulating factor. Patients with axillary lymph node involvement after primary chemotherapy received adjuvant treatment with cyclophosphamide, methotrexate and fluorouracil.
Results: The clinical response rate was 80%, and complete remissions of the primary tumor occurred in 10 patients (25%). Breast conservation surgery was performed in 19 out of 20 patients (95%) with an initial tumor size of less than 3 cm and in 14 patients (70%) with a tumor size 3 cm. Seven patients had histologically confirmed complete responses accounting for a pCR rate of 17.5%. Expression of Ki-67 was the most important predictive parameter for response with high 38.9% breast pCR rate in patients with elevated Ki-67 expression. Although the predominant toxicity was myelosuppression with grade 3/4 neutropenia in 61% of patients few neutropenic complications resulted. Non-hematological toxicity was generally moderate with grade 3 or 4 toxicity in 10.0% of cycles. Most common non-hematologic toxicities were nausea, vomiting, alopecia, mucositis, asthenia and elevation of liver enzymes.
Conclusion: The evaluated schedule provides a safe and highly effective combination treatment for patients with early breast cancer, which is suitable for phase III studies.
Key words: adjuvant treatment, docetaxel, gemcitabine, liposomal doxorubicin, locally advanced breast cancer, neoadjuvant treatment, primary chemotherapy
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Introduction |
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Primary systemic treatment has been evaluated in a number of randomized trials comparing neoadjuvant and adjuvant anthracycline-based chemotherapy [17
]. Although primary chemotherapy was associated with higher rates of breast-conserving surgery, it generally failed to increase disease-free or overall survival in early stage breast cancer. However, several randomized trials showed that pathologic tumor response to neoadjuvant chemotherapy is correlated with prolonged disease-free and overall survival [8
, 9
].
Anthracycline-based chemotherapy regimens are currently considered as standard for primary chemotherapy [10]; however, the role of taxanes remains to be defined. Both paclitaxel and docetaxel have shown considerable activity as single agent primary chemotherapy [11
, 12
]. In stage II or IIIA breast cancer, single agent paclitaxel has shown comparable efficacy to anthracycline-based polychemotherapy [13
]. Furthermore, the sequential use of docetaxel after anthracycline-based primary chemotherapy has been shown to significantly increase response rates in anthracycline-sensitive and -refractory patients [14
]. In combination, anthracyclines and taxanes have shown superior response rates compared with non-taxane containing anthracycline-based regimens [15
18
]. The impact on disease-free and overall survival, however, has yet to be defined.
Combinations of anthracyclines, taxanes and gemcitabine have shown high activity in primary and advanced breast cancer [1921
]. The presented trial was initiated to evaluate a modified triple regimen that differed in several aspects from previous combination regimens.
Non-pegylated liposomal doxorubicin (NPLD; Myocet®) was selected to replace conventional doxorubicin in order to minimize the risk of anthracycline-induced cardiotoxicity [2224
]. Gemcitabine was given 72 h after docetaxel and NPLD because of potential time- and schedule-dependent drug interactions. Preclinical studies showed an antagonistic effect if gemcitabine was given within 24 h after paclitaxel, whereas synergism was observed if gemcitabine was administered 4872 h after paclitaxel. These effects were attributed to a temporary cell cycle arrest following taxane treatment [25
].
In addition, gemcitabine was applied over 4 h instead of the standard 30-min infusion in order to increase the accumulation of active metabolites. Gemcitabine is a pro-drug that has to be phosphorylated intracellulary to the active triphosphate [2628
]. Pharmacological studies indicate that higher intracellular concentrations of active metabolites can be achieved through prolongation of the application time since the rate-limiting enzyme in the formation of gemcitabine-triphosphate can be saturated during standard infusions [29
31
]. Several trials have therefore evaluated gemcitabine as a 36-h infusion and have shown substantial activity at considerably lower maximum tolerated doses ranging from 250 mg/m2 to 450 mg/m2 [32
36
].
A previous phase I trial established the optimum doses for the proposed triple regimen and showed high activity in patients with locally advanced breast cancer [37]. This phase II trial was therefore performed to evaluate further the efficacy and tolerability of the regimen as primary chemotherapy and to define potential predictive parameters for response.
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Patients and methods |
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Objectives
The primary study objective was to determine the clinical and pathological response to primary chemotherapy with gemcitabine, NPLD and docetaxel. Secondary end points included tolerability and the rate of breast-conserving surgery.
Patient eligibility
Previously untreated patients aged 1865 years with newly diagnosed, histologically confirmed breast cancer with T2-4 N0-1 M0 disease were included in the trial. The primary tumor had to be measurable in two dimensions by ultrasound and/or MR-mammography with one diameter of at least 2 cm. Patients were required to have adequate hematological, renal, hepatic and cardiac function [ANC 1.5 x 109/l; platelets
100 x 109/l; hemoglobin
8 g/dl; serum bilirubin <1.5 x ULN; serum transaminase levels <2.5 x ULN; serum creatinine level within normal range; left ventricular ejection fraction (LVEF) of at least 50%], a Karnofsky performance status of at least 70, a negative pregnancy test and appropriate contraception throughout the study (in premenopausal women only). Written, informed consent was required.
Exclusion criteria included inflammatory breast cancer, previous systemic or local treatment for breast cancer (including surgery, radiotherapy, cytotoxic and endocrine treatments), evidence of distant metastases, a history of prior other malignancies (except for curatively treated non-melanoma skin cancer or carcinoma in situ of the cervix), pre-existing peripheral neuropathy greater than grade 1 (NCI Common Toxicity Criteria), severe cardiac arrhythmias, congestive heart failure, active infection or other serious underlying medical or psychiatric condition which would impair the ability of the patient to receive protocol treatment. Pregnant or lactating women were not eligible.
Treatment plan
Eligible patients received up to six 3-week cycles of primary chemotherapy with gemcitabine, NPLD and docetaxel. In each cycle, NPLD [60 mg/m2, intravenous (i.v.) infusion over 60 min] was administered first, followed by docetaxel (75 mg/m2, i.v. infusion over 60 min) on day 1 and gemcitabine (350 mg/m2, i.v. infusion over 4 h) on day 4.
All patients were given prophylactic oral corticosteroid premedication (dexamethasone 8 mg) at 12- and 1-h intervals before docetaxel infusion and at 12, 24 and 36 h after docetaxel infusion. Standard antiemetic therapy was administered as needed on a prophylactic or treatment basis in compliance with the standards of the center. Recombinant granulocyte colony-stimulating factor (G-CSF; 5 µg/kg s.c.) was given on days 512 or until ANC >1.5 x 109/l.
Treatment was planned for six cycles unless there was evidence of unacceptable toxicity, disease progression or inadequate efficacy (defined as a decrease in tumor size <25% after two courses or <50% after four courses measured by ultrasound or MR-mammography), or if the patient requested to be released. A new cycle was only started if ANC was 1.5 x 109/l, platelet count was
100 x 109/l and the non-hematologic toxicity grade was
1 (with the exception of alopecia, nausea and vomiting). If a delay of treatment became necessary, blood counts were repeated every 2 days, so that treatment could be continued as soon as possible. If treatment had to be delayed for more than 2 weeks, the patient was withdrawn from the study.
Treatment was also to be discontinued if: resting LVEF decreased by 20 points from baseline to final values of LVEF
50% or by
10 points from baseline to a final LVEF value <50%; there was evidence of symptomatic arrhythmia or second-degree atrioventricular block; there was any grade 3 non-hematologic toxicity except for nausea, vomiting, alopecia, infection and gastrointestinal side-effects; or any grade 4 non-hematologic toxicity.
Doses of gemcitabine, NPLD and docetaxel were to be reduced to 300 mg/m2, 50 mg/m2 and 60 mg/m2, respectively, if ANC <500/µl for more than 7 days, ANC <100/µl for more than 3 days, or there was an episode of febrile neutropenia or grade 3 gastrointestinal side-effects. If grade 2 elevation of serum transaminase levels occurred, gemcitabine was reduced to 300 mg/m2 while NPLD and docetaxel remained unchanged. In the case of grade 3 elevation of serum transaminase levels, treatment with gemcitabine was discontinued. If grade 2 neurotoxicity was experienced, docetaxel was reduced by one dose level. For grade 3 neurotoxicity, docetaxel was discontinued.
Patients were scheduled to undergo surgery within 28 days after the start of the last chemotherapy cycle. Surgery consisted of either a modified-radical mastectomy or breast-conserving surgery in order to provide tumor-free margins of at least 1 cm. Standard axillary lymph node surgery with excision of 10 lymph nodes was to be performed in all cases. Patients who underwent breast-conserving surgery received adjuvant irradiation of the breast.
Patients with axillary lymph node involvement after primary chemotherapy received three cycles of adjuvant treatment with cyclophosphamide (100 mg/m2 orally on days 114), methotrexate (40 mg/m2 i.v. on days 1 and 8) and fluorouracil (600 mg/m2 i.v. on days 1 and 8) in 4-week intervals. In addition, tamoxifen was given for 5 years to patients with hormone-receptor positive tumors after completion of chemotherapy.
Patient evaluation and follow-up
Before entry into the study, all patients underwent staging work-up including a complete history and physical examination, complete blood count, chemistry profile, chest X-ray, abdominal ultrasound and/or a computed tomography, bone scan, and mammograms of both breasts. Cardiac function was assessed by electrocardiogram (ECG) and measurement of the LVEF by bidimensional echocardiography (ECHO). Primary tumor size and axillary lymph node involvement were assessed by clinical, X-ray and sonographic evaluation. In patients with unclear findings, primary tumor size was also assessed by MR-mammography. Histological confirmation of the invasive tumor was performed by core needle biopsy.
Clinical tumor size and nodal status were assessed by palpation before each cycle of chemotherapy and by ultrasound (and MR-mammography in the case of unclear findings) within 1 week prior to cycles 3 and 5, and 23 weeks after cycle 6, respectively. The product of the two greatest perpendicular diameters was used to compare tumor size before and after chemotherapy.
A clinical complete response (cCR) was considered a complete disappearance of all clinically detectable malignant disease in the breast by palpation as well as imaging techniques. Partial response was defined as 50% or more decrease in total tumor size (PR). A decrease in tumor size of less than 50% or an increase of less than 25% was classified as stable disease (SD). An increase of 25% in tumor size at any time was considered to be progressive disease (PD). In patients with clinically negative nodes at study entry, the development of palpable nodes during preoperative chemotherapy was considered evidence of PD.
Surgical specimens were evaluated for pathologic tumor status. Samples with no histologic evidence of invasive tumor in the breast were classified as pathologic complete responses (pCR). Histologic response was furthermore classified using the criteria proposed by Sinn et al. [38] (grade 0, no effect; grade 1, marked cytopathic effects and/or resorption and/or tumor sclerosis; grade 2, minimal focally invasive residues of <5 mm; grade 3, only non-invasive tumor residues; grade 4, no viable tumor cell detectable). Core biopsies and surgical specimens were reviewed centrally.
Adverse events and toxicities were recorded for every cycle. They were graded using the NCI Common Toxicity Criteria (CTC, version 2.0). Cardiac function was monitored after every second cycle by ECG and assessment of the LVEF by ECHO.
During follow-up, a clinical assessment for each patient was performed at 3-month intervals for the first 3 years and every 6 months thereafter. In addition to the routine physical examination with particular attention to local recurrence and lymph nodes, which was performed at each visit, mammography was applied every 6 months during the first 3 years and once a year thereafter to the involved breast (in case of breast-conserving surgery) and once a year to the contra-lateral breast, respectively. Cardiac function was monitored every 6 months by LVEF assessment and ECG.
Immunohistochemistry
Tissue samples were routinely fixed in 4% neutral buffered formaldehyde and embedded in paraffin. The following primary antibodies were used (clones and dilution in brackets): HER2/neu (HercepTest), Ki-67 (MIB-1, 1:25), estrogen receptor (ER) (1D5, 1:50) and progesterone receptor (PgR) (PgR636, 1:100) (all reagents from DAKO). Antigen-retrieval was performed by sodium citrate pH6 (PgR and MIB-1) or Target Retrieval Solution pH9 (ER) in a microwave four times for 5 min (600W). Slides (4 µm thickness) were incubated with the primary antibody (ER, PgR and MIB-1) for 30 min (37°C), rinsed afterwards, overlayed with a biotinylated multilink secondary antibody (mouse, rabbit, rat), and a biotin-streptavidin-amplified detection HRP system (Zytomed). Staining was visualized using an AEC chromogen system (Zytomed), counterstained with Haemalaun. Staining with the HercepTest was done according to manufacturer's instructions.
The nuclear staining pattern of ER and PR were evaluated according to the percentage of positive cells and the intensity of staining. The percentage of positive cells was scored as: 0 (0%); 1 (<10%); 2 (1050%); 3 (5080%); 4 (>80%). The staining intensity was scored as: 0 (negative), 1 (weak), 2 (moderate) and 3 (strong). For the immunoreactive score (IRS) the percentage of positive cells and staining intensity were multiplicated, resulting in a value between 0 and 12 [39]. Receptor positivity was assumed when the semi-quantitative score was 3 points or more. HER2/neu immunoreactivity was evaluated according to the DAKO score from 0 to 3. MIB-1 was scored as a percentage of stained nuclei.
Statistical analysis
The sample size was estimated at 44 patients assuming a pCR rate of 5% as null hypothesis, a true response rate of
15%, a power of 80% and a significance level of 10%. Standard descriptive methods were applied. Categorical variables were described by contingency table methods and percentages. Continuous variables were described by mean and median values, standard deviations and minimum and maximum values.
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Results |
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All patients were assessed for safety analysis, and 40 patients were assessed for efficacy. Patient characteristics at the time of study registration are listed in Table 1.
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Chemotherapy administration
A total of 243 cycles were administered during the study. The mean number of cycles per patient was 5.0 (range 16). Thirty-three patients (75%) completed the planned six cycles of chemotherapy. Two patients withdrew from the study after two courses because of NPLD infusion-related back pain. Another patient developed an acute myocardial infarction after the first course. Although this event was not considered to be related to the study treatment the patient was discounted from the study. All remaining patients received at least two cycles. The remaining discontinuations were as a result of disease progression or inadequate tumor regression.
Dose reductions were required in 12 patients with a total of 29 cycles. Reasons for dose reduction were stomatitis (11 cycles), febrile neutropenia (10 cycles), elevation of liver enzymes (six cycles), and other infections (two cycles). Most treatment cycles (219 of 227; 96%) were administered, as planned, every 3 weeks. Treatment delays were a result of prolonged neutropenia in four patients, and persistent mucositis on day 22 and patients request in one case each. The median relative dose intensities for gemcitabine, NPLD and docetaxel were 0.93, 0.97 and 0.97, respectively.
Toxicity
The tolerability and toxicity of the regimen was evaluated in 227 documented courses (Tables 2 and 3). The combination was generally well tolerated.
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Non-hematologic toxicities were usually mild. No grade 4 non-hematologic toxicities were reported. Grade 3 toxicities were reported for stomatitis (eight patients, 6.8% of cycles), infection (four patients, 2.7% of cycles), elevation of liver enzymes (four patients, 1.8% of cycles), nausea, diarrhea and asthenia (one patient each).
Predominant non-hematologic toxicity was mucositis with 37 patients (84.1%) experiencing stomatitis and 18 patients (40.9%) reporting diarrhea, respectively. Although generally mild to moderate, stomatitis affected 65% of courses and had a considerable effect on quality of life. Mucositis was the most frequent cause for delay of treatment or dose reduction. No cases of palmarplantar erythrodysesthesia were observed throughout the study.
Elevations of serum transaminase or alkaline phosphatase levels were observed in 29 patients (33% of cycles). Hepatotoxicity resolved in all patients after interruption or discontinuation of the treatment with gemcitabine and was clinically not significant.
Mild to moderate peripheral neuropathy occurred in five patients, with no grade 3 or 4 toxicity reported. No cases of cardiac, renal or pulmonary toxicity were reported throughout the study.
Efficacy
Forty patients were evaluable for efficacy (Table 4). The overall clinical response rate in breast and axillary lymph nodes as assessed by sonographic evaluation was 80%. Complete and partial clinical responses were achieved in 10 patients (25%) and 22 patients (55%), respectively (Fig. 1). The median tumor diameter decreased from 3.5 cm (range 210 cm) to 1.4 cm (range 08) (P <0.01).
|
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Preoperative chemotherapy was associated with a significant downstaging effect. Tumor stage was significantly decreased after chemotherapy (P <0.01). Whereas all patients had stage II or III disease at the start of treatment, 40% were found to have stage 0 or 1 disease on pathologic evaluation. Of 23 evaluable patients with clinical lymph node involvement at the beginning of the study, 14 patients had clinically uninvolved lymph nodes after primary chemotherapy.
All patients proceeded to surgery and breast conservation was possible in 33 patients (82.5%). Breast conservation surgery was performed in 19 out of 20 patients (95%) with an initial tumor size of less than 3 cm and in 14 patients (70%) with a tumor size 3 cm. The remaining patients received modified mastectomies.
Predictors of clinical and pathologic complete response
The value of various clinical and histological parameters in predicting pCR was analyzed by univariate and multivariate regression analyses. Variables included age, histology, largest pretreatment tumor diameter (as measured by ultrasound), clinical nodal status, grading, ER and PgR status, HER2/neu expression and Ki-67.
Only expression of Ki-67 was of significant predictive value in both univariate and multivariate logistic regression models. Patients with high Ki-67 expression (>15%) before chemotherapy had a significantly higher pCR rate than patients with lower expression (38.9% versus 0%; P = 0.04). The median Ki-67 score in patients with pCR was 45.7% compared with 16.9% for patients without pCR (P = 0.002). Ki-67 score correlated significantly with preoperative negative ER and PgR scores as well as grading (P = 0.001).
In addition, there was a trend to a higher pCR rate in patients with ER-negative tumors (26.3% versus 9.5%, P = 0.16), PgR-negative tumors (25.0% versus 10.0%, P = 0.21), higher grading (0% for G1 versus 10.5% for G2 and 33.3% for G3, P = 0.10), and lower disease stage (20.0% for stage 2 disease versus 0% for stage 3 disease, P = 0.22). No correlation was observed between HER2 status and response.
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Discussion |
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Following anthracycline- and taxane-based primary chemotherapy, the absence of viable tumor cells in the removed breast tissue has been reported in 6%19% of patients [4247
, 17
, 18
]. Furthermore, trials in the preoperative or palliative setting indicate that gemcitabine might enhance the activity of taxanes and/or anthracyclines when given in two- or three-drug combinations. Thus, the present study was performed to evaluate the efficacy and tolerability of a modified triple regimen and to define potential predictive parameters for response. The overall clinical response rate was 80% and the pCR rate was 17.5%. Breast-conserving surgery was possible in 70% of patients with an initial tumor size of
3 cm and in 95% of patients with smaller tumors. Other combinations of anthracyclines, taxanes and gemcitabine reported objective response rates in 85%92% of patients with complete clinical response in 20.6%30.7% and the complete absence of viable tumor cells in 13.7%15.8%, respectively [21
, 48
50
]. Thus, the efficacy of our modified triple regimen compares favorably with the best results reported from other trials evaluating new, highly active anthracyclinetaxane combination regimens in this setting.
The toxicity of the regimen investigated in the present trial was moderate, and adherence to the treatment was very high. As expected, leukopenia and neutropenia were the predominant side-effects. However, they were generally well managed, as reflected in a low rate of neutropenic complications, and did not require discontinuation of therapy.
Predominant non-hematologic toxicity was mucositis. Although generally mild to moderate, stomatitis had a considerable effect on quality of life and was the most frequent cause for delay of treatment or dose reduction. Similar incidences were, however, reported in other trials using combinations of anthracyclines, taxanes and gemcitabine.
Other grade 3 toxicities were infrequently reported for elevation of liver enzymes, nausea, diarrhea and asthenia, and were clinically not significant. Overall, the toxicity profile appeared similar to that reported in other trials involving anthracyclinetaxane containing regimens.
The identification of clinical and molecular predictors of pCR is considered an important strategy to tailor preoperative chemotherapy in early breast cancer. Although pCR provides a strong correlation with long-term outcome, this correlation might, however, not have the same utility for all patients with breast cancer. Several studies have demonstrated that pCR rates are several-fold higher for patients with ER-negative breast cancer, compared with ER-positive tumors where pCR rates range from 3% to 7% [5153
]. Similar results were obtained in the present trial with low pCR rates of 9.5% and 10.0% for patients with ER- or PgR-positive tumors, respectively. The implications of these observations are currently unclear as pCR rates of 1.5%6.8% have been reported in selected patients with ER-positive tumors after primary endocrine therapy with aromatase inhibitors [54
, 55
]. It is, however, controversially debated whether pCR is the ideal end point in ER-positive patients since no correlation of pCR and long-term survival has been demonstrated in this group.
Our trial shows that Ki-67 might be useful for selecting patients and tailoring primary chemotherapy as it was the only parameter of significant predictive value in both univariate and multivariate logistic regression models. Patients with high Ki-67 expression had a pCR rate of 38%, whereas no pCR was observed in patients with 15% or less Ki-67-positive tumor cells. All other parameters such as ER- or PgR-status, and grading that appeared to correlate with response, were also strongly correlated with Ki-67 status. Patients with high Ki-67 responded to chemotherapy irrespective of positive ER or PgR status, whereas patients with low Ki-67 expression responded poorly irrespective of other predictive parameters. This underlines the potential relevance of Ki-67 as a predictive parameter for patients undergoing primary chemotherapy. However, the observations need to be confirmed in large-scale prospective trials ideally establishing a correlation not only with pCR but also with disease-free and overall survival before practical conclusions can be made.
In summary, the results of the present study show that this modified gemcitabine, anthracycline and taxane combination is a safe and highly active regimen for primary chemotherapy in patients with breast cancer. Considering the high pCR rate, especially in tumors with elevated Ki-67 expression, this regimen seems suitable for further evaluation. However, with respect to the increased costs of this regimen, which in some countries may approximately double the costs of standard anthracyclinetaxane combinations, future trials should also include a cost-efficacy analysis in order to evaluate the potential benefits of this treatment.
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Acknowledgements |
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Received for publication April 13, 2005. Revision received May 31, 2005. Revision received June 13, 2005. Accepted for publication June 14, 2005.
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