High-dose mitoxantrone–vinblastine–cyclophosphamide and autologous stem cell transplantation for stage III breast cancer: final results of a prospective multicentre study

D. A. Stewart1,*, A. H. G. Paterson1, J. D. Ruether1, J. Russell1, P. Craighead2, M. Smylie3 and J. Mackey3

1 Department of Medical Oncology and 2 Department of Radiation Oncology, University of Calgary, and Tom Baker Cancer Centre, Calgary; 3 Department of Medical Oncology, University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada

* Correspondence to: Dr D. Stewart, 1331–29th Street NW, Calgary, AB, Canada T2N 4N2. Tel: +1-403-944-8569; Fax: +1-403-283-1651; Email: douglast{at}cancerboard.ab.ca


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: Stage III breast cancer patients continue to suffer high relapse and death rates despite standard chemotherapy regimens. High-dose alkylator chemotherapy does not further improve outcome. This phase II study evaluated a novel high-dose chemotherapy regimen which combined active breast cancer agents with differing mechanisms of action.

Patients and methods: Eligibility included at least seven involved axillary nodes (AxLNs) for tumours <5 cm, at least four AxLNs for tumours >5 cm or locally advanced breast cancer (LABC). Patients received four cycles of fluorouracil–adriamycin–cyclophosphamide (FAC) followed by one cycle of mitoxantrone 63 mg/m2–vinblastine 12.5 mg/m2–cyclophosphamide 6 g/m2 (MVC) with autologous blood stem cell transplantation (ASCT).

Results: Between April 1995 and December 1998, 92 patients aged 21–65 years (median 45 years) were enrolled, of whom 25 were treated preoperatively for LABC and 67 were treated postoperatively. Although there was no early treatment-related mortality, one late death occurred from secondary acute myeloid leukaemia. The 7-year event-free and overall survival rates were 53% (95% confidence interval 42–64%) and 62% (95% CI 52–73%), respectively, with no significant difference between pre- and postoperative groups.

Conclusion: FAC followed by MVC–ASCT is feasible and reasonably well tolerated, but does not result in improved survival rates compared with other conventional or high-dose regimens for stage III breast cancer.

Key words: adjuvant, autologous, breast, hematopoietic, neo-adjuvant, transplantation


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In the mid-1990s, high-dose alkylator-based therapy with autologous stem cell transplantation (ASCT) reportedly gave encouraging disease-free survival rates but relatively high treatment-related morbidity and mortality rates (5–10%) when used for poor-prognosis breast cancer [1Go, 2Go]. Results of randomized controlled phase III trials evaluating high-dose alkylator-based consolidation chemotherapy have not demonstrated improved event-free (EFS) or overall survival (OS) compared with conventional adjuvant chemotherapy alone [3Go–7Go]. In addition, treatment-related morbidity and mortality rates for high-dose alkylator chemotherapy are relatively high, particularly those associated with the cisplatin–BCNU–cyclophosphamide regimen [5Go]. Therefore high-dose chemotherapy and ASCT is not a standard treatment option for stage III breast cancer, and many academic centres are no longer studying this form of experimental therapy.

During the time that phase III high-dose alkylator studies were being conducted, we initiated a prospective multicentre clinical trial to evaluate the feasibility and efficacy of a novel high-dose regimen that incorporated three active breast cancer agents with mutually independent mechanisms of action. The regimen included the agents mitoxantrone, vinblastine and cyclophosphamide (MVC). Vinblastine was given by continuous infusion over 5 days to maximise the potential benefit of the cell-cycle-specific activity of this agent. Mitoxantrone, an anthracenedione, was included because of its similar mechanism of action to anthracycline chemotherapy, but, unlike anthracyclines, it could be substantially dose escalated. Cyclophosphamide was included because this agent also had known activity against breast cancer and could be dose escalated. At the time of study design, it had not yet been reported that cyclophosphamide dose escalation was not beneficial for breast cancer patients [8Go]. We hypothesised that this MVC regimen might be less toxic than alkylator-only-based regimens and had the potential for higher activity as it incorporated a higher dose of mitoxantrone than any other reported adjuvant breast cancer regimen.

To define an appropriately high-risk population to include in this study of high-dose chemotherapy, the Northern Alberta Breast Registry (NABR) database was interrogated. Of the 1077 breast cancer patients without metastases treated in Alberta between 1978 and 1985, three groups of patients had distant disease-free survival (DDFS) rates <40% (A. Lees and H. Jenkins H, NABR, 1994, personal communication). These three groups included T1–2 tumours with at least seven involved axillary nodes (n=40, DDFS=37%), T3 tumours with at least four involved axillary nodes (n=34, DDFS=35%), and T4 tumours (n=161, DDFS=28%).

This report describes the long-term outcome of MVC–ASCT consolidation therapy used both as adjuvant therapy for resected stage III breast cancer and as preoperative neoadjuvant therapy for stage III locally advanced breast cancer (LABC).


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Eligibility criteria for patients who had undergone definitive surgical resection (postoperative group) included seven or more involved axillary nodes for patients with tumours <5 cm in size, or four or more involved axillary nodes for patients with T3 (>5 cm) or T4 (involvement of skin or chest wall or inflammatory) tumours. Patients who received protocol chemotherapy preoperatively were required to have T3 tumours and palpable axillary nodes (cT3N1-2), or T4 tumours regardless of axillary status. According to the new revised staging system for breast cancer, all patients in this study were to have stage III disease [9Go]. Other eligibility criteria included age 18–65 years and no definitive evidence of metastatic disease on chest radiographs, radionuclide bone scan, or abdominal ultrasonography. Patients who had abnormalities on these tests that were not strongly suggestive of metastases were considered eligible. Patients required a white blood cell (WBC) count >3.0 x 109/litre, platelet count >100 x 109/litre, creatinine <133 µmol/l, alanine transaminase (ALT) less than three times normal, bilirubin less than three times normal, a left ventricular ejection fraction (LVEF) >0.50 on a MUGA nuclear cardiac scan and pulmonary function tests showing a forced vital capacity (FVC) >50% predicted, forced expiratory volume (FEV1)>50% predicted and DLCO >50% predicted. All patients gave written informed consent before starting protocol therapy. The study received local scientific and ethical approval at both the Calgary and Edmonton sites from the respective institutional scientific and health research ethics boards.

Protocol treatment:
Four cycles of FAC chemotherapy were administered as follows: 5-fluorouracil 500 mg/m2 all cycles, doxorubicin 50 mg/m2 all cycles and cyclophosphamide 500 mg/m2 in cycles 1 and 2, then 2000 mg/m2 in cycles 3 and 4. FAC cycles 3 and 4 were supported with granulocyte colony-stimulating factor (GCSF) 300 µg s.c. (for patients of weight <70 kg) or 480 µg s.c. (for patients of weight >70 kg) from day 7 until apheresis or absolute neutrophil count (ANC) recovery >1.5 x 109/litre if apheresis was not performed. Autologous blood stem cells were collected by apheresis upon blood count recovery from cycle 3 FAC. If <2 x 106 CD34+ cells/kg were collected following the cycle 3 of FAC, apheresis was repeated after cycle 4. The MVC high-dose chemotherapy regimen consisted of mitoxantrone 21 mg/m2 on days –6 to –4 (63 mg/m2 in total), vinblastine 12.5 mg/m2 continuous infusion over 5 days from day –6 to –2 and cyclophosphamide 3 g/m2 on days –3 and –2 (6 g/m2 in total), with ASCT on day 0.

Patients who had resectable stage III breast cancer received the above chemotherapy treatment postoperatively after definitive surgical resection of their cancers. Patients who had unresectable LABC received the same chemotherapy treatment, including high-dose MVC–ASCT, preoperatively and then underwent definitive surgical resection. All patients went on to receive 45–50 Gy adjuvant local-regional radiotherapy to the breast or chest wall, plus axillary and supraclavicular nodal areas. Internal mammary node irradiation with 45 Gy was only performed for medial tumours associated with 10 or more positive axillary nodes. Adjuvant tamoxifen 20 mg daily for 5 years was recommended only for postmenopausal patients who had oestrogen- or progesterone-receptor-positive breast cancers.

Statistics
This study was originally designed in 1994 as a prospective clinical trial to evaluate the feasibility of treating 30–40 patients with a novel high-dose MVC–ASCT regimen at two university-based cancer centres in the province of Alberta, Canada. Secondary endpoints included event-free, distant disease-free and overall survival rates, toxicity and quality-of-life changes for patients with poor prognosis stage III breast cancer treated with FAC–MVC–ASCT. The companion quality-of-life study will be reported in a separate publication. Because of strong pressure from patients, colleagues and institutions to offer high-dose adjuvant chemotherapy for breast cancer in the period 1995–1998, accrual to the study continued beyond the original target, with annual approval from local research ethics boards.

The data were analysed using Intercooled Stata 8 (Stata Corporation, College Station, TX) and GraphPad PRISM 4 (GraphPad Software Inc. San Diego, CA). Kaplan–Meier estimates of the survivor function were plotted and used to determine the 7-year survival rate and 95% confidence interval (95% CI) for overall survival (OS), event-free survival (EFS) (local-regional or distant relapse or death from any cause) and distant disease-free survival (DDFS). The log-rank test was used to determine whether differences in survival experience exist between individuals within the following groups: operative stage, age, pretreatment menopausal state, type of surgery (mastectomy or breast conservation), number of involved lymph nodes (<10 compared with ≥10), stage (IIIA, IIIB or IIIC), hormone receptor positivity (oestrogen or progesterone receptor), Scarfe–Bloom–Richardson tumour grade (1–2 compared with 3), HER-2 status determined by immunohistochemistry on primary tumour (3+ compared with other), and pre- or postoperative FAC–MVC–ASCT. A toxicity analysis was performed using a paired t-test to assess any change in LVEF from baseline to 3 months or 2 years. Univariate analysis was performed using the Kaplan–Meier method to evaluate possible association between the above factors and OS, DDFS and EFS.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
From April 1995 to October 1998, 92 patients were accrued. The characteristics of these patients are summarised in Table 1. Of the 67 patients who received postoperative chemotherapy, 50 underwent mastectomy and 17 underwent segmentectomy and axillary dissection, while of the 25 patients who received preoperative chemotherapy, 16 underwent mastectomy, seven underwent segmentectomy and axillary dissection and two refused definitive surgical treatment. Although the study was designed to enrol patients who did not have metastatic disease, patients were eligible if they had abnormalities of uncertain significance on staging bone scans. Two of these patients were subsequently proven to have bone metastases soon after study enrolment by additional imaging studies. These patients continued to receive protocol therapy and are included in the intention-to-treat survival analysis.


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Table 1. Patient characteristics

 
Of the 67 postoperative patients, 24 had T3 or T4 tumours and one had metastatic disease. The postoperative patients whose tumours were <5 cm in size had 7–25 involved axillary nodes (median 10), while those with T3–T4 tumours had 4–29 involved axillary nodes (median 10). Of the 25 preoperative patients with LABC, 17 had cT4 tumours (cN0=5, cN1=9, cN2=3) while eight had cT3 tumours (cN1=6, cN2=2). One patient with cT4dN1 disease had an abnormal bone scan at enrolment that was later diagnosed as metastatic disease. This patient received protocol therapy for cT4dN1M1 disease but is included in analysis.

Pathological response of preoperative MVC for LABC patients (n=25)
Of the 25 LABC patients who received preoperative MVC–ASCT, six achieved a pathological complete response (pT0N0M0), 12 achieved a pathological partial response (six patients pT1aN0M0, and six patients pT1b-T2 or N1) and seven patients had no significant response (pT3 or T4). Fifteen patients had negative axillary nodes and four had one or two involved nodes.

Survival data and univariate analysis of factors associated with outcome
At the time of this analysis, the median follow-up of surviving patients was 6.6 years (range 3.3–9.6). The 7-year OS rate was 62% (95% CI 52–73%), the DDFS rate was 57% (95% CI 47–67%) and the EFS rate was 53% (95% CI 42–64%) (see Figure 1). By univariate analysis, none of the following factors was associated with OS, DDFS or EFS: age, menopausal status, pre- or postoperative FAC–MVC–ASCT, segmental or total mastectomy, stage IIIA, IIIB or IIIC, high grade, HER-2 positivity or hormone receptor positivity. There was a trend for association between hormone receptor positivity (oestrogen or progesterone receptor) and improved OS (P=0.063), DDFS (P=0.154) and EFS (P=0.08). A multivariate analysis attempting to identify prognostic factors was considered inappropriate because no factor was significantly associated with EFS or OS in univariate analysis, and because the number of events was too small considering the relatively large number of potential prognostic factors to evaluate.



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Figure 1. Outcome following adjuvant or neo-adjuvant FAC and then high dose MVC–ASCT for 92 patients with stage III breast cancer.

 
The 7-year EFS and OS for LABC patients treated preoperatively with MVC–ASCT were 47% and 58%, respectively. This 7-year OS rate is not significantly different from the rates of 57% and 70% seen in resectable stage IIIA and stage IIIC patients who received postoperative FAC–MVC–ASCT (P=0.63). Distant relapse occurred in eight of the 17 patients (47%) with T4 tumours, but in only one of the eight patients (13%) with T3 tumours. Seven-year OS rates were 39% and 88% (log rank P=0.079) for patients with T4 and T3 tumours, respectively.

MVC–ASCT toxicity and engraftment
No patient experienced early treatment-related mortality or Bearman grade 3–4 regimen-related toxicity [10Go]. The only common Bearman grade 2 toxicity was stomatitis. The median length of hospital stay was 20 days (8–32 days). The median engraftment times to ANC >0.5 and to platelets >20 x 109/litre were 11 days (8–25 days) and 10 days (6–25 days), respectively. The median number of red blood cell transfusions was 4 units (2–8 units), while the median period in which platelet transfusion was required was 2 days (1–7 days).

In terms of late toxicity, one patient developed secondary myelodysplasia 8 months post-ASCT and died of acute myeloid leukemia 19 months post-ASCT despite receiving an allogeneic bone marrow transplant. Four FAC cycles followed by MVC–ASCT resulted in only mild asymptomatic cardiotoxicity. The study was designed to prospectively measure LVEF at baseline and at 3 months and 2 years after MVC–ASCT. In total, 79 patients had LVEF testing at baseline and again 3 months after MVC, while only 37 patients had repeat LVEF assessment 2 years after ASCT. In the 79 patients who could be compared before and after ASCT, the mean LVEF dropped from 0.63 at baseline (95% CI 0.62–0.65) to 0.57 by 3 months after MVC (95% CI 0.55–0.59) (P <0.001). Although this drop was statistically significant, it was not associated with cardiac symptoms or signs. In the 37 patients who were tested 2 years after MVC, the mean LVEF was 0.58 (95% CI 0.55–0.60), suggesting no further decrease in cardiac function to that point. No patient developed late clinical congestive heart failure.


    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The results of this study demonstrate that four cycles of FAC chemotherapy followed by high-dose MVC–ASCT for poor-prognosis stage III breast cancer was relatively well tolerated with no early treatment-related mortality, no clinical congestive heart failure and only a single (1.1%) case of secondary acute leukemia. This regimen produced substantially higher DDFS than historical controls treated in Alberta between 1978 and 1985. Furthermore, preoperative MVC–ASCT resulted in similar DDFS and OS for locally advanced stage III breast cancer to that obtained with postoperative adjuvant MVC–ASCT for resected stage III disease. Unfortunately, the participating patients have so far continued to experience disease relapse over time, without evidence of a plateau on the DDFS curve.

This study has several limitations. The improved outcome relative to historical controls may be due to factors other than high-dose MVC–ASCT therapy. Such factors include selection bias, stage migration from better surgical or pathological techniques, improvements in supportive care or the use of FAC before ASCT therapy. For example, it was not possible to determine details of the adjuvant systemic therapy administered to the stage-matched comparator cases derived from the NABR. Therefore the improved results of patients treated with FAC followed by MVC–ASCT relative to historical controls may have been due to the fact that a substantial proportion of historical patients did not receive standard adjuvant chemotherapy. Crump et al. [11Go] reported the potential impact of selection bias on the results of ASCT studies. However, it is unlikely that stage migration played a significant role in the present study because patients were staged by chest radiography, liver ultrasound and bone scan, rather than by body CT or MRI scans. In addition, patients who were diagnosed with metastatic disease after registration were not excluded from analysis.

Most of the reported randomized controlled phase III trials comparing high-dose with conventional dose therapy for stage III breast cancer have evaluated high-dose alkyating chemotherapy [3Go, 4Go]. These trials are generally regarded as negative trials with no significant difference in disease-free or overall survival between high-dose and standard-dose treatment arms. Although the response of breast cancer to alkylating chemotherapy agents increases with dose, the baseline response rate to alkylating agents is relatively low. In addition, studies have now demonstrated that cyclophosphamide dose escalation to 2 g/m2/cycle does not improve breast cancer outcome [8Go].

Although dose escalation of alkylating agents does not substantially improve outcomes in adjuvant breast cancer therapy, there may be some benefit to dose escalation of adjuvant anthracycline chemotherapy. Two phase III studies demonstrated improved outcome from intensive epirubicin-based adjuvant chemotherapy (FEC100) for node-positive breast cancer compared with less intensive epirubcin-based (FEC50) or cyclophosphamide–methotrexate–fluorouracil (CMF) chemotherapy [12Go, 13Go]. In contrast, the CALGB 9344 study found no benefit of increasing the doxorubicin dose from 60 to 90 mg/m2 in combination with cyclophosphamide (AC) [14Go].

Mitoxantrone is closely related to the anthracyclines in mechanism of action and disease-specific activity, and can be substantially dose escalated with ASCT. It is possibly the most relevant agent to study in high-dose therapy trials for breast cancer. In the PEGASE 01 trial, Roché et al. [15Go] randomised 314 patients with seven or more involved axillary nodes to four FEC100 cycles either alone or followed by high-dose cyclophosphamide 120 mg/kg–mitoxantrone 45 mg/m2–melphalan 140 mg/m2 (CMA–ASCT). At a median follow-up of ~3 years, the high-dose CMA resulted in significantly superior disease-free survival (68% compared with 53%) but, at the time of reporting, no improvement in overall survival. Zander et al. [16Go] recently published a study involving 302 patients with stage IIIC disease who were randomised to either four cycles of epirubicin 90 mg/m2–cyclophosphamide 600 mg/m2 (EC) followed by cyclophosphamide 1500 mg/m2–thiotepa 150 mg/m2–mitoxantrone 10 mg/m2 daily for 4 days (CTM–ASCT) or to four cycles of EC followed by three cycles of CMF. After a median follow-up of 3.8 years, there was a trend to improved 4-year EFS in favour of CTM–ASCT (52% compared with 42%, P=0.09), but no significant difference in 4-year OS.

An important aspect of our trial was that our MVC regimen contains the highest dose of mitoxantrone ever studied in the adjuvant chemotherapy setting for breast cancer, and therefore had the potential to improve outcomes for stage III breast cancer patients. However, the 7-year results of MVC–ASCT, including the overall survival rate of 62% (95% CI 52–73%) and event-free survival rate of 53% (95% CI 42–64%) are comparable to those reported in other studies of high-dose chemotherapy for poor-prognosis stage III breast cancer [3Go–7Go] Indeed, the results are not obviously better than the 10-year overall survival rate of 50% for 443 patients with stage III breast cancer treated with conventional anthracycline-based adjuvant chemotherapy [17Go]. In addition, a similarly high dose of mitoxantrone was used in a study evaluating late high-dose consolidation chemotherapy following six cycles of induction chemotherapy for metastatic breast cancer in a randomised controlled trial conducted by the National Cancer Institute of Canada [18Go]. Concordant with other phase III trials of late high-dose alkylator-based consolidation chemotherapy, this high-dose mitoxantrone-based regimen did not result in improved survival rates compared with conventional dose therapy alone for metastatic breast cancer patients [19Go].

Regarding LABC, Low et al. [20Go] recently reported 15-year follow-up data on 107 stage III breast cancer patients treated at the National Cancer Institute to best response with anthracycline-based combination chemotherapy followed by definitive local therapy and then further chemotherapy. The 15-year survival was 20% for 46 inflammatory breast cancer (IBC) patients, 23% for 13 non-IBC stage IIIB patients and 50% for 48 stage IIIA patients. Woodward et al. [17Go] reported 10-year survival results of 59% for 436 patients with stage IIIA disease, and 36% for seven patients with stage IIIB (T4) disease or 258 patients with stage IIIC (N3) disease treated in prospective clinical trials at the M. D. Anderson Cancer Center between 1975 and 1994. Our results for preoperative FAC–MVC–ASCT compare favourably with these results of conventional dose chemotherapy for stage IIIA and IIIB cancer, but because of small patient numbers no firm conclusions can be drawn. Data from the European Group for Blood and Marrow Transplantation (EBMT) Registry reported the results of high-dose chemotherapy followed by ASCT for 7471 breast cancer patients treated between 1990 and 1999 [21Go]. For 921 patients coded as having inflammatory breast cancer, the 5-year progression-free survival rate was 42% [21Go]. It is possible that LABC may be a subgroup of breast cancer that is best treated by high-dose preoperative chemotherapy. This issue can only be addressed by prospective randomised controlled trials.

The importance of our trial is reduced by reports of several randomised phase III trials that did not demonstrate superior outcome of high-dose consolidation chemotherapy relative to conventional chemotherapy alone [3Go–7Go] However, these prior phase III trials can be criticised for several reasons including the use of a non-conventional intensive chemotherapy ‘control arm’, relatively short follow-up, the fact that 10–20% of patients in high-dose arms never received the assigned high-dose therapy and contamination of the control arm by high-dose therapy. Finally, breast cancer is a heterogeneous disease, and although high-dose therapy may not improve outcomes for all breast cancer patients, it may benefit selected subgroups of breast cancer. Recent studies are attempting to correlate outcome with molecular markers in order to identify subgroups of breast cancer that may benefit from high-dose therapy [22Go–24Go].

One promising refinement of ASCT-based therapy is to use up-front multicycle high-dose chemotherapy. Recently published randomised controlled trials suggest a benefit for GCSF-supported dose-dense adjuvant chemotherapy relative to conventionally scheduled chemotherapy for breast cancer. The CALGB 9741 trial of adriamycin and cyclophosphamide followed by paclitaxel (AC-T) given every 2 weeks instead of every 3 weeks statistically improved 3-year DFS from 81% to 85% and overall survival from 90% to 92% [25Go]. Furthermore, preliminary results of randomised trials suggest improved disease-free survival relative to conventional dose therapy following multiple cycles of high-dose therapy, each supported by autologous blood stem cells. Nitz et al. [26Go] have reported a study of four cycles of dose-dense epirubicin 90 mg/m2–cyclophosphamide 600 mg/m2 every 14 days followed by three cycles of CMF (600 mg/m2–40 mg/m2–600 mg/m2) every 14 days compared with two cycles of EC followed by two cycles of tandem EC–thiotepa (90 mg/m2–3000 mg/m2–400 mg/m2) every 28 days in 403 patients with 10 or more involved axillary nodes. The 4-year EFS rates favoured high-dose therapy (61% compared with 41%; P=0.0019) with no treatment-related mortality.

In conclusion, four cycles of FAC followed by MVC–ASCT is feasible and is associated with relatively low morbidity and mortality rates, but does not seem to result in improved DDFS or OS rates compared with other conventional or high-dose regimens for stage III breast cancer. Late consolidation with high-dose chemotherapy and ASCT is not an appropriate strategy for managing these patients. The concept of high-dose therapy could be refined by evaluating optimal regimens given in repeated cycles to treat patients whose breast cancer expresses molecular markers predicting benefit from this treatment. Additional trials are required to determine whether such an approach will be feasible, safe and effective.

Received for publication December 19, 2004. Revision received April 13, 2005. Accepted for publication April 18, 2005.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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