Comparative effects of anastrozole, tamoxifen alone and in combination on plasma lipids and bone-derived resorption during neoadjuvant therapy in the impact trial

S. Banerjee1, I. E. Smith1,*, L. Folkerd2, J. Iqbal2, P. Barker3, M. Dowsett2 On behalf of the IMPACT trialists

1 Breast Unit, Royal Marsden Hospital, London & Sutton; 2 Academic Department of Biochemistry, Royal Marsden Hospital, London, UK; 3 AstraZeneca, Macclesfield, UK

* Correspondence to: Prof. I. E. Smith, Department of Medicine, Royal Marsden Hospital, Fulham Road, London SW3 6JJ. Tel: +44-207-808-2751; Fax: +44-207-352-5441; E-mail: ian.smith{at}rmh.nthames.nhs.uk


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: Estrogen has beneficial effects on lipid metabolism and bone preservation. The IMPACT trial evaluated neoadjuvant therapy with anastrozole or tamoxifen alone, or a combination. The comparative effects of these treatments on serum lipids and bone resorption were assessed.

Patients and methods: Non-fasting clotted blood samples were taken from 176 postmenopausal patients at baseline, 2 and 12 weeks for assessment of serum levels of estradiol, the bone resorption marker CTx and lipid profiles [total cholesterol (TC), high density lipoprotein cholesterol (HDL-C) and non-HDL cholesterol (N-HDL-C)].

Results: After 12 weeks, tamoxifen was associated with a significant increase in HDL-C (26.5%), and a decrease in TC (6.5%) and N-HDL-C (12.3%). Anastrozole was associated with a significant increase in HDL-C (11.2%), and a non-significant increase in TC (2.9%) and N-HDL-C (3.4%), both of which were significantly different from tamoxifen. The combination was associated with a significant increase in HDL-C (9.4%), and a decrease in TC (10.9%) and N-HDL-C (13.9%). For tamoxifen and the combination, there were non-significant decreases in CTx compared with a significant increase (45.6%) with anastrozole. No correlation between serum estradiol and CTx was seen in any of the treatment groups.

Conclusion: Anastrozole did not have a detrimental effect on lipid profiles following 3 months of therapy. There was a significant increase in CTx with anastrozole in contrast to tamoxifen.

Key words: anastrozole, bone, breast cancer, lipids, neoadjuvant, tamoxifen


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Estrogen has beneficial effects on lipid metabolism in postmenopausal women as it decreases total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) and increases high-density lipoprotein cholesterol (HDL-C) [1Go]. Estrogen is also a major determinant of bone turnover with low estradiol levels in postmenopausal women being associated with increased bone turnover [2Go].

Endocrine therapy for breast cancer targets estrogen. Tamoxifen has been the gold standard for many years and acts by competitive antagonism of estrogen at the receptor site. It also has partial tissue-specific agonist effects, which include effects on lipid profiles and bone mineral density. A reduction in serum LDL-C, serum TC and lipoprotein a (Lip a) levels and an increase in triglyceride (TG) levels with minimal effect on serum HDL-C have been reported with tamoxifen treatment [3Go]. Preservation of bone mineral density (BMD) and a decrease of bone resorption biomarkers have also been reported with tamoxifen [4Go, 5Go].

Over recent years the third generation aromatase inhibitors (AIs), including anastrozole, have shown themselves to be more effective than tamoxifen in all stages of breast cancer [6Go]. AIs work by inhibiting or inactivating the aromatase enzyme responsible for the synthesis of estrogens from androgenic substrates. In this way, circulating estrogen in postmenopausal women is reduced to very low levels. The consequences of this estrogen deprivation on lipid and bone metabolism would therefore be expected to differ substantially from the effects of tamoxifen. These differences are important to characterise, in order to allow balanced comparison of the relative benefits and disadvantages of the AIs compared with tamoxifen.

The IMPACT (Immediate Preoperative Arimidex, Tamoxifen or Combined with Tamoxifen) trial evaluated neoadjuvant therapy for 3 months with anastrozole, tamoxifen or the combination in postmenopausal women with estrogen receptor-positive non-metastatic breast cancer. The aims of the study were to compare the relative efficacies of the therapies in achieving tumour regression and so allow breast-conserving surgery in postmenopausal women. The clinical results have been reported [7Go].

As part of the study, the effects of these therapies on serum lipids and markers of bone resorption were also assessed and are reported here.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Study design
This was a phase III randomised, double-blind multicentre trial. Patients were randomised 1:1:1 to receive a daily dose of anastrozole 1 mg and tamoxifen placebo, or tamoxifen 20 mg and anastrozole placebo, or a combination of tamoxifen 20 mg and anastrozole 1 mg for 12 weeks prior to surgery [7Go]. Non-fasting clotted blood samples were taken at baseline, 2 and 12 weeks for assessment of serum levels of estradiol, the bone resorption marker type I collagen C-terminal telopeptide (CTx), and at baseline and 12 weeks for lipid profiles.

Patient inclusion criteria
Eligible patients were postmenopausal women with core needle biopsy proven invasive ER-positive breast cancer that was operable or potentially operable.

Lipid analysis
TC and HDL-C were measured in a central laboratory using a timed end point method on a Synchron CX9. Non-HDL cholesterol (N-HDL-C) was calculated: NHDLC = (TC) – (HDL-C).

Bone resorption marker analysis
Serum concentrations of CTx were assessed in a central laboratory with the serum CrossLaps One Step ELISA (Osteometer BioTech A/S, Herlev, Denmark). This test utilises two highly specific monoclonal antibodies against amino acid sequences in the products from the COOH-terminal telopeptides of type 1 collagen in the serum.

Estradiol measurement
Estradiol was measured in serum by radioimmunoassay after prior extraction with diethyl ether using previously described methodology [8Go].

Statistical analysis
Levels of TC, HDL-C and N-HDL-C were summarised at baseline and 3 months for each treatment group, together with the percentage change from baseline to 3 months. As these variables were approximately normal, the mean was the preferred summary statistic. Formal treatment comparisons of the percentage change from baseline (anastrozole versus tamoxifen and combination versus tamoxifen) were made using ANOVA with treatment fitted as a factor. Differences were tested at the two-sided 5% level.

Actual levels of serum CTx were summarised at baseline, 2 weeks and 3 months for each treatment group. Serum CTx was approximately log-normal so the geometric mean was used to summarise this data; the percentage change from baseline to 2 weeks and baseline to 3 months was estimated via a transformation of the geometric mean of the post baseline/baseline serum CTx ratio. Formal treatment comparisons (A versus T and C versus T) of the baseline to 3 months change in serum CTx were tested at the two-sided 5% level via an ANOVA of the change in log-transformed values.

Serum estradiol was approximately log-normal and was analysed in the same way as serum CTx, described above.

Pretreatment levels of serum CTx were correlated with baseline serum estradiol for all patients, and the percentage change in CTx was correlated with serum estradiol for patients in the anastrozole group using the Pearson Correlation coefficient of the log-transformed values.

Ethical considerations
The trial was conducted in accordance with the principles of Good Clinical Practice as specified in the Declaration of Helsinki (1996 version). The study protocol was approved first by a national multicentre research ethical committee and subsequently by individual local research ethics committees. All patients gave written informed consent before study enrolment.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Between October 1997 and October 2002 a total of 330 patients (median age 73 years) from 19 oncology centres across the UK and Germany were randomised to receive treatment with anastrozole (n = 113), tamoxifen (n = 108) or the combination (n = 109). Not all centres entered patients into this substudy and therefore data were available for 176 patients. Table 1 shows characteristics of the 176 patients entered in the trial for whom data on estradiol, lipid parameters and CTx were available. Data were available on at least one of the analytes for 56 patients on anastrozole, 57 patients on tamoxifen and 63 patients on the combination.


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Table 1. Baseline characteristics of participants in the IMPACT trial for whom lipid and bone resorption assessments are available

 
Lipid changes
The results are summarised in Table 2 and Figure 1. Following 12 weeks of treatment, tamoxifen resulted in a statistically significant 6.5% decrease in TC (95% CI –12.5 to –0.5, P <0.05). Anastrozole treatment led to a non-significant 2.9% increase in TC (95% CI –0.9 to 6.6). The difference between these two treatment effects was statistically significant (P <0.05). The treatment combination of anastrozole and tamoxifen resulted in a significant 10.9% decrease in TC (95% CI –14.3 to –7.5, P <0.05). There was no statistically significant difference in TC change between the combination and tamoxifen groups.


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Table 2. Mean values for TC, HDL-C, N-HDL-C and estradiol at baseline and 12 weeks by treatment group, and % change from baseline to 12 weeks

 


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Figure 1. Percentage change in arithmetic mean lipid parameters at 12 weeks by treatment group, with 95% confidence intervals: (A) total cholesterol (TC); (B) high density lipoprotein cholesterol (HDL-C); (C) non-high density lipoprotein cholesterol (N-HDL-C).

 
Anastrozole, tamoxifen and the combination significantly raised HDL-C by 11.2%, 26.5% and 9.4%, respectively (P <0.05 versus baseline for all three groups). The difference between the treatment groups was not significant.

N-HDL-C levels significantly decreased by 12.3% with tamoxifen (P <0.05) and showed a non-significant increase with anastrozole (3.4%). As observed for TC, the difference in N-HDL-C effects between the two monotherapy treatment groups was statistically significant (P <0.0001). The treatment combination of anastrozole and tamoxifen resulted in a statistically significant 13.9% decrease of N-HDL-C (–17.8, –9.9, P <0.05). The difference between the combination and tamoxifen groups was not statistically significant.

Bone resorption
The results are summarised in Table 3 and Figure 2. After 2 weeks of treatment, a non-significant 13.1% decrease in CTx was seen in the tamoxifen group (95% CI –25.3 to 1.1). A non-significant 8.8% increase in CTx was found with anastrozole treatment (95% CI –1.2 to 19.9). Combination treatment resulted in a statistically significant 19.5% decrease in CTx (95% CI –29.4 to –8.3).


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Table 3. Geometric mean bone resorption marker (serum CTx) values at baseline, 2 and 12 weeks

 


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Figure 2. Percentage change in geometric mean CrossLaps (CTx) at 2 and 12 weeks by treatment group, with 95% confidence intervals.

 
Following 3 months of treatment, a non-significant 8.6% decrease in CTx was observed with tamoxifen (95% CI –22.3 to 7.5). A statistically significant 45.6% increase in CTx was found with anastrozole (95% CI 26.9–67.1, P <0.05). The difference between these two groups was also statistically significant (P <0.001). The combination of anastrozole and tamoxifen resulted in a non-significant 11.5% decrease in CTx, which did not differ significantly from tamoxifen.

Estradiol levels
As expected, treatment with anastrozole statistically significantly decreased estradiol serum levels by 87.5% and treatment with the combination of anastrozole and tamoxifen by 86.2% between baseline and 12 weeks. No statistically significant change from baseline was seen with tamoxifen alone. Both anastrozole and the combination groups had statistically significant differences in oestradiol change compared with tamoxifen. The results are shown in Table 2 and Figure 3.



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Figure 3. Percentage change in geometric mean serum estradiol at 12 weeks by treatment group, with 95% confidence intervals.

 
There were no significant correlations noted between baseline estradiol levels and either baseline levels or change in levels of CTx in any of the treatment groups.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The serum analyses conducted were performed on non-fasting blood samples but nonetheless revealed significant differences between the treatment arms for lipids and the bone resorption marker CTx.

The beneficial effects of tamoxifen on serum lipids found in this study concurred with those previously reported [3Go, 9Go]. Love et al. [3Go] investigated the effects of tamoxifen on lipids in 62 postmenopausal women randomised into a placebo-controlled 2 versus 5 years tamoxifen trial. At the 5-year point, levels of total serum cholesterol (P <0.001), LDL-C (P <0.0001) and Lip a (P <0.001), were significantly lower in those continuing on tamoxifen than in those on placebo. TG levels in the tamoxifen group increased compared with placebo but the difference was not statistically significant. HDL-C levels were not significantly different in the two groups.

In another study, serum lipids and apolipoprotein levels were measured in 20 postmenopausal women with primary breast cancer, before and 3 months after tamoxifen therapy [9Go]. Tamoxifen caused a significant reduction in total serum cholesterol (10%; P <0.02), and in low-density lipoprotein cholesterol (17%; P <0.01), and a significant 47% increase in the high-density lipoprotein cholesterol (P <0.01). In addition, tamoxifen caused a 37% reduction in the serum concentration of lipoprotein (a) (P <0.01).

So far, data on the aromatase inhibitors anastrozole, fadrozole, vorozole and exemestane have suggested that these agents have no detrimental effect on lipid profiles [10Go–16Go].

Wojtacki et al. [10Go] studied the effects of anastrozole as second line therapy on lipid profile in 27 postmenopausal metastatic breast cancer (MBC) patients treated for a median duration of 32 weeks. There were no significant changes in lipid parameters throughout the treatment. Two randomised trials comparing anastrozole and tamoxifen as first-line treatment for MBC compared the effects of anastrozole and tamoxifen on lipid profiles [11Go, 12Go]. Lipid assessments were performed at baseline, 84 and 108 weeks. The combined results from these trials have been reported and have shown that anastrozole had no detrimental effect on lipids [13Go]. However, the concomitant treatment received by patients with MBC makes this a less than ideal setting for assessing pharmacologically induced biomarker changes.

Sawada et al. [14Go] evaluated the effects of anastrozole and tamoxifen as adjuvant therapy on lipid metabolism in 49 postmenopausal Japanese women with early breast cancer treated for 12 weeks. There was a significant reduction in TG and a significant increase in HDL-C with anastrozole, both beneficial effects. There was a significant reduction in LDL-C and TC levels with tamoxifen, consistent with previously reported studies [3Go]. There was a significant increase in TG levels with tamoxifen.

Wojtacki et al. [15Go] reported on the effects of adjuvant anastrozole on lipid profile in 51 postmenopausal patients pretreated with tamoxifen. Measurements were taken at baseline and 24, 60 and 130 weeks. There were no significant changes over time in lipid parameters and BMI (body mass index) values. In another study, Wojtacki et al. [16Go] studied the effect of adjuvant anastrozole on apolipoprotein A-1 and apolipoprotein B levels in 27 postmenopausal women. There were no significant changes over time (baseline, 1, 3 and 6 months) of apolipoproteins A-1 and B and BMI.

Our results in the neoadjuvant setting support previous observations that treatment with anastrozole does not have a detrimental effect on lipid profile, although we did show a non-significant trend towards a rise in TC and N-HDL-C after 3 months of anastrozole therapy. Balanced against this, we also found a significant increase in HDL-C with anastrozole, a beneficial effect.

The lipid effects of fadrozole, a second-generation non-steroidal aromatase inhibitor, were assessed in 21 postmenopausal MBC patients at baseline and every 3 months up to 24 months; no significant effects were seen [17Go].

The effect of vorozole, a third generation non-steroidal aromatase inhibitor was evaluated in a neoadjuvant endocrine trial that compared the systemic and intratumoural effects of vorozole with tamoxifen [18Go]. Non-fasting lipid profiles were assessed at baseline and weeks 4, 8 and 12. No significant lipid changes were seen with vorozole. There was a significant reduction in LDL-C and TC levels with tamoxifen, consistent with previously reported studies [3Go].

Exemestane is a steroidal compound unlike the other third-generation AIs, which raises the possibility of different effects on lipid and bone metabolism. A randomised phase II study of exemestane versus tamoxifen in first-line endocrine treatment for MBC (a companion study to EORTC Trial 10951) compared the effect of exemestane on lipid profiles in 72 postmenopausal women [19Go]. Overall, exemestane was reported to have no detrimental effect on cholesterol levels at 8, 24 and 48 weeks of treatment. In addition, exemestane lowered TG levels, a beneficial effect. Kataja et al. [20Go] reported a randomised trial comparing the effects of adjuvant anastrozole, exemestane, tamoxifen and toremifene on lipid profile with 30 postmenopausal women in each treatment group, and showed that anastrozole and exemestane had no significant effect on lipid profile. In contrast to other AIs, studies of the effects of letrozole on plasma lipids have shown conflicting results. Harper-Wynne et al. [21Go] evaluated the impact of letrozole on breast cell proliferation, lipids and bone indices in 32 postmenopausal healthy women. As with the above studies, this showed no substantial effects on plasma lipids after 3 months of treatment. The MA-17 trial addressed the effectiveness of 5 years of letrozole therapy in postmenopausal women with early breast cancer who have completed 5 years of tamoxifen therapy compared with placebo [22Go]. This found no significant increase in the incidence of hypercholesterolaemia with the switch to letrozole. In contrast, the Letrozole International Trial Group conducted a randomised phase III study comparing the efficacy and safety of letrozole (2.5 mg and 0.5 mg/day) with aminoglutethemide (250 mg twice daily) as second-line endocrine treatment in postmenopausal MBC [23Go]. In the letrozole arm, 3.8% of the patients developed hypercholesterolemia. Elisaf et al. [24Go] prospectively evaluated the effect of letrozole (2.5 mg/day) on lipid parameters in 20 postmenopausal women with MBC and likewise observed increases in TC (P = 0.005) and LDL-C (P <0.001). Very recently, first results of the BIG1-98 trial comparing adjuvant letrozole with tamoxifen have shown a significantly higher incidence of hypercholesterolemia with letrozole than with tamoxifen [25Go], an observation that could have been entirely tamoxifen-related or associated with a direct TC-raising effect of letrozole.

In summary, most of the evidence currently available suggests that aromatase inhibitors have either no detrimental effect on lipid profile or only a mild adverse effect. There are no good comparative data to determine whether there is any difference in effects between the different agents

Data on the effects of endocrine therapy on bone metabolism is limited. Studies in women with advanced breast cancer are confounded by the propensity of the disease to metastasise to bone. This may alter the equilibrium between osteoblastic and osteoclastic activity and hence markers of bone turnover.

Our results reinforce the beneficial effects of tamoxifen on bone preservation that have already been reported [5Go]. Marttunen et al. [5Go] evaluated the effects of tamoxifen and toremifene on bone metabolism and density in 30 postmenopausal patients with early breast cancer who were randomised to receive tamoxifen or toremifene for 1 year. Biochemical markers of bone resorption urinary hydroxyproline, serum cross-linked carboxyterminal telopeptide type 1 collagen-CTx, urinary cross-linked aminterminal telopeptide type I collagen- NTx) and bone formation (serum bone specific alkaline phosphatase-BAP, osteocalcin-BGP, aminoterminal and carboxyterminal propeptide type 1 procollagen) were assessed before treatment and at 6 and 12 months of therapy. Urinary NTx decreased after 6 months use of tamoxifen (mean 33%) and of toremifene (mean 16%). Tamoxifen increased the bone mineral density by 2% in the lumbar spine and 1% in the femoral neck (P <0.05).

Likewise the ATAC trialists reported on the effects of anastrozole, tamoxifen alone or in combination in early breast cancer on bone mineral density and bone turnover [26Go] and found that 1 year of tamoxifen therapy was associated with an increase in BMD and a decrease in markers of bone turnover [27Go].

In the ATAC trial, 1 year of anastrozole treatment was associated with bone loss at the spine and hip and an increase in markers of bone resorption (NTx) and bone formation (BAP). Anastrozole therapy continued to be associated with bone loss while tamoxifen was associated with an increase in BMD at 2 years [27Go].

Our data supports these findings and shows that following 3 months of neoadjuvant anastrozole treatment there was a significant increase in bone resorption biomarkers. In our study, however, the decrease in CTx observed with 3 months of tamoxifen treatment, was not significant. In addition, no correlation between serum estradiol and CTx was seen in any of the treatment groups. This is in contrast to the findings of Sypniewska et al. [28Go], who demonstrated a significant inverse correlation between estradiol and CTx.

Letrozole given for 3 months to 32 healthy postmenopausal women has been shown to cause a significant increase of 25% in the levels of CTx (P = 0.02) consistent with an increase in bone resorption [21Go]. As in the current study, no significant association between pre- or post-treatment serum oestradiol and CTx was shown.

The MA-17 trial reported on the effects of letrozole on BMD and bone turnover in postmenopausal women who had previously completed 5 years of adjuvant tamoxifen [29Go]. Patients treated with letrozole had a significant decrease in BMD of the spine (P = 0.008) and hip (P = 0.044) at 24 months compared with placebo controls. Urinary NTx levels were increased significantly at 6 months (P = 0.054), 12 months (P < 0.001) and 24 months (P = 0.016). A larger percentage of women developed osteoporosis of the lumbar spine by BMD criteria on letrozole than placebo (3.3% versus 0%) but this was not significant (P = 0.1264).

The effects of exemestane on bone have been reported in the Intergroup Exemestane Study (IES) in which women who were disease-free after 2–3 years tamoxifen were then randomised to further tamoxifen or exemestane to complete a total of 5 years adjuvant endocrine therapy [30Go]. It had been anticipated that pretreatment with tamoxifen coupled with the possible anabolic effect of exemestane with its steroidal structure might lessen bone adverse effects. After 12 months, exemestane was associated with a significant reduction in lumbar spine (2.9% CI 2.1–3.6) and total hip (2.1% CI 1.6–2.7) BMD. The changes in BMD with tamoxifen were significantly less (lumbar spine 0.02% CI –0.7 to 0.7). Bone marker data are currently being analysed. However, it should be remembered that here, and in the MA-17 study, interpretation of the effects of the aromatase inhibitor are complicated by the effects of the withdrawal of tamoxifen.

In conclusion our neoadjuvant data are likely to be cleaner than those obtained in patients with MBC given the potential confounding pharmacological effects of concurrent therapy on lipids and the uninterpretable data obtained on bone biomarkers in patients with MBC. Thus, they may be an important guide to potential long-term risk. Nevertheless their true implications for the eventual incidence of cardiovascular disease and osteoporosis compared with tamoxifen must await late follow-up from adjuvant trials.


    Acknowledgements
 
We are grateful to the IMPACT investigators from the UK and Germany who participated in this trial: W. H. Allum, S. Ashley, A. Bradley, I. Boedinghaus, D. Brett, G. Gui, J. Diggins, J. Holborn, A. Ring, N. Sacks, C. Shannon, I. Smith, G. Walsh (Royal Marsden Hospital, London, UK); S. Detre, M. Dowsett, M. Hills, J. Salter (Royal Marsden Laboratory, London, UK); S. Ebbs, J. Kember, C. Chu (Mayday University Hospital, London, UK); I. Batty, K. Kazim, A. Skene (Royal Bournemouth Hospital, Bournemouth, UK); J. M. Dixon, J. Murray, L. Renshaw (Western General Hospital, Edinburgh, UK); F. McNeill, K. Rooke (Essex County Hospital, UK); C. Griffith, J. Bevington (Royal Victoria Infirmary, Newcastle, UK); A. Evans, M. Pidgley (Poole General Hospital, Poole, UK); J.-U. Blohmer, W. Lichtenegger (Universitätsklinikum Charité, Berlin, Germany); P. Sauven, K. Rooke (Chelmsford & Essex Centre, Chelmsford, UK); C. Holcombe, K. Makinson (Royal Liverpool University Hospital, Liverpool, UK); L. Barr, N. J. Bundred, T. Pritchard (University Hospital of South Manchester, Manchester, UK); N. Harbeck (Frauenklinik der TU München, München, Germany); J. Clarke, J. Mansi (St. George's Hospital, London, UK); H. Stehle (Marienhospital, Stuttgart, Germany); T. Reimer (Universitäts-Frauenklinik, Rostock, Germany); K. Brunnert (Zentrum für Senologie und Plastische Chirurgie, Osnabrück, Germany); M. Lansdown, J. Hepper (St. James's University Hospital, Leeds, UK); D. Dubois, H. Stansby (Portsmouth Oncology Centre, Portsmouth, UK); Z. Rayter (Bristol Royal Infirmary, Bristol, UK).

We also thank the AZ Scientific Team as follows: Peter Barker, Stephen Bird, Phil Davies, Jo Diver, Sonia Harris, Martin Quinn and Karen Langfeld.

Received for publication March 10, 2005. Revision received June 1, 2005. Accepted for publication June 15, 2005.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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