Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial.
ABSTRACT To compare the incidence and timing of bone fractures in postmenopausal women treated with 5 years of adjuvant tamoxifen or letrozole for endocrine-responsive early breast cancer in the Breast International Group (BIG) 1-98 trial.
We evaluated 4895 patients allocated to 5 years of letrozole or tamoxifen in the BIG 1-98 trial who received at least some study medication (median follow-up 60.3 months). Bone fracture information (grade, cause, site) was collected every 6 months during trial treatment.
The incidence of bone fractures was higher among patients treated with letrozole [228 of 2448 women (9.3%)] versus tamoxifen [160 of 2447 women (6.5%)]. The wrist was the most common site of fracture in both treatment groups. Statistically significant risk factors for bone fractures during treatment included age, smoking history, osteoporosis at baseline, previous bone fracture, and previous hormone replacement therapy.
Consistent with other trials comparing aromatase inhibitors to tamoxifen, letrozole was associated with an increase in bone fractures. Benefits of superior disease control associated with letrozole and lower incidence of fracture with tamoxifen should be considered with the risk profile for individual patients.
- SourceAvailable from: Per Eystein Lønning[show abstract] [hide abstract]
ABSTRACT: Following the introduction of potent aromatase inhibitors for the treatment of breast cancer patients, highly sensitive methods have become mandatory to evaluate the influence of these drugs on plasma estrogen levels. Commercially available kits for estrogen measurements are not suitable for these kinds of evaluations due to their detection limits that are close to baseline estrogen levels in postmenopausal women. We describe here an optimised radioimmunoassay suitable for the simultaneous measurement of plasma estrone (E1), estradiol (E2) and estrone sulfate (E1S) levels in the ultra-low range. Following incubation with [3H]-labelled estrogens as internal standards, crude estrogen fractions were separated by ether extraction. The E1S fraction was hydrolysed with sulfatase followed by eluation on a Sephadex column. Free estrogens (E1, E2) were separated by chromatography (LH-20). Estrone and E1S (following hydrolysis) were converted into E2, and each estrogen fraction was measured by the same highly sensitive and specific radioimmunoassay using estradiol-6-(O-carboxymethyl)-oximino-2-(2-[125 I]-iodo-histamine) as ligand. Although several purification steps were involved, the internal recovery values for tritiated estrogens were found to be 88%, 90%, and 49% for E1, E2 and E1S, respectively. The intra-assay coefficient of variation was <5% for all recovery measurements. The detection limits were calculated following repeated blank measurements and found to be 1.14 pmol/L for E1, 0.67 pmol/L for E2, and 0.55 pmol/L for E1S, respectively. The intra-assay coefficient of variation (CV) was found to be 3.4% for E1, 5.1% for E2 and 6.1% for E1S, while the inter-assay CV was 13.6%, 7.6% and 7.5% for E1, E2, and E1S, respectively. Considering normal plasma levels for E2 (15 pmol/L), E1 (80 pmol/L) and E1S (400 pmol/L) in postmenopausal women, the method allows theoretically to detect suppression of plasma E2, E1 and E1S levels by 95.5%, 98.6% and 99.9% when starting from average, normal postmenopausal levels. Thus, the method presented here is to our knowledge the currently most sensitive assay available for plasma estrogen measurements in the ultra-low range and, as such, a reliable tool for a proper evaluation of potent aromatase inhibitors and other potential drugs influencing on plasma estrogen levels.The Journal of Steroid Biochemistry and Molecular Biology 03/2008; 109(1-2):90-5. · 3.98 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: The aromatase inhibitor letrozole is a more effective treatment for metastatic breast cancer and more effective in the neoadjuvant setting than tamoxifen. We compared letrozole with tamoxifen as adjuvant treatment for steroid-hormone-receptor-positive breast cancer in postmenopausal women. The Breast International Group (BIG) 1-98 study is a randomized, phase 3, double-blind trial that compared five years of treatment with various adjuvant endocrine therapy regimens in postmenopausal women with hormone-receptor-positive breast cancer: letrozole, letrozole followed by tamoxifen, tamoxifen, and tamoxifen followed by letrozole. This analysis compares the two groups assigned to receive letrozole initially with the two groups assigned to receive tamoxifen initially; events and follow-up in the sequential-treatment groups were included up to the time that treatments were switched. A total of 8010 women with data that could be assessed were enrolled, 4003 in the letrozole group and 4007 in the tamoxifen group. After a median follow-up of 25.8 months, 351 events had occurred in the letrozole group and 428 events in the tamoxifen group, with five-year disease-free survival estimates of 84.0 percent and 81.4 percent, respectively. As compared with tamoxifen, letrozole significantly reduced the risk of an event ending a period of disease-free survival (hazard ratio, 0.81; 95 percent confidence interval, 0.70 to 0.93; P=0.003), especially the risk of distant recurrence (hazard ratio, 0.73; 95 percent confidence interval, 0.60 to 0.88; P=0.001). Thromboembolism, endometrial cancer, and vaginal bleeding were more common in the tamoxifen group. Women given letrozole had a higher incidence of skeletal and cardiac events and of hypercholesterolemia. In postmenopausal women with endocrine-responsive breast cancer, adjuvant treatment with letrozole, as compared with tamoxifen, reduced the risk of recurrent disease, especially at distant sites. (ClinicalTrials.gov number, NCT00004205.)New England Journal of Medicine 01/2006; 353(26):2747-57. · 51.66 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Tamoxifen preserves bone in postmenopausal women, but non-steroidal aromatase inhibitors accelerate bone loss and increase fracture risk. We aimed to study the effect on bone health in a subgroup of women included in the Intergroup Exemestane Study (IES), a large randomised trial that compared the switch to the steroidal aromatase inhibitor exemestane with continuation of tamoxifen in the adjuvant treatment of postmenopausal breast cancer. Results were analysed from 206 evaluable patients from the IES, in which postmenopausal women with histologically confirmed and completely resected unilateral breast cancer (that was oestrogen-receptor positive or of unknown status), who were disease-free after 2-3 years of treatment with tamoxifen were randomised to continue oral tamoxifen 20 mg/day or switch to oral exemestane 25 mg/day to complete a total of 5 years of adjuvant endocrine therapy. The primary endpoint was change in bone-mineral density (BMD) assessed by dual energy X-ray absorptiometry. Changes in biochemical markers of bone turnover were also analysed in this substudy, and the incidence of fractures in the entire study reported. The IES is registered on the Current Controlled Trials website . Within 6 months of switching to exemestane, BMD was lowered by 0.051 g/cm(3) (2.7%; 95% CI 2.0-3.4; p<0.0001) at the lumbar spine and 0.025 g/cm(3) (1.4%; 0.8-1.9; p<0.0001) at the hip compared with baseline. BMD decreases were only 1.0% (0.4-1.7; p=0.002) and 0.8% (0.3-1.4; p=0.003) in year 2 at the lumbar spine and hip, respectively. No patient with BMD in the normal range at trial entry developed osteoporosis. Bone resorption and formation markers increased at all time points in women receiving exemestane (p<0.001). With a median follow-up in all IES participants (n=4274) of 58 months, 162 (7%) and 115 (5%) patients in the exemestane and tamoxifen groups, respectively, had fractures (odds ratio 1.45 [1.13-1.87]; p=0.003). These results indicate that the increase in survival shown previously with the IES switch strategy is achieved at the expense of some detriment to skeletal health, so the risk-benefit ratio to women needs to be individually assessed.The Lancet Oncology 02/2007; 8(2):119-27. · 25.12 Impact Factor
Annals of Oncology 20: 1489–1498, 2009
Published online 27 May 2009
Bone fractures among postmenopausal patients with
endocrine-responsive early breast cancer treated with
5 years of letrozole or tamoxifen in the BIG 1-98 trial
M. Rabaglio1*, Z. Sun2, K. N. Price3, M. Castiglione-Gertsch4, H. Hawle4, B. Thu ¨rlimann5,
H. Mouridsen6, M. Campone7, J. F. Forbes8, R. J. Paridaens9, M. Colleoni10, T. Pienkowski11,
J.-M. Nogaret12, I. La ´ng13, I. Smith14, R. D. Gelber15, A. Goldhirsch16,17& A. S. Coates18for the
BIG 1-98 Collaborative and International Breast Cancer Study Groups
1IBCSG Coordinating Center and Inselspital, Bern, Switzerland;2IBCSG Statistical Center, Dana-Farber Cancer Institute, Boston, MA;3IBCSG Statistical Center and
Frontier Science and Technology Research Foundation, Boston, MA, USA;4IBCSG Coordinating Center, Bern;5Senology Center of Eastern Switzerland and Swiss
Group for Clinical Cancer Research (SAKK), Kantonsspital, St Gallen, Switzerland, Swiss Group for Clinical Cancer Research (SAKK);6Danish Breast Cancer
Cooperative Group, Rigshospitalet, Copenhagen, Denmark;7Institut du Cancer Nantes Atlantique, CLCC Rene ´ Gauducheau, Saint Herblain, Fe ´de ´ration Nationale des
Centres de Lutte Contre le Cancer, France;8Australian New Zealand Breast Cancer Trials Group, University of Newcastle, Calvary Mater Newcastle, Newcastle, New
South Wales, Australia;9Department of Medical Oncology, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium;10Research Unit in
Medical Senology, Department of Medicine, European Institute of Oncology, Milan, Italy;11Cancer Center Maria Sklodowska-Curie Memorial Institute of Oncology,
Warsaw, Poland;12Department of Mammary and Pelvic Surgery, Jules Bordet Institute; Brussels, Belgium;13Department of Medical Oncology, National Institute of
Oncology, Budapest, Hungary;14Breast Unit, The Royal Marsden Hospital, London, UK;15IBCSG Statistical Center, Dana-Farber Cancer Institute, Harvard School of
Public Health and Harvard Medical School, Boston, MA, USA;16Department of Medicine, European Institute of Oncology, Milan, Italy;17Oncology Institute of Southern
Switzerland, Bellinzona, Switzerland and18International Breast Cancer Study Group and University of Sydney, Sydney, New South Wales, Australia
Received 2 December 2008; revised 15 January 2009; accepted 19 January 2009
Background: To compare the incidence and timing of bone fractures in postmenopausal women treated with 5
years of adjuvant tamoxifen or letrozole for endocrine-responsive early breast cancer in the Breast International Group
(BIG) 1-98 trial.
Methods: We evaluated 4895 patients allocated to 5 years of letrozole or tamoxifen in the BIG 1-98 trial who received
at least some study medication (median follow-up 60.3 months). Bone fracture information (grade, cause, site) was
collected every 6 months during trial treatment.
Results: The incidence of bone fractures was higher among patients treated with letrozole [228 of 2448 women
(9.3%)] versus tamoxifen [160 of 2447 women (6.5%)]. The wrist was the most common site of fracture in both
treatment groups. Statistically significant risk factors for bone fractures during treatment included age, smoking
history, osteoporosis at baseline, previous bone fracture, and previous hormone replacement therapy.
Conclusions: Consistent with other trials comparing aromatase inhibitors to tamoxifen, letrozole was associated with
an increase in bone fractures. Benefits of superior disease control associated with letrozole and lower incidence of
fracture with tamoxifen should be considered with the risk profile for individual patients.
Key words: aromatase inhibitor, bone fracture, hormonal therapy, letrozole, tamoxifen
Aromatase inhibitors (AIs) profoundly lower circulating
estrogen levels in postmenopausal women [1, 2], predisposing
them to increased bone loss and fracture risk, while tamoxifen
has a protective effect on bone loss in postmenopausal women
. The increase of bone fractures for patients who receive AIs
compared with tamoxifen is described in all recent adjuvant
trials comparing AIs to tamoxifen in postmenopausal breast
cancer patients, including the Breast International Group (BIG)
1-98 trial [4–10]. All these studies consistently show that AIs
are associated with superior disease control compared with
tamoxifen. In 2004, an expert panel of the American Society of
Clinical Oncology, after review of the published data,
recommended including an AI in the adjuvant setting either as
initial treatment or after treatment with tamoxifen for adjuvant
hormonal therapy for postmenopausal women with hormone
receptor-positive breast cancer . Apart from AIs being
regarded as part of routine adjuvant therapy for
postmenopausal breast cancer patients, they are being studied
*Correspondence to: M. Rabaglio, International Breast Cancer Study Group
Coordinating Center, Effingerstrasse 40, CH-3008 Bern, Switzerland; Tel: +41 31 389
93 91; Fax: +41 31 389 93 92; E-mail: email@example.com.
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: firstname.lastname@example.org
in combination with ovarian suppression in premenopausal
breast cancer patients and even for prevention. It is therefore
important to thoroughly evaluate these newer agents for side-
effects. Postmenopausal women naturally experience increased
bone loss and are at risk of fractures, which can severely impact
their quality of life and impair their ability to cope with the
activities of daily life. Any increase in this risk is of importance
in evaluating the costs and benefits of AIs in adjuvant therapy.
Most of the large clinical trials involving AIs compared an AI
to the standard agent tamoxifen, either as 5 years of initial
therapy [4, 5, 10] or after 2–3 years of tamoxifen [6, 7, 12]. Bone
loss and increased fracture rates for the patients who received an
AI have been observed in all these trials, and any difference in
bone loss might partially reflect the protective effect of tamoxifen
. In the MA.17 trial comparing letrozole to placebo in patients
who had received 5 years of tamoxifen, there was no statistically
significant difference in the clinical fracture incidence or in
reported osteoporosis , but a bone substudy concluded that
in this setting letrozole caused a modest increase in bone
resorption and reduction in bone mineral density (BMD) in the
spine and hip compared with placebo . A recent update that
accounted for patients from the control group who were offered
to switch from placebo to letrozole after the results were known
reported a statistically significant increase in bone fractures
among those patients who switched to letrozole compared with
those who remained on placebo . A recent published review
summarized the clinical and preclinical data regarding the effects
of AIs on BMD, markers of bone turnover, and clinical fracture
In this study, we investigate the incidence and timing of bone
fractures for patients on letrozole compared with tamoxifen in
the BIG 1-98 trial and develop a risk profile of patients more
likely to have a bone fracture while on treatment.
BIG study 1-98 is a phase 3, double-blind trial to evaluate the effect of
letrozole compared with tamoxifen administered postoperatively to patients
with operable breast cancer. From March 1998 to May 2003, 8010
postmenopausal women with hormone receptor-positive invasive breast
cancer were randomized to one of the four following options: monotherapy
with tamoxifen (20 mg daily) for 5 years, letrozole (2.5 mg daily) for
5 years, sequential therapy comprising tamoxifen for 2 years followed by
letrozole for 3 years, or letrozole for 2 years followed by tamoxifen for
3 years. Patients were enrolled in the two-arm option of letrozole or
tamoxifen from March 1998 to March 2000 and the four-arm option from
April 1999 to May 2003. The current analysis focuses on the 4895 patients
who were randomized to the two monotherapy arms (two- and four-arm
options) in BIG 1-98 and received at least some study medication.
The study was coordinated by the International Breast Cancer Study
Group (IBCSG) on behalf of the BIG. The ethics committees and required
health authorities of each participating center approved the study protocol,
and all patients gave written informed consent. Details of study conduct
and results of the primary core analysis of the comparison of letrozole to
tamoxifen using data from patients randomized to all four arms  and
results from patients randomized to the two monotherapy arms  have
been previously reported.
The trial case report forms collected specific information on bone
fractures every 6 months during trial treatment, including grade, date, cause
(osteoporosis, metastasis, trauma, other), and site. Bone fractures were
graded as grade 2 (fracture not requiring surgery) or grade 3 (fracture
requiring surgery). All bone fractures were centrally reviewed by the
medical review team (MR and HH) at the IBCSG Coordinating Center and
investigators were asked to provide details of the cause of the fracture.
Particular attention was given to the adequacy of the traumas to the
presence of osteoporosis, assessment tools used to measure the bone
density, and concomitant medication or condition promoting bone loss.
The trial protocol mentioned that the use of bisphosphonates was
permitted and should be recorded, but it did not make any
recommendation with regard to the identification of risk factors for
osteoporosis, measurement of BMD, or the use of calcium or vitamin D
The end point in this study was any bone fracture. In addition, we
evaluated causes of fracture as recorded in the case report form, including
osteoporosis, trauma, and metastasis, but because of small numbers and
lack of clear definitions, these are not presented. Only fractures occurring
during study medication were included. The 425 patients (17%)
randomized to receive 5 years of tamoxifen but who chose to crossover to
letrozole (subsequent to the publication of initial efficacy results and
according to addendum 5 of the protocol) are included in the analysis but
only fractures up to the time patients went off tamoxifen treatment were
The baseline characteristics listed in Table 1 were collected at study entry
and were compared between treatments using two-sided Fisher’s exact tests
 and two sample t-tests. Baseline risk factors examined for potential
increased risk of bone fracture included treatment allocation, age, body
mass index (BMI), smoking history, prior osteoporosis and prior bone
fracture. Subpopulation treatment effect pattern plots (STEPPs) were used
to investigate the pattern of differences in incidence of bone fractures
between treatment arms according to patient age at study entry [18, 19]. In
these plots, the y-axis shows the incidence (percentage) of bone fractures for
each treatment group. The incidence rates per 1000 women-years were also
provided for each treatment group, calculated either allowing only one
fracture per patient or including all fractures in patients who had multiple
Table 1. Baseline patient characteristics and co-morbidities
(N = 2448)
(N = 2447)
Mean age, years (SD)
Body mass index, kg/m2(SD)
History of bisphosphonates use
History of bone fracture
History of smoking
HRT before randomization
Within the last 3 months
>3 months ago but <5 years
5 years ago or more
SD, standard deviation; HRT, hormone replacement therapy
Annals of Oncology
1490 | Rabaglio et al. Volume 20|No. 9|September 2009
fractures during treatment. The 95% exact confidence intervals of the
incidence rates per 1000 women-years were calculated based on a Poisson
Time from randomization to the first report of the bone fracture was
compared via a stratified log-rank test, with strata defined by randomization
option (two arm or four arm) and chemotherapy (yes or no, based on the
stratum at randomization and combining the two chemotherapy strata ).
Cox proportional hazards models were used to compare time to first bone
fracture of a given type between the treatment groups . These models
were also stratified by randomization option and chemotherapy. In the
univariate Cox model, only treatment effect was included. To test the
interactions of treatment by a specific risk factor, the Cox model including
the treatment group, the specific risk factor, and their interaction term was
used. A more extensive multivariate Cox model was also employed to
examine the treatment effect. Besides the treatment group, the model was
adjusted for potential risk factors such as age at randomization (‡55 versus
<55 years), BMI (‡30 versus < 30 kg/m2), smoking history, presence of
osteoporosis at baseline, previous history of bone fracture at baseline,
previous history of hormone replacement therapy (HRT) at baseline (no
versus yes), and whether or not the patient had received bisphosphonates
before the bone fracture (as a time-varying variable). The relatively young age
cut-off was used to separate patients who may have some continuing ovarian
function into the younger group. If >1.5% of patients had a missing value for
a particular covariate, an indicator for whether or not the covariate was
missing was included in the model.
Competing risk models with disease-free survival (DFS) events (disease
recurrence, secondary malignancy, and death without recurrence) as
competing events were also used to evaluate the treatment effects on time to
first bone fracture .
The median follow-up for this analysis is 60.3 months. Of the
4895 patients, 2448 received letrozole and 2447 received
tamoxifen. Table 1 shows the baseline patient and disease
characteristics observed according to treatment group. The
groups were well balanced with no statistically significant
differences between them for any of the baseline characteristics.
bone fracture incidence
Table 2A gives the incidences of bone fractures and multiple
fractures by grade. The incidence of bone fractures overall was
higher among patients treated with letrozole [L: 228 of 2448
women (9.3%) versus T: 160 of 2447 women (6.5%)].
Incidence according to grade was similar. The incidence of
multiple bone fractures while on treatment was also higher
among patients treated with letrozole [L: 23 of 2448 women
(0.9%) versus T: 10 of 2447 women (0.4%)]. Table 2B shows
the incidence of bone fractures, per 1000 woman-years.
Figure 1 shows the incidences of bone fractures during
treatment according to age using the STEPP method. Patients
who received letrozole had a higher incidence of bone fractures
than patients who received tamoxifen. The pattern of differences
in bone fracture incidence was generally consistent with regard
to age at study entry, with relatively smaller differences for
patients aged <55 and relatively larger differences for patients
from 59 to 69 years old (Figure 1). The incidence of bone
fractures was higher in older patients in both treatment arms.
sites of bone fractures
In the letrozole group, the most frequently observed sites of
fractures were wrist (68 patients), femur (33 patients), thoracic
spine (27 patients), humerus (25 patients), and ankle (21
patients). In the tamoxifen group, the most frequently observed
sites of fractures were wrist (34 patients), thoracic spine (22
patients), rib (22 patients), and ankle (14 patients) (Table 3).
time to first bone fracture
A forest plot of hazard ratios for time to first bone fracture for
all patients and various subgroups based on univariate Cox
models is shown in Figure 2. Under letrozole, there were
significantly more bone fractures (P = 0.002) than under
tamoxifen. This difference remained consistent across most of
the factors examined. Patients who received letrozole had more
bone fractures regardless of whether their BMI ‡30 kg/m2
(interaction P = 0.61), whether they had smoking history
Table 2. Incidence of bone fractures
Letrozole (N = 2448)Tamoxifen (N = 2447) Total (N = 4895)
A: According to grade
Any fracture (grade 2 or 3)
Any multiple fractures
B: Incidence rates per 1000 woman-years (95% CI)
Allowing one fracture per patient
Allowing multiple fractures per patient
aGrade 2: fracture not requiring surgery; grade 3: fracture requiring surgery.
CI, confidence interval.
Annals of Oncology
Volume 20|No. 9|September 2009 doi:10.1093/annonc/mdp033 | 1491
(interaction P = 0.74), history of osteoporosis (interaction
P = 0.77), history of bone fracture (interaction P = 0.99),
received bisphosphonates before randomization (interaction
P = 0.42), or received HRT before randomization (interaction
P = 0.93). As shown on the forest plot (Figure 2), letrozole
resulted in more bone factures in patients >55 years old.
However, the interaction of treatment by age category is not
significant (P = 0.19).
Adjusting for potential risk factors, the treatment effects
predictive of bone fracture from a multivariate Cox model
fractures while on treatment included age >55 at randomization
(P= 0.01),smokinghistory(P= 0.05),presenceofosteoporosisat
baseline (P = 0.01), previous history of bone fracture at baseline
(P < 0.0001), and previous history of HRT at baseline (P = 0.04).
Whether or not the patient had received bisphosphonates before
the bone fracture (157 patients randomized to letrozole and 128
to tamoxifen received bisphosphonates before bone fracture) was
not significantly associated with the occurrence of bone fracture
(P = 0.24).
Figure 3 presents the cumulative incidence of bone fracture,
making allowance for a DFS event as a competing risk event.
Competing risk models confirmed the results of the Cox
models, showing significantly more or earlier occurrence of
bone fractures in patients receiving letrozole (P = 0.0004).
In this study population, the overall incidence of bone fracture
was higher during treatment with letrozole, which is consistent
with previous reports from other trials analyzing adjuvant
treatment with AIs in postmenopausal women. The most recent
update of the Arimidex, Tamoxifen Alone or in Combination
(ATAC) trial , which is most closely similar in design to the
monotherapy comparisons from BIG 1-98 in the present
report, confirms the relative increased fracture rate of 55% for
women during treatment with anastrozole.
Studies involving switch to an AI after prior tamoxifen may
be more difficult to compare with ATAC or BIG 1-98 since the
initial tamoxifen may have served to strengthen bone . In
contrast to the recent report of the International Exemestane
Study (IES) , which tested the AI exemestane after 2 or 3
years of tamoxifen given before randomization, we found the
higher incidence of fracture in women treated with an AI to be
independent of baseline conditions (osteoporosis, previous
bone fracture). Furthermore, the reported incidence of bone
fracture per 1000 women-years among patients assigned to
letrozole in the present study (27.08 per 1000 woman-years) is
higher than the 19.2 per 1000 woman-years described in
patients assigned exemestane . Another difference between
the findings of IES and BIG 1-98 is the frequency of hip, wrist,
and spine fractures. These were rare in the IES report, in which
the large majority of fractures were at other sites . In
contrast, we found that typically bone loss driven fractures (hip,
wrist, and spine) accounted for 53.5% of patients who had
fractures (122 of 228) during treatment with letrozole, and in
particular wrist fractures made up 29.8% of all patients
assigned to letrozole who had a bone fracture (68 of 228). In
the MA.17 trial, in which letrozole or placebo followed previous
treatment with tamoxifen, despite decreased BMD, the rate of
bone fracture was not significantly higher with letrozole .
Adjuvant treatment with AIs has been shown to improve
outcome in postmenopausal women with early breast cancer
and their use is steadily increasing. For this reason, it is
important to recognize and if possible prevent adverse events.
As illustrated in Figure 3, the trade-off between increased DFS
with letrozole and increased risk of bone fractures with
letrozole needs to be considered. The benefits of superior
disease control associated with letrozole and lower incidence of
fracture with tamoxifen should be considered with the risk
profile for each individual patient. Bone loss and subsequent
bone fractures may be avoided by accurately selecting and
counseling patients and if appropriate treating women at risk
Incidence of Any Bone Fracture (%)
Median Age in Subpopulations (years)
59 61 6365 69 7274
Figure 1. Subpopulation treatment effect pattern plot analysis of
incidence of any bone fracture for letrozole versus tamoxifen among
overlapping subpopulations defined according to age at study entry.
Table 3. Sites of bone fractures
Site of bone fracturea
Letrozole (N = 2448)
Tamoxifen (N = 2447)
aIndividual patient may be counted more than once.
bPatella, fibula, metatarsal, toe, knee, and foot (not specified).
cMetacarpal, thumb, phalanx, elbow, olecranon, shoulder, scapula, and
forearm (not specified).
dNose, sternum, occipital, mandibula, and zygoma.
Annals of Oncology
1492 | Rabaglio et al. Volume 20|No. 9|September 2009
for bone loss. This systematic evaluation should include risk
factors such as those identified in this study, especially age,
smoking history, osteoporosis, history of bone fracture, and
history of HRT use, though this latter association may be due to
a confounding of HRT use with decline in BMD.
In this trial, patients were not encouraged to take vitamin D
and calcium for bone health, and no standardized guidelines for
bisphosphonates use were recommended. More recent
guidelines suggest routine recommendation of calcium and
vitamin D supplements, plus baseline BMD measurement, with
follow-up if the initial result is in the osteopenic range .
Application of these guidelines would be likely to reduce the
excess risk of bone fracture associated with AI use in future
. Meanwhile, the recognition of risk factors associated with
increased fracture risk may assist in reaching a clinical balance
Figure 2. Univariate Cox model analysis (hazard ratios for time to first bone fracture; letrozole versus tamoxifen) for relevant risk factors among patients
with any bone fracture. The box size is proportional to the inverse of the standard error of the hazard ratio estimates. The horizontal line gives the 95%
Table 4. Time to first bone fracture
Multivariate Cox model results
Hazard ratio95% CIP value
Age ‡ 55 years
BMI ‡ 30 kg/m2
History of bone fracture
the bone fracture
HRT before randomization
CI, confidence interval; BMI, body mass index; HRT, hormone replacement
Figure 3. Cumulative incidence of first bone fracture with first disease-
free survival (DFS) event as competing events. In the competing risk
analysis, for patients who had DFS events before the first bone fracture, the
probability of bone fracture at a later time (after the DFS event) was
assumed to be zero.
Annals of Oncology
Volume 20|No. 9|September 2009 doi:10.1093/annonc/mdp033 | 1493
between the superior antitumor efficacy of AIs over tamoxifen
and the risks of bone fracture.
Novartis to BIG 1-98; Swedish Cancer Society, The Cancer
Council Australia, Australian New Zealand Breast Cancer Trials
Group, Frontier Science and Technology Research Foundation,
Swiss Group for Clinical Cancer Research (SAKK), National
Cancer Institute (CA-75362), Cancer Research Switzerland/
Oncosuisse and the Foundation for Clinical Cancer Research of
Eastern Switzerland (OSKK) to IBCSG.
The BIG 1-98 trial coordinated by IBCSG.
BIG 1-98 Collaborative Group Participants
M. Castiglione, A. S. Coates, T. Cufer, P. Dinh, J. F. Forbes, R. D.
Gelber, A. Giobbie-Hurder, A. Goldhirsch, A. Hiltbrunner, S. B.
T. Mouridsen, R. Paridaens, K. N. Price, M. Rabaglio, B. B.
G. Viale; Novartis: H. A. Chaudri-Ross, R. Dias, D. B. Evans,
C. Sguotti, and U. Trostmann.
IBCSG Scientific Committee: A. Goldhirsch, A. S. Coates
(Co-Chairs), L. Blacher, J. F. Forbes, R. D. Gelber, B. A.
Gusterson, A. Hiltbrunner, C. Hu ¨rny, E. Murray, K. N. Price,
M. Rabaglio, R. Studer, G. Viale, and A. Wallgren.
IBCSG Foundation Council (members from 1998 to 2008):
S. Aebi, A. S. Coates, M. Colleoni, J. P. Collins, H. Corte ´s
Funes, R. D. Gelber, A. Goldhirsch, M. Green, A. Hiltbrunner,
S. B. Holmberg, P. Karlsson, I Ko ¨ssler, I. La ´ng, J. Lindtner,
F. Paganetti, M. de Stoppani, C.-M. Rudenstam,, H.-J. Senn,
R. Stahel, B. Thu ¨rlimann, and A. Veronesi.
Coordinating Center (Berne, Switzerland): A. Hiltbrunner
(Director), M. Rabaglio, G. Egli, B. Cliffe, S. Ribeli-Hofmann,
F. Munarini, R. Kammler, R. Studer, B. Ruepp, R. Maibach,
N. Munarini, and M. Castiglione.
Statistical Center (Dana-Farber Cancer Institute, Boston,
MA, USA): R. D. Gelber (Group Statistician), K. N. Price
(Director of Scientific Administration), A. Giobbie-Hurder
(Trial Statistician), A. Keshaviah, H. Litman, M. M. Regan,
Z. Sun, H. Huang, L. J. Somos, B. Timmers, and L. Nickerson.
Data Management Center (Frontier Science & Technology
Research Foundation, Amherst, NY, USA): L. Blacher (Director
of Data Management), T. Heckman Scolese (Coordinating Data
Manager), M. Belisle, M. Caporale, J. Celano, L. Dalfonso,
L. Dooley, S. Fischer, K. Galloway, J. Gould, R. Hinkle,
M. Holody, G. Jones, R. Krall, S. Lippert, J. Meshulam, L. Mundy,
A. Pavlov-Shapiro, K. Scott, M. Scott, S. Shepard, J. Swick,
L. Uhteg, D. Weinbaum, C. Westby, and T. Zielinski.
Central Pathology Review Office (University of Glasgow,
Glasgow, UK): B. A. Gusterson and E. Mallon; (European
Institute of Oncology, Division of Pathology, Milan, Italy):
G. Viale, P. Dell’Orto, M. Mastropasqua, and B. Del Curto.
Data and Safety Monitoring Committee: J. E. Garber,
W. Gradishar, S. W. Lagakos, and I. Lindgren.
Study Support (Novartis Corp., Basel, Switzerland):
E. Waldie, I. van Hoomissen, M. De Smet, W. Schmidt,
A. Bolton, and W. Hackl.
Breast International Group (BIG)
International Breast Cancer Study Group (IBCSG)
Australian New Zealand Breast Cancer Trials Group (ANZ
BCTG)—Board Chair: R. D. Snyder, Group Co-ordinator: J. F.
Forbes, Chair Scientific Advisory Committee: A. S. Coates;
ANZ BCTG Operations Office (Newcastle, Australia)—D.
Lindsay (Head Data Management), D. Preece (Senior Study
Coordinator), J. Cowell, D. Talbot, and A. Whipp.
Australia—The Cancer Council Victoria, Melbourne, VIC:
F. Abell, R. Basser, R. Bell, B. Brady, D. Blakey, P. Briggs,
I. Burns, P. Campbell, M. Chao, J. Chirgwin, B. Chua, K. Clarke,
J. Collins, R. De Boer, J. C. Din, R. Doig, A. Dowling,
R. Drummond, N. Efe, S. T. Fan, M. Francis, P. Francis,
V. Ganju, P. Gibbs, G. Goss, M. Green, P. Gregory, J. Griffiths,
I. Haines, M. Henderson, R. Holmes, P. James, J. Kiffler,
M. Lehman, M. Leyden, L. Lim, G. Lindeman, R. Lynch, B. Mann,
J. McKendrick, S. McLachlan, R. McLennan, G. Mitchell,
S. Mitra, C. Murphy, I. Parker, K. Phillips, I. Porter,
G. Richardson, J. Scarlet, S. Sewak, J. Shapiro, R. Snyder,
R. Stanley, C. Steer, D. Stoney, A. Strickland, G. Toner,
C. Underhill, K. White, M. White, A. Wirth, and S. Wong; W P
Holman Clinic, Launceston General Hospital, Launceston,
Tasmania: D. Byram and I. Byard; Liverpool Hospital, Sydney,
NSW: S. Della-Fiorentina, A. Goldrick, E. Hovey, E. Moylan,
and E. Segelov; Mount Hospital, Perth, WA: A. Chan, M. Buck,
D. Hastrich, D. Ingram, G. Van Hazel, and P. Willsher; Nepean
Cancer Care Centre, Sydney, NSW: N. Wilcken and
C. Crombie; Calvary Mater Newcastle, Newcastle, NSW: J. F.
Forbes, F. Abell, S. Ackland, A. Bonaventura, S. Cox, J.
Denham, R. Gourlay, D. Jackson, R. Sillar, and J. Stewart;
Prince of Wales Hospital, Sydney, NSW: C. Lewis, B. Brigham,
D. Goldstein, and M. Friedlander; Princess Alexandra Hospital,
Woolloongabba, QLD: E. Walpole and D. Thompson; Royal
Adelaide Hospital, Adelaide, SA: P. G. Gill, M. Bochner, J.
Coventry, J. Kollias, P. Malycha, and I. Olver; Royal Brisbane
and Women’s Hospital, Brisbane, QLD: M. Colosimo, R.
Cheuk, L. Kenny, N. McCarthy, and D. Wyld; Royal Hobart
Hospital, Hobart, Tasmania: R. Young, R. Harrup, R. Kimber,
and R. Lowenthal; Royal Perth Hospital, Perth, WA: J. Trotter,
E. Bayliss, A. Chan, and D. Ransom; Sir Charles Gairdner
Hospital, Perth, WA: M. Byrne, M. Buck, J. Dewar, A. Nowak,
A. Powell, and G. Van Hazel; Toowoomba Hospital,
Toowoomba, QLD: E. A. Abdi, R. Brodribb, and Z. Volobueva;
Westmead Hospital, Sydney, NSW: P. Harnett, V. Ahern,
H. Gurney, and N. Wilcken.
New Zealand—Auckland Hospital, Auckland: V. J. Harvey,
B. Evans, W. Jones, M. McCrystal, D. Porter, P. Thompson, and
M. Vaughan; Christchurch Hospital, Christchurch: D. Gibbs,
C. Atkinson, R. Burcombe, B. Fitzharris, B. Hickey, M. Jeffery,
and B. Robinson; Dunedin Hospital, Dunedin: B. McLaren, S.
Costello, J. North, and D. Perez; Waikato Hospital, Hamilton:
J. Long, G. Round, L. Spellman, D. Whittle, and D. Woolerton.
Brazil—Hospital de Clinicas de Porto Alegre, Porto Alegre:
C. Menke, J. Biazu ´s, R. Cericatto, J. Cavalheiro, N. Xavier, A.
Bittelbrunn, and E. Rabin.
Annals of Oncology
1494 | Rabaglio et al. Volume 20|No. 9|September 2009
Chile—Chilean Cooperative Group for Oncologic Research,
GOCCHI: J. Gutie ´rrez (Chairman), R. Arriagada (Scientific
Adviser), L. Bronfman (Principal Investigator), M. Zun ˜iga
(Data Manager); Clinica Las Condes, Santiago: J. Gutie ´rrez,
J. C. Acevedo, S. Torres, A. Leo ´n, and E. Salazar; Hospital
DIPRECA, Las Condes, Santiago: L. Soto Diaz, R. Duval,
N. Oddeshede, and M. C. Venti; Hospital San Juan de Dios,
Santiago: K. Pen ˜a, L. Puente, and V. Maidana; IRAM/Instituto
de Radiomedicina, Vitacura, Santiago: R. Baeza, R. Arriagada,
P. Olfos, J. Sole ´, E. Vine ´s, and C. Mariani.
Hungary—National Institute of Oncology, Budapest: I. La ´ng,
E. Hitre, E. Szabo ´, Z. Horva ´th, E. Ganofszky, and E. Juhos.
Italy—Centro di Riferimento Oncologico, Aviano: A.
Veronesi, D. Crivellari, M. D. Magri, A. Buonadonna, F. Coran,
E. Borsatti, E. Candiani, S. Massarut, M. Roncadin, M.
Arcicasa, A. Carbone, T. Perin, and A. Gloghini; Ospedali
Riuniti di Bergamo, Bergamo: C. Tondini, R. Labianca,
P. Poletti, and A. Bettini; Ospedale degli Infermi, Biella:
M. Clerico, M. Vincenti, A. Malossi, E. Seles, E. Perfetti, and
B. Sartorello; Spedali Civili, Brescia: E. Simoncini, G. Marini,
P. Marpicati, R. Farfaglia, A. M. Bianchi, P. Grigolato, L. Lucini,
P. Frata, A. Huscher, E. Micheletti, and C. Fogazzi; U. O.
Medicina Oncologica, Ospedale Carpi, Ospedale Mirandola:
F. Artioli, K. Cagossi, L. Scaltriti, E. Bandieri, L. Botticelli, and
G. Giovanardi; Ospedale di Cattolica ‘‘Cervesi’’, Cattolica:
A. Ravaioli, E. Pasquini, and B. Rudnas; Ospedale Civile, Gorizia:
L. Foghin; Ospedale ‘‘A. Manzoni’’ Lecco, Lecco: M. Visini,
L. Zavallone, and G. Ucci; Istituto Europeo di Oncologia, Milano:
M. Colleoni, G. Viale, P. Veronesi, G. Peruzzotti, L. Corsetto,
R. Ghisini, G. Renne, A. Luini, L. Orlando, R. Torrisi, A. Rocca,
T. De Pas, E. Munzone, V. Galimberti, S. Zurrida, M. Intra,
F. Nole ´, R. Orecchia, G. Martinelli, F. de Braud, and A. Goldhirsch;
Ospedale Infermi, Rimini: A. Ravaioli and L. Gianni.
Peru—Instituto de Enfermedades Neopla ´sicas, Lima: H.
Slovenia—Institute of Oncology, Ljubljana: T. Cufer, B. Pajk,
and J. Cervek.
South Africa—Groote Schuur Hospital and University of
Cape Town, Cape Town: I. D. Werner, E. Murray, D.
Govender, S. Dalvie, T. Erasmus, B. Robertson, B. Read, E. Nel,
J. Toop, N. Nedeva, and E. Panieri; Sandton Oncology Centre,
Johannesburg: D. Vorobiof, M. Chasen, G. McMichael, and C.
Mohammed. Local funding provided by the Cancer Association
of South Africa.
Sweden—West Swedish Breast Cancer Study Group: S. B.
Holmberg; Sahlgrenska U Hospital, Moelndal: S. B. Holmberg
and J. Mattsson; Boras Hospital, Boras; Karlstads Hospital,
Karlstads: H. Sellstro ¨m; Kungalvs Hospital, Kungalvs: B.
Switzerland—Swiss Group for Clinical Cancer Research
(SAKK): A. Goldhirsch (up to January 2004), R. Herrmann
(from June 2004): Kantonsspital Aarau, Zentrum f. Onkologie,
Aarau: A. Scho ¨nenberger, W. Mingrone, Ch. Honegger, E.
Ba ¨rtschi, M. Neter, M. Rederer, and G. Scha ¨r; University
Hospital Basel, Basel: C. Rochlitz, R. Herrmann, D. Oertli, E.
Wight, and H. Moch; Institute of Oncology of Southern
Switzerland: Ospedale San Giovanni, Bellinzona: J. Bernier, L.
Bronz, F. Cavalli, E. Gallerani, A. Richetti, and A. Franzetti;
Ospedale Regionale di Lugano (Civico & Italiano), Lugano: M.
Conti-Beltraminelli, M. Ghielmini, T. Gyr, S. Mauri, and P. C.
Saletti; Ospedale Regionale Beata Vergine, Mendrisio: A.
Goldhirsch, O. Pagani, R. Graffeo, M. Locatelli, S. Longhi, P.C.
Rey, and M. Ruggeri; Ospedale Regionale La Carita `, Locarno: E.
Zucca and D. Wyss; Istituto Cantonale di Patologia, Locarno: L.
Mazzucchelli, E. Pedrinis, and T. Rusca; Inselspital, Berne: S.
Aebi, M. F. Fey, M. Castiglione, and M. Rabaglio; Kantonsspital
Olten, Olten: S. Aebi, M. F. Fey, M. Zuber, and G. Beck;
Bu ¨rgerspital, Solothurn: S. Aebi, M. F. Fey, and R.
Scho ¨nenberger; Spital Thun-Simmental AG Thun: J. M. Lu ¨thi
and D. Rauch; Ho ˆpital Cantonal Universitaire HCUG, Geneva:
H. Bonnefoi; Ra ¨tisches Kantons- und Regionalspital, Chur: F.
Egli, R. Steiner, and P. Fehr; Centre Pluridisciplinaire
d’Oncologie, Lausanne: L. Perey, P. de Grandi, W. Jeanneret, S.
Leyvraz, and J.-F. Delaloye; Kantonsspital St Gallen, St Gallen:
B. Thu ¨rlimann, D. Ko ¨berle, F. Weisser, S. Mattmann, A.
Mu ¨ller, T. Cerny, B. Spa ¨ti, M. Ho ¨fliger, G. Fu ¨rstenberger, B.
Bolliger, C. O¨hlschlegel, U. Lorenz, M. Bamert, J. Kehl-Blank,
and E. Vogel; Kantonales Spital Herisau, Herisau: B.
Thu ¨rlimann, D. Hess, I. Senn, D. Ko ¨berle, A. Ehrsam, C. Nauer,
C. O¨hlschlegel, J. Kehl-Blank, and E. Vogel; Stadtspital Triemli,
Zu ¨rich: L. Widmer and M. Ha ¨fner; Universita ¨tsspital Zu ¨rich,
Zu ¨rich: B. C. Pestalozzi, M. Fehr, R. Caduff, Z. Varga, R. Tru ¨b,
and D. Fink.
Swiss Private MDs—Private Praxis, Zu ¨rich: B. A. Ba ¨ttig;
Sonnenhof-Klinik Engeried, Berne: K. Buser; Frauenklinik
Limmattalspital, Schlieren: N. Bu ¨rki; Private Praxis, Birsfelden:
A. Dieterle; Private Praxis, Biel: L. Hasler; Private Praxis, Baar:
M. Mannhart-Harms; Brust-Zentrum, Zu ¨rich: C. Rageth;
Private Praxis, Berne: J. Richner; Private Praxis, Bellinzona:
V. Spataro; Private Praxis, Winterthur: M. Umbricht.
UK: King’s College Hospital/Breast Unit, London: P. Ellis,
S. Harris, N. Akbar, H. McVicars, C. Lees, R. Raman, and G.
Danish Group (DBCG)
H. T. Mouridsen; Rigshospitalet, Copenhagen: H. T.
Mouridsen; Vejle Hospital, Vejle: E. Jakobsen; Odense University
Hospital, Odense: S. Cold; KAS Herlev/Herlev University
Hospital, Herlev: C. Kamby; Aalborg Sygehus Syd, Aalborg: M.
Ewertz; Hilleroed Hospital, Hilleroed: P.M. Vestlev; Aarhus
University Hospital, Aarhus: J. Andersen; Roskilde County
Hospital, Roskilde: P. Grundtvig; Esbjerg Central Hospital,
Esbjerg: E. Sandberg; Naestved Central Hospital, Naestved: P.
V. Haahr; Landspitali University Hospital, Reykjavik, Iceland: J.
French Group (FNCLCC)
Institut Bergonie ´, Bordeaux: L. Mauriac, M. Debled, and
P. Campo; Centre Hospitalier de la Co ˆte Basque, Bayonne
D. Larregain-Fournier, S. Remy, Centre Jean Perrin, Clermont-
Ferrand: H. Auvray; Centre Georges Franc xois Leclerc, Dijon:
C. De Gislain, F. Delille, and M.-C. Porteret; Centre Oscar
Lambret, Lille: V. Servent and M. Chapoutier; CHRU, Limoges:
N. Tubiana-Mathieu, S. Lavau-Denes, and P. Bosc; Centre Le ´on
Be ´rard, Lyon: J. P. Guastalla, Th. Bachelot, and C. Arbault;
Centre Hospitalier Meaux, Meaux: G. Netter-Pinon; C.H.G.
Andre ´ Boulloche, Montbe ´liard: V. Perrin, A. Monnier, and
Y. Hammoud; Centre Paul Lamarque, Montpellier: G. Romieu,
Annals of Oncology
Volume 20|No. 9|September 2009doi:10.1093/annonc/mdp033 | 1495
L. Culine, and V. Pinosa; Clinique Francheville, Pe ´rigueux:
L. Cany and C. Maguire; Ho ˆpital de la Mile ´trie, Poitiers:
A. Daban, M. Le Saux, and C. Grandon; Centre Euge `ne
Marquis, Rennes: P. Kerbrat and C. Catheline; Centre Henri
Becquerel, Rouen: C. Veyret, E. Jugieau, and V. Talon; Centre
Rene ´ Gauducheau, Saint-Herblain: A. Le Mevel and S. Maury;
Centre Claudius Re ´gaud, Toulouse: L. Gladieff and N. Lignon.
North Yorkshire Group
D. Dodwell; Harrogate District Hospital, Harrogate, North
Yorkshire: D. Dodwell; Huddersfield Royal Infirmary,
Huddersfield: J. Joffe; Castlehill Hospital, Hull: P. Drew;
Airedale General Hospital, Keighley: W. Yorkshire: A. Nejim;
Leeds General Infirmary, Leeds: D. Dodwell and K. Horgan; St
James’s University Hospital, Leeds: M. Lansdown and T.
Perren; Weston Park Hospital, Sheffield: R. E. Coleman.
Argentina—Centro Oncolo ´gico Confidence, Buenos Aires:
D. Campos; Hospital Allema ´n, Buenos Aires: F. Co ´ppola;
Hospital Brita ´nico, Buenos Aires: J. Martinez; Hospital Evita,
Buenos Aires: M. Freue; Hospital Posadas, Buenos Aires: C.
Wainstein; Hospital Zubizarreta, Buenos Aires: A. Zori Comba;
Instituto Dr. Estevez, Buenos Aires: E. Cazap; Instituto
Oncolo ´gico Dr. Angel H. Roffo, Buenos Aires: E. Mickiewicz;
Sanatorio Municipal Julio A. Mendez, Buenos Aires: L.
Balbiani; Centro Privado de Ginecologı ´a, Co ´rdoba: A. Osuna;
Hospital Privado de Co ´rdoba, Co ´rdoba: E. Palazzo; Instituto
Modelo de Ginecologı ´a y Obstetricia, Co ´rdoba: M. de Romedis;
Fundacio ´n Mainetti-Centro Oncolo ´gico de Excelencia, La
Pllata: S. Cagnolati; Hospital Privado de la Comunidad, Mar
del Plata: C. A. Delfino and G. Caccia; Escuela de Medicina
Nuclear (COIR), Mendoza: R. L. de Angelis; Centro
Oncolo ´gico de Rosario, Rosario: L. Fein and R. Sala; Hospital
Provincial de Rosario, Rosario: C. Nassurdi and A. Colombo
Berra; Clı ´nica Especializada ISIS, Santa Fe: R. Viroglio and C.
Blajman; Hospital Regional de Concepcio ´n, Tucuma ´n: H.
Requejo; Instituto de Maternidad y Ginecologı ´a Nuestra
Sen ˜oras de las Mercedes, Tucuma ´n: L. Silberman.
Eaton, and C. Hoffman; Queen Elizabeth Hospital, Adelaide, SA:
Bell, F.Abell,M.Francis, J.Kiffer,R.Lynch, R.McLennan,andK.
White;Royal MelbourneHospital,Melbourne,VIC: M.Green,R.
Basser, J. Collins, R. De Boer, J. C. Din, N. Efe, S. T. Fan, G.
Lindeman, and S. Wong; Western General Hospital, Melbourne,
T. Fan, G. Lindeman, and S. Wong; Newcastle Mater Hospital,
Newcastle, NSW: J. Stewart, F. Abell, S. Ackland, and A.
Bonaventura; Royal Perth Hospital, Perth, WA: J. Trotter, E.
Bayliss, A. Chan, D. Ransom, and A. Redfern; St George Hospital,
Sydney, NSW: P. de Souza and M. Links; St Vincent’s Hospital,
Sydney, NSW: D. Dalley, J. Grygiel, and R. Ward; Murray Valley
Private Hospital, Wodonga, VIC: C. Underhill, K. Clarke, and C.
Steer; Princess Alexandra Hospital, Woolloongabba, QLD: E.
Walpole and D. Thompson.
Belgium—Institut Jules Bordet, Bruxelles: J. M. Nogaret;
University Hospitals Leuven, Leuven: M. R. Christiaens, P.
Neven, R. Paridaens, A. Smeets, I. Vergote, C. Weltens, and H.
Wildiers; Les Cliniques Saint-Joseph ASBL, Lie `ge: C. Focan;
Clinique du Parc Le ´opold, Bruxelles: L. Marcelis; C. H.
Etterbeek - Ixelles, Bruxelles: J. P. Kains; Service d’Oncologie
Clinique Notre-Dame, Charleroi: J.-L. Canon; C. H. U. Andre ´
Ve `sale, Montigny-Le Tilleul: D. Brohe `e.
Canada—Cambridge Memorial Hospital, Cambridge: J.
Gowing; CHUM- Campus Notre-Dame, Montreal: L. Yelle;
Ho ˆpital Maisonneuve-Rosemont, Montreal: P. Dube ´.
Chile—Fundacion Lopez Perez, Santiago: C. Vogel; Hospital
Carlos Van Buren, Valparaiso: M. Leo ´n Prieto.
Czech Republic—Institute of Oncology, Brno: K. Petrakova,
M. Palacova, and R. Demlova; Department of Clinical and
Radiation Oncology, Ceske Budejovice: H. Siffnerova, J.
Fischer, and I. Bustova; Centre of Breast Diseases, Prague: H.
Kankova and M. Pintova; Institute of Radiation Oncology,
Prague: P. Vitek; University Hospital, Prague: J. Abrahamova
and D. Kordikova; University Hospital Prague: L. Petruzelka, E.
Sedlackova, and H. Honova.
Germany—Onkologische Gemeinschaftspraxis, Augsburg: B.
Heinrich; Zentralklinikum/Frauenklinik, Augsburg: A.
Wischnik; Universita ¨tsklinikum Essen, Essen: C. Oberhoff and
A. E. Schindler; Universita ¨ts-Frauenklinik d. JLU Giessen,
Giessen: K. Mu ¨nstedt; Onkologische Gemeinschaftspraxis,
Go ¨ttingen: D. Meyer; Martin-Luther-Universita ¨t Halle-
Wittenberg, Halle: R. Grosse and H. Ko ¨lbl; Universita ¨tskliniken
des Saarlandes, Homburg: W. Schmidt and D. Mink;
Universita ¨ts-Frauenklinik und Poliklinik
Universita ¨tskrankenhaus Eppendorf, Hamburg: F. Ja ¨nicke;
Kliniken d. Med. Hochschule, Frauenklinik, Hannover: H. J.
Lu ¨ck; Krankenanstalt Mutterhaus der Borroma ¨erinnen, Trier:
W. Dornoff; Gyna ¨kologische Abteilung des St Josefshospital,
Wiesbaden: G. Hoffmann; Gyna ¨kologische Abteilung d.
Marienhospitals, Universita ¨t Witten-Herdecke, Witten: J.
Hackmann and W. Bader.
Hungary—SZOTE Onkotera ´pia ´s Klinika, Szeged: Z. Kahan;
BM Ko ¨zponti Ko ´rha ´z, Budapest: G. Pajkos and K. Kristo; SOTE
Radiolo ´giai e ´s Onkotera ´pia ´s Klinika, Budapest: M. Dank;
Uzsoki Utcai Ko ´rha ´z, Budapest: T. Nagykalnai and L. Landherr;
Alma ´si Balogh Pa ´l Ko ´rha ´z, O´zd: E. Kner; Teru ¨leti Ko ´rha ´z
Onkologia, Szentes: M. Kispa ´l; Szent Borba ´la Ko ´rha ´z, Megyei
Onkolo ´giai Gondozo ´, Tataba ´nya: A´. Dani.
Italy—Policlinico S. Orsola-Malpighi, Bologna: A. Martoni,
C. Zamagni, S. Giaquinta and E. Piana; Ospedale S. Croce,
Fano: R. Mattioli and L. Imperatori; Istituto Clinica
Humanitas, Milan/Rozzano: A. Santoro, C. Carnaghi, and L.
Rimassa; Azienda Ospedaliera San Filippo Neri, Rome: G.
Gasparini, G. Sciarretta, and A. Morabito; Az. Ospedaliera
Treviglio-Caravaggio, Treviglio: S. Barni, M. Cazzaniga, and M.
Cabiddu; Policlinico Universitario (PUDG), Udine: F. Puglisi;
Ospedale di Torrette, Ancona: R. Cellerino, S. Antognoli, F.
Freddari; Universitiy of Cagliari, Policlinico Universitario,
Cagliari: G. Mantovani, E. Massa, and G. Astara; Ospedale
Civile Feltre, Feltre: R. Segati; Istituto Nazionali Ricerca
Cancro, Genova: R. Rosso, L. Del Mastro, M. Venturini, and C.
Bighin; Istituto Nazionale dei Tumori, Milano: E. Bajetta, N.
Zilembo, D. Paleari, and G. Procopio; Azienda Ospedaliera di
Parma, Parma: S. Salvagni, M. A. Perrone and V. Franciosi;
Azienda Ospedaliera ‘‘S. Salvatore’’, Pesaro: G. Catalano and S.
Luzi Fedeli; Azienda Ospedaliera ‘‘Ospedale di Circolo e
Fondazione Macchi’’ Varese: G. Pinotti, G. Giardina, and I.
Annals of Oncology
1496 | Rabaglio et al.Volume 20|No. 9|September 2009
Vallini; Universitiy of Cagliari, Policlinico Universitario,
Cagliari: B. Massidda, M. T. Ionta, and M. C. Deidda; Ospedale
Maggiore, Lodi: G. Nalli and G. Sita; Policlinico Universitario,
Palermo: I. Carreca, S. Cucciarre ´, and D. Burgio; Ospedale
Civile dello Spirito Santo, Pescara: M. Lombardo, G. Pandoli,
and P. Di Stefano; Azienda Ospedaliera Santa Maria Nuova,
Reggio Emilia: C. Boni, G. Bisagni, M. C. Banzi, and P.
Linarello; Azienda Ospedaliera Desenzano del Garda,
Manerbio: G. Colosini, A. Spasiano, and A. Caldonazzo;
Ospedale Civile ASL 20, Tortona: M. G. Pacquola.
The Netherlands—Ziekenhuis Leyenburg, Den Haag: H. P.
Sleeboom; Catharina Ziekenhuis, Eindhoven: H. J. T. Rutten; St
Anna Ziekenhuis, Geldrop: E. J. T. Luiten; Tweesteden
Ziekenhuis, Tilburg: H. Th. J. Roerdink; Maxima Medisch
Centrum, Veldhoven: R. H. M. Roumen.
New Zealand—Dunedin Hospital, Dunedin: B. McLaren, S.
Costello, J. North, D. Perez, K. Bayston, and M. Pfieffer;
Waikato Hospital, Hamilton: I. Kennedy, I. D. Campbell, L.
Gilbert, R. Gannaway, M. Jameson, J. Long, G. Round, L.
Spellman, D. Whittle, and D. Woolerton.
Poland—Department of Oncology and Radiotherapy, Medical
University of Gdansk, Gdansk: J. Jassem, M. Welnicka-Jaskiewicz, E.
Senkus-Konefka, and K. Matuszewska; Rydygier’s Memorial
Hospital, Krakow-Nova Huta: P. Koralewski and J. Pernal;
Klinika Nowotworo ´w Piersi i, Chirurgii Rekonstrukcyjnej-
Warszawa, Warszawa: T. Pienkowski, E. Brewczynska, B.
Bauer-Kosinska, R. Sienkiewicz-Kozlowska, A. Jagiello-
Gruszfeld, and K. Sudol; Centrum Onkologii w Bydgoszczy,
Oddzial Onkologii Klinicznej, Bydgoszcz: J. Tujakowski and B.
Zurawski; Collegium Medicum Jagiellonian University,
Krakow: J. Pawlega, E. Jablonska, and A. Zygulska; Oddzial
Kliniczny Onkologiczny, Centralnego Szpitala Klinicznego
Wojskowej, Akademii Medycznej-Warszawa, Warszawa: M.
Go ´rnasiowa; Dolnoslaskie Centrum Onkologii, Wroclaw: E.
Filypczyk-Cisarz, K. Pajak.
Portugal—Hospital de S. Joa ˜o, Porto: M. Damasceno;
Instituto Portugue ˆs de Oncologia de Coimbra, Coimbra: J. Q.
Albano; Hospital de Santa Maria, Lisboa: B. da Costa and L.
Costa; Instituto Portugue ˆs de Oncologia de Lisboa, Lisboa: A.
Henriques and H. Amaral; Hospital Geral de Santo Anto ´nio,
Porto: F. Marques.
Russia—Cancer Research Centre, Moscow: D. V. Komov and
S. B. Polikarpova; Moscow Municipal Hospital No. 62,
Moscow: A. N. Makhson and N. V. Zabaznyi; Moscow
Research Institute of Diagnostics and Surgery, Moscow: E. K.
Vozny, N. Y. Dobrovolskaya, S. Bolshakova, and O. V. Yurgina;
N. M. Emmanuel Institute of Biochemical Physics, Moscow: D.
B. Korman and I. A. Maslova; N.N. Petrov Research Institute of
Oncology, St Petersburg: V. Semiglazov and V. Ivanov; Saint-
Petersburg City Oncological Dispensary, St Petersburg: G.
Manikhas, G. Dolmatov.
South Africa—Mamma Clinic, Tygerberg Hospital, Cape
Town: J. Apffelstaedt; Southern Cross Hospital, Cape Town: D.
Eedes; Pretoria Academic Hospital, Pretoria: C. Slabber;
Pretoria East Hospital, Pretoria: M. A. Coccia-Portugal; Eastern
Cape Oncology Centre, Port Elizabeth: K. Maart.
Spain—Hospital Ruber Internacional, Madrid: J. E. Ale ´s
Martinez, P. Aramburo, and R. Sa ´nchez; Hospital Son Dureta,
Palma del Mallorca: J. Rifa and J. Martin; Centro Oncolo ´gico
Integral de Madrid (CONIM), Madrid: R. Pe ´rez-Carrio ´n, J. L.
Gonza ´lez Larriba, and A. Cubillo; Hospital Universitario San
Carlos, Madrid: M. M. Jime ´nez and A. Casado; Hospital Central
de Asturias, Oviedo: J. Fra, J. M. Vieitez, E. Esteban, A. J. Lacave.
Switzerland—Universita ¨tsfrauenklinik, Basel: E. Wight, S.
Bartens, R. Decio, and U. Gu ¨th; Klinik am Park, Zu ¨rich: U.
Turkey—Ankara University Ibni Sina Hospital, Ankara: F.
Icli and D. Dincol; Hacettepe University Oncology Institute,
Ankara: E. Baltali and Y. Ozisik; Istanbul University Oncology
Institute, Istanbul: E. Topuz, M. Basaran and A. Aydiner; Ege
University Medical School, Izmir: E. Ozdedeli; 9 Eylul
University Medical School, Izmir: O. Harmancioglu, A. U.
UK: The Royal Marsden Hospital, London, Royal Marsden
NHS Trust, Surrey: I. E. Smith; University of Dundee, Dundee:
A. M. Thompson; Christie Hospital NHS Trust, South
Manchester University Hospital Trust, Manchester: A. Wardley;
Royal Bournemouth Hospital, Bournemouth: T. Hickish;
North Middlesex Hospital, London: F. Neave.
Uruguay—Hospital de Clinicas Dr. Manuel Quintela,
Montevideo, Uruguay: G. Sabini.
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