JCO 2001 Mouridsen 2596 606

RAPID PUBLICATION
S u p e r i o r E f fi c a c y o f L e t r o z o l e V e r s u s T a m o x i f e n a s
First-Line Therapy for Postmenopausal Women With
Advanced Breast Cancer: Results of a Phase III Study of
the International Letrozole Breast Cancer Group
By Henning Mouridsen, Mikhail Gershanovich, Yan Sun, Ramon Perez-Carrion, Corrado Boni, Alain Monnier,
Justus Apffelstaedt, Robert Smith, Harm P. Sleeboom, Fritz Ja
nicke, Anna Pluzanska, Magdolna Dank, Dominique Becquart,
Poonamalle P. Bapsy, Eeva Salminen, Ray Snyder, Mercedes Lassus, J. Arnold Verbeek, Beatrix Staffler,
Hilary A. Chaudri-Ross, and Margaret Dugan
Purpose: To compare the efficacy and tolerability of
tamoxifen with that of letrozole, an oral aromatase
inhibitor, with tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer.
Patients and Methods: Nine hundred seven patients
were randomly assigned letrozole 2.5 mg once daily
(453 patients) or tamoxifen 20 mg once daily (454
patients). Patients had estrogen receptor and/or progesterone receptorpositive tumors, or both receptors
were unknown. Recurrence during adjuvant antiestrogen therapy or within the following 12 months or prior
endocrine therapy for advanced disease precluded enrollment. One prior chemotherapy regimen for metastatic disease was allowed. The primary end point was
time to progression (TTP). Secondary end points included overall objective response rate (ORR), its duration, rate and duration of clinical benefit, time to treatment failure (TTF), overall survival, and tolerability.
Results: TTP was significantly longer for letrozole than

for tamoxifen (median, 41 v 26 weeks). Treatment with
letrozole reduced the risk of progression by 30% (hazards ratio, 0.70; 95% confidence interval, 0.60 to 0.82,
P .0001). TTP was significantly longer for letrozole
irrespective of dominant site of disease, receptor status,
or prior adjuvant antiestrogen therapy. Similarly, TTF
was significantly longer for letrozole (median, 40 v 25
weeks). ORR was higher for letrozole (30% v 20%; P
.0006), as was the rate of clinical benefit (49% v 38%; P
.001). Survival data are currently immature and not reported here. Both treatments were well tolerated.
Conclusion: Letrozole was significantly superior to
tamoxifen in TTP, TTF, ORR, and clinical benefit rate. Our
results support its use as first-line endocrine therapy in
postmenopausal women with advanced breast cancer.
J Clin Oncol 19:2596-2606. 2001 by American
Society of Clinical Oncology.
NITIAL PALLIATIVE treatment for postmenopausal

women with hormone-sensitive advanced breast cancer
is endocrine. Such therapy is better tolerated than cytotoxic
chemotherapy and is at least as effective in stopping or
slowing tumor growth. Tamoxifen, the current agent of

choice as first-line therapy, is at least as effective as other
endocrine therapies with less toxicity.1,2 Response rates of
between 30% and 45% have been reported for first-line
therapy with tamoxifen as well as with other hormonal
agents, such as the nonspecific aromatase inhibitor aminoglutethimide or the progestins medroxyprogesterone acetate and megestrol acetate.2-5 However, data suggest that
neither progestins nor aminoglutethimide are superior to
tamoxifen in efficacy or tolerability.6-8
Patients whose tumors progress after responding to tamoxifen initially can achieve a series of further responses
from subsequent second-line therapy with agents such as
megestrol acetate or aminoglutethimide. More selective and
potent aromatase inhibitors, such as letrozole, have shown
superior efficacy and tolerability to megestrol acetate and
aminoglutethimide as second-line therapy of advanced
breast cancer in postmenopausal women after tamoxifen has
failed.9-13 Response rates for these agents used in secondline therapy range from 8% to 24%.
Two studies with the selective aromatase inhibitor anastrozole versus tamoxifen were published recently.14,15 In
both studies, response rates were similar. In the North
American study,14 time to progression (TTP) was in favor
From the Rigshospitalet, Copenhagen, Denmark; Petrov Research

Institute of Oncology, St Petersburg, Russia; Chinese Academy of
Medical Sciences, Beijing, China; Hospital Universitario de la Princesa, Madrid, Spain; Arcipedale Santa Maria Nuova, Reggio Emilia,
Italy; Centre Hospitalier General Andre-Boulloche, Montbeliard,
France; University of Stellenbosch, Cape Town, South Africa; South
Carolina Oncology Associates, Columbia, SC; Ziekenhuis Leyenburg,
Den Haag, the Netherlands; University of Hamburg, Hamburg, Germany; Regional Center of Oncology, Lodz, Poland; Semmelweis
University, Budapest, Hungary; General Hospital, Middelheim, Antwerp, Belgium; Kidwai Memorial Institute of Oncology, Bangalore,
India; Turku University Central Hospital, Turku, Finland; St Vincents
Hospital, Fitzroy, Victoria, Australia; Independent Consultant, Basel;
Novartis Pharma AG, Milan, Italy; and Novartis Pharmaceuticals
Corporation, East Hanover, NJ.
Submitted September 26, 2000; accepted March 6, 2001.
Supported by Novartis Pharma AG, Basel, Switzerland.
Address reprint requests to Hilary A. Chaudri-Ross, DEP, Novartis
Pharma AG, WSJ-27.2.023, CH-4002 Basel, Switzerland; email:
hilary_anne.chaudri@pharma.novartis.com.
2001 by American Society of Clinical Oncology.
0732-183X/01/1910-2596
2596
Journal of Clinical Oncology, Vol 19, No 10 (May 15), 2001: pp 2596-2606

Downloaded from jco.ascopubs.org on January 4, 2016. For personal use only. No other uses without permission.
Copyright 2001 American Society of Clinical Oncology. All rights reserved.
2597
SUPERIOR EFFICACY OF LETROZOLE
Fig 1.
Study design.
of anastrozole, but in the larger, mainly European study,

TTP was similar for both treatments. Analysis of the two
studies combined16 showed comparable efficacy of anastrozole to tamoxifen, and the authors concluded that their data
supported the use of anastrozole as an alternative treatment
to tamoxifen in postmenopausal women with advanced
breast cancer.
The better efficacy and improved safety of letrozole when
compared against two other endocrine treatments as secondline therapy suggested that letrozole could show at least
similar activity as first-line therapy in advanced breast
cancer. This hypothesis led to the study reported here.
PATIENTS AND METHODS
Study Design
This phase III, randomized, double-blind, double-dummy, parallelgroup study was originally designed as a three-arm study, involving
two monotherapy arms (letrozole or tamoxifen) and a combination arm
of both treatments. After results of a pharmacokinetic study showed
that adding tamoxifen to letrozole lowered letrozole blood levels by
38% on average, randomization to the combination arm was stopped.17
The study was then redesigned and rerandomized to include only the
monotherapy arms (Fig 1) and was conducted at 201 centers in 29
countries. Patients were randomly assigned once daily treatment with
either letrozole (Femara; Novartis Pharma AG, Basel, Switzerland) 2.5
mg or tamoxifen (Tamofen; Leiras Oy, Turku, Finland) 20 mg using a
double-dummy technique with matching placebo tablets. Patients
continued treatment until progressive disease (PD) or other reason
necessitated discontinuation. If after disease progression or discontinuation of treatment due to an adverse event the patient remained
suitable for further endocrine therapy, she could be switched to the
alternative (crossover) treatment in a double-blind fashion. Treatment
was allocated according to computer-generated randomization lists that
used permuted blocks of a fixed size and no stratification. Treatment
compliance was monitored by tablet count at each patient visit. All

patients are being monitored for overall survival.
The study was conducted in accordance with the ethical principles
that originated in the Declaration of Helsinki and the Good Clinical
Practice (GCP) requirements of the International Conference on
Harmonisation. The appropriate local ethics review boards approved
the protocol. All patients gave written informed consent before
study enrollment.
Inclusion Criteria
Postmenopausal women with histologically or cytologically confirmed breast cancer and with locally advanced (stage IIIB by American Joint Committee on Cancer criteria, 1992) or locoregionally
recurrent disease not amenable to treatment by surgery or radiotherapy
or with metastatic disease were eligible for the study. Measurable or
assessable disease was required except in the case of patients with
blastic bone only disease; their lesions were considered nonassessable.
Bone lesions were considered to be assessable disease if they had at
least a 50% lytic component. Lesions with less than a 50% lytic
component were not assessable for response but were monitored for
progression. Patients were required to have tumors with estrogen
receptor (ER) and/or progesterone receptor (PgR)positive status or
with both receptors unknown. Patients were regarded as ER- or
PgR-positive if any assay (cytochemical, immunochemical, immunohistochemical, or radioimmunoassay) of primary or secondary tumor
tissue was positive. Patients were regarded as having an unknown
receptor status if no assay was known to be positive or negative.
Patients previously treated with one regimen of chemotherapy for
advanced disease were allowed in the study provided that they had
objective evidence of progression within 3 months before study
enrollment. A Karnofsky performance status score of at least 50 (World
Health Organization grade 0 to 2) was required.
Exclusion Criteria
Patients were excluded from the study if they had evidence of CNS
metastasis, bilateral diffuse lymphangitis carcinomatosa of the lung
with more than 50% lung involvement, metastasis estimated as more
2598
MOURIDSEN ET AL
than one third of the liver defined by sonogram and/or computed

tomography (CT) scan, inflammatory breast cancer, concurrent or
previous malignant diseases (except for contralateral breast carcinoma,
in situ carcinoma of the cervix treated by cone biopsy, or adequately
treated basal or squamous cell carcinoma of the skin), or uncontrolled
medical conditions such as cardiac disease or diabetes mellitus. Patients
whose disease relapsed or recurred during adjuvant antiestrogen therapy or within 12 months of completing such therapy were excluded.
Adjuvant endocrine therapy other than antiestrogens, prior systemic
endocrine treatment for advanced disease, systemic investigational
drugs within the past 30 days, or topical investigational drugs within
the past 7 days precluded enrollment onto the study. Concomitant
anticancer treatments, prolonged systemic corticosteroid treatment
(except for topical applications, inhaled sprays, eye drops or local
injections), chronic concomitant bisphosphonate therapy for hypercalcemia, and bisphosphonate treatment for the prevention of bone
metastases were not permitted during the study. Bisphosphonate
treatment at the time of randomization or at the start of crossover
therapy when progression in bone was documented was allowed for the
treatment of bone metastases. Radiation or surgery to a sole site of
disease was not permitted. However, radiation or surgery to a limited
area other than a sole site of disease was allowed. Irradiated or excised
lesions were then considered nonassessable and monitored only for
disease progression.
Clinical and Radiologic Assessments

Complete medical histories, chest x-rays or chest CT scans, abdominal CT scans or ultrasounds of the liver, bone scans with radiologic
assessments of abnormal areas or full skeletal surveys, and measurements of any superficial or palpable lesions were obtained at baseline.
Physical examinations were performed, symptoms and/or adverse
events were assessed, hematology and blood chemistry profiles were
obtained, previous and/or current medications were reviewed, and
performance status was evaluated at baseline and repeated every 3
months. A complete tumor assessment was performed at baseline, and
areas found positive for disease at baseline were monitored every 3
months for response assessment according to International Union
Against Cancer criteria.18 Additional scans and x-rays were performed
at any time as warranted by signs and symptoms. Each center had a
designated central radiologist who reviewed all patients radiographic
data. In addition, an internal Novartis data evaluation committee
reviewed in a blinded fashion all tumor assessment and overall
response data. Discrepancies were resolved with the investigator. All
patients were monitored for survival at least every 6 months after
termination of study treatment.
Primary Efficacy Assessments

The primary efficacy end point was TTP. TTP was defined as the
interval between the date of randomization and the earliest date of
disease progression. An increase of 25% or more in measurable
lesions (single lesion or sum of products of all measurable lesions),
an estimated increase of 25% or more in existing assessable or
nonmeasurable/nonassessable disease, and the appearance of new
lesions were considered progression. Discontinuation of treatment
with documented evidence of clinical deterioration due to breast
cancer, or death due to breast cancer or death of unknown cause
(with documented evidence of clinical deterioration due to breast
cancer) while receiving treatment or within 6 weeks of discontinuation of treatment, also constituted disease progression.
Secondary Efficacy Assessments

Secondary end points included overall objective tumor response rate
(ORR), duration of overall response, rate of clinical benefit, duration of
clinical benefit, time to treatment failure (TTF), time to response
(TTR), number of deaths, and overall survival. Overall survival is not
reported here because the data were immature at the time of the
analysis of the mature primary end point of TTP. ORR was defined as
the proportion of patients who achieved a complete response (CR) or a
partial response (PR) as confirmed by a second evaluation at least 1
month but generally 3 months later. Overall response was evaluated at
3-month intervals after initiation of therapy. Response in patients with
only blastic bone lesions or with mixed blastic and lytic lesions with
50% or higher blastic component was categorized as not assessable
unless disease progression (PD) occurred. Response was then assessed
as PD and not as not assessable.
Duration of overall objective response was defined for those patients
with a confirmed response (CR or PR) as the interval between the date
of randomization and the earliest date of disease progression. TTR was
defined for those patients with a confirmed response (CR or PR) as the
interval between randomization and the earliest documentation of
response. The rate of clinical benefit was defined as the proportion
of patients who achieved a confirmed objective response (CR or PR)
or who had stabilization or no change lasting for 24 weeks or more.
Duration of clinical benefit was defined for these patients as the
interval between the date of randomization and the earliest date of
disease progression.
TTF was defined as the interval between the date of randomization
and the earliest date of disease progression, withdrawal of study
treatment for any reason, withdrawal of consent, loss to follow-up, or
death from any cause. The duration of the study was defined as the
interval between the earliest date of randomization and the latest date
of contact, irrespective of treatment.
Safety Assessments
Safety was assessed through monitoring and recording of all
adverse events using the National Cancer Institute common toxicity
criteria (version 1.3) and routine monitoring of hematologic, renal,
and liver function.
Statistical Methodology
Sample size was calculated on the basis of TTP, assuming the
following: a hazards rate for tamoxifen of 0.9; 5% two-sided significance with 80% power to detect as significant a hazards ratio of 0.80
(letrozole to tamoxifen); 10% loss to follow-up; steady enrollment over
2 years; and TTP with an exponential distribution. The study was
powered for superiority, defined as a hazards ratio of less than 0.80, ie,
a reduction of at least 20% in the risk of progression with the superior
treatment compared with the risk with the inferior one. To fulfill these
conditions, a total of approximately 900 patients (equal distribution in
both arms) needed to be enrolled over 2 years to observe 632 events of
progression, approximately 1 year from completion of enrollment.
The same sample size would also be sufficient to detect as significant
an absolute difference of 10% in overall objective tumor response
under similar conditions (two-sided, 5%; 80% power; 10% loss to
follow-up or nonassessability of response).
All patients with advanced breast cancer documented at study entry
and treated at GCP-compliant centers were included in the efficacy
intent-to-treat population. Safety analysis excluded patients who never
received study drug and patients in GCP-noncompliant centers. Only
2599

treatment-emergent adverse events were considered in the analyses. A
patient was counted once for any adverse event term, even if the event
occurred multiple times.
The main end point was TTP. ORR and TTF were major secondary
end points, as defined in the protocol. Treatments were compared by
Cox proportional hazards regression for all time-to-event variables.
Median time to event was estimated by the Kaplan-Meier product-limit
method. TTP was censored in the following circumstances: patient was
still receiving treatment without evidence of progression, patient died
of unknown cause without evidence of clinical deterioration due to
breast cancer, and patient discontinued treatment for any reason
without evidence of clinical deterioration due to breast cancer before
discontinuation.
The same censoring rules applied to the estimates of duration of
objective response and duration of clinical benefit. TTF was censored
for patients who continued to receive treatment without evidence of
progression or clinical deterioration due to breast cancer, as well as for
patients whose reasons for withdrawal of treatment were clearly
documented as unrelated to either study drug or to breast cancer.
Overall objective (CRPR) tumor response rate (ORR) was analyzed by logistic regression. Supportive (prospectively planned) multivariate and stratified analyses were conducted for TTP and ORR. A
similar methodology was applied as previously described, but treatment
comparisons were adjusted on key baseline covariates of receptor status
(at least one receptor positive v no receptor known to be positive), prior
adjuvant therapy with antiestrogens (no or yes), and dominant site of
disease (soft tissue, bone, or viscera). The dominant site as assessed at
baseline was defined as soft tissue if only soft tissue disease was
present, as bone if skeletal metastases were present (regardless of
coexistent soft tissue disease) without involvement of visceral sites, and
as viscera if visceral metastases were present (irrespective of soft tissue
or bone involvement).
Multivariate analyses (Cox proportional hazards for TTP and logistic
regression for ORR) tested the influence of the baseline covariates on
the treatment comparison, as well as examined the effect of each
covariate in the presence of the other covariates. Stratified analyses
(stratified log-rank test for TTP and stratified Mantel-Haenszel test for
ORR) compared treatments one covariate at a time. More detailed
analyses were also conducted for selected baseline covariates (treatments compared within each stratum of the covariate, applying Cox
regression for TTP, and logistic regression for ORR).
RESULTS
A total of 939 postmenopausal women with advanced

breast cancer were enrolled onto the study between November 1996 and early January 1999. Thirty-two patients were
excluded from the intent-to-treat analysis: 23 had been
allocated combination treatment; four (two letrozole, two
tamoxifen) had been enrolled at a site found to be GCPnoncompliant (one patient receiving combination therapy
was also enrolled at the GCP-noncompliant center); and
five patients (three letrozole, two tamoxifen) did not have
active, advanced breast cancer at study enrollment. An
analysis of TTP, ORR, and TTF including the four
patients receiving monotherapy at the GCP-noncompliant
center as well as an analysis based on all randomized
patients provided almost identical results, and these data
are not reported here. Two patients (one letrozole, one

tamoxifen) were never treated but were included in the
intent-to-treat population. Of the 907 patients in the
intent-to-treat population, 453 patients were allocated
letrozole therapy and 454 were allocated tamoxifen.
Patient baseline characteristics were well balanced in the
two treatment arms (Table 1), as were relevant medical
histories and concomitant medical conditions. Patients were
predominantly white (86%). The Karnofsky performance
status score was 80 to 100 (World Health Organization
grades 0 and 1) in 92% of patients. At study entry, 93% (841
of 907) of the study population had metastatic disease; they
presented with either stage IV disease at enrollment (25%:
114 letrozole, 111 tamoxifen) or with relapsing metastatic
disease (68%: 308 patients in each arm). In addition, 62
patients (29 letrozole, 33 tamoxifen) had locally advanced
disease and four patients (two letrozole, two tamoxifen) had
stage IIA/B disease.
Soft tissue lesions were present in 63% (288 of 456) of
the patients in the letrozole arm and 61% (277 of 456) in the
tamoxifen arm, with soft tissue being the dominant site in a
quarter of all patients. Bone metastases were present in 54%
(247 of 456) and 50% (226 of 456) of patients in the
letrozole and tamoxifen arms, respectively, and bone was
the dominant site in around 30% of patients in each arm.
The dominant site of disease was viscera in 43% of the
patients in the letrozole arm and 46% of the patients in the
tamoxifen arm (Table 1). Liver metastases were present in
13% (60 of 453) of the patients receiving letrozole and 12%
(55 of 454) receiving tamoxifen.
The percentage of study population who received chemotherapy either as adjuvant chemotherapy or for metastatic
disease was low. Of those patients who received adjuvant
tamoxifen, the majority (109 of 167) received the antiestrogen for at least 2 years, and the treatment-free interval
between stopping the adjuvant therapy and entering the
study was more than 2 years in most (126 of 167).
The cutoff date for this analysis was March 2000, at
which time the overall median duration of the study was
approximately 18 months. At this time, 111 patients were
still receiving letrozole and 67 patients were receiving
tamoxifen. Of the 729 patients who discontinued treatment,
197 letrozole-treated patients and 194 tamoxifen-treated
patients entered crossover.
Efficacy Results
Letrozole was superior to tamoxifen in TTP, reducing the
risk of progression by 30% (hazards ratio, 0.70; 95%
confidence interval [CI], 0.60 to 0.82; P .0001) compared
with tamoxifen. Median TTP was prolonged by 57%, 41
weeks for letrozole and 26 weeks for tamoxifen (Fig 2 and
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MOURIDSEN ET AL
Table 1.
Patient Demographics and Baseline Characteristics

Letrozole (n 453)
Characteristic
Age, years
Median
Range
Karnofsky performance score
90-100
70-80
50-60
Not reported
Receptor status
ER and/or PgR positive
ER and PgR unknown
Receptor negative*
Stage of disease at study entry
Stage IV or earlier disease
Metastatic, relapsed
Median disease-free interval, years
Site of disease
Soft tissue only
Bone
Bone only
Bone and soft tissue
Viscera
Viscera only
Viscera and bone
Viscera and soft tissue
Viscera, bone, and soft tissue
Prior chemotherapy
None
Adjuvant only
Treatment for advanced disease
Prior adjuvant antiestrogen therapy
Yes
No
Bisphosphonates used
Yes
No
No.
Tamoxifen (n 454)
%
No.
65
31-96
64
31-93
253
170
30
56
38
7
264
150
39
1
58
33
9
1
294
156
3
65
34
1
305
149
67
33
145
308
32
68
146
308
32
68
5.9
5.5
113
146
69
77
194
52
44
41
57
25
32
15
17
43
12
10
9
13
116
130
72
58
208
61
44
51
52
25
29
16
13
46
13
10
11
11
320
93
40
71
21
9
301
105
48
66
23
11
84
369
19
81
83
371
18
82
40
413
9
91
49
405
11
89
*Two patients, ER unknown/PgR negative; one patient, ER negative/PgR negative.

Includes patients with mixed blastic ( 50% blastic component) or blastic-only lesions (15 letrozole, five tamoxifen).
Table 2). Letrozole was superior to tamoxifen in TTF (P

.0001), with a median of 40 weeks for letrozole and 25
weeks for tamoxifen. Treatment failure occurred in 75% of
letrozole-treated patients, compared with 85% of patients
treated with tamoxifen. ORR was significantly higher for
letrozole patients at 30%, compared with 20% for tamoxifen-treated patients (odds ratio, 1.71; 95% CI, 1.26 to 2.31,
P .0006), as was clinical benefit at 49% for letrozole
compared with 38% for tamoxifen (P .001). There was,
however, no significant difference between letrozole and
tamoxifen in the duration of overall response or in duration
of overall clinical benefit (Table 3). TTR did not differ
significantly in the two arms. Median TTR was 14 weeks for
both treatments.
Fig 2. Time to progression: for letrozole (n 453), the median TTP was
41 weeks (9.4 months); for tamoxifen (n 454), median TTP was 26 weeks
(6.0 months).
2601

Table 2.
End Point
Median
Median
Median
Median
Results: End Point
Weeks of Letrozole
(n 453)
Weeks of Tamoxifen
(n 454)
Hazards Ratio
95% CI
41
40
102
81
26
25
100
84
0.70
0.71
0.84
0.81
0.60-0.82
0.61-0.82
0.56-1.26
0.62-1.07
.0001
.0001
.4
.1
TTP
TTF
duration overall response*
clinical benefit*
*Calculated from date of randomization.
Supportive Analyses
The results of the supportive multivariate analysis of
TTP, with the treatment comparison adjusted on the key
baseline covariates of receptor status, prior adjuvant antiestrogen therapy, and dominant site of disease, were very
similar to the results of the unadjusted analysis, with
letrozole significantly decreasing the risk of progression
(hazards ratio, 0.70; 95% CI, 0.60 to 0.81; P .0001)
(Table 4). This analysis indicated that the presence of
visceral metastases significantly increased the risk of progression compared with soft tissue as the dominant site.
Bone as the dominant site significantly increased the risk of
progression compared with soft tissue as the dominant site.
Neither receptor status nor prior adjuvant therapy with
antiestrogens significantly affected TTP (Table 4).
The supportive stratified analysis of TTP (for each key
baseline covariate) revealed the superiority of treatment
with letrozole over tamoxifen (P .0001 for each covariate). Detailed analysis (within each stratum of the covariate)
showed superiority of letrozole over tamoxifen for all strata
of the baseline covariates (Table 5). The median TTP in
each stratum was very similar to the overall study results for
each treatment.
The results of the supportive multivariate analysis of
ORR adjusted on the same key baseline covariates as the
analysis of TTP were similar to the results of the unadjusted
analysis, with letrozole significantly increasing the odds of
achieving CR or PR compared with tamoxifen (odds ratio,
1.80; 95% CI, 1.32 to 2.47; P .0002) (Table 6). This
Table 3.
Letrozole (n 453)
Response
No. of
Patients
95% CI
OR (CRPR)
CR
PR
Clinical benefit CRPRNC 24 wks
Progression of disease
Not assessable*
137
34
103
221
200
32
30
8
23
49
44
7
26-35
44-54
analysis indicated that the covariates that influenced overall

response were similar to those that influenced TTP, with the
addition of prior adjuvant antiestrogen therapy. The odds of
achieving a response were significantly reduced in patients
with visceral involvement or bone as the dominant site of
disease compared with patients with soft tissue disease only;
prior adjuvant antiestrogen therapy significantly reduced the
odds of achieving a response compared with antiestrogennaive patients; a trend was observed for higher odds of
achieving an objective tumor response in receptor-positive
patients compared with receptor-unknown patients (Table 6).
The supportive stratified analyses of ORR were consistent with the multivariate analyses and revealed the superior
ORR of letrozole over tamoxifen on key covariates (P
.001 for each covariate). Detailed analysis of ORR showed
superiority of letrozole over tamoxifen for all strata of the
baseline covariates except for unknown hormone receptor
status and bone as the dominant site of disease, where a
clear trend toward superiority in favor of letrozole was seen
(Table 7). In general, ORR in each stratum was very similar
to the overall study results. However, in patients who had
been exposed to adjuvant antiestrogen therapy, ORR was
dramatically lowered for tamoxifen (8%) compared with the
overall study results for tamoxifen (Table 7).
Safety
A total of 910 patients (455 in each treatment arm) were
included in the safety analysis of the two monotherapies.
Most patients experienced at least one adverse event during
Results: Response
Tamoxifen (n 454)
No. of
Patients
95% CI
Odds Ratio
95% CI
92
13
79
173
250
31
20
3
17
38
55
7
17-24
1.71
1.26-2.31
.0006
34-43
1.55
1.19-2.01
.001
*Includes patients with blastic bone only lesions who were assessable for progression of disease only and patients with incomplete or partial tumor assessments
throughout study participation.
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MOURIDSEN ET AL
Table 4.
TTP: Multivariate Analysis (key baseline covariates)

Covariate
Treatment, letrozole:tamoxifen
Prior adjuvant antiestrogen therapy, yes:no
Receptor status, positive:otherwise
Dominant site viscera, yes:no
Dominant site bone, yes:no
Table 6.
Hazards
Ratio
95% CI
0.70
1.13
0.90
1.52
1.26
0.60-0.81
0.93-1.38
0.77-1.06
1.25-1.85
1.02-1.56
.0001
.2
.2
.0001
.03
Objective Tumor Response: Multivariate Analysis

(key baseline covariates)
Covariate
Odds Ratio
95% CI
1.80
0.64
1.37
0.37
0.29
1.32-2.47
0.41-0.98
0.98-1.92
0.26-0.53
0.19-0.44
.0002
.04
.07
.0001
.0001
Treatment, letrozole:tamoxifen
Prior adjuvant antiestrogen therapy, yes:no
Receptor status, positive:otherwise
Dominant site viscera, yes:no
Dominant site bone, yes:no
NOTE. A hazards ratio of less than 1 favors the stratum to the left of the ratio
symbol (:), while a hazards ratio greater than 1 favors the stratum to the right
of the ratio symbol. Significance levels are reported to the first significant digit.
NOTE. An odds ratio greater than 1 favors the stratum to the left of the ratio
symbol (:), while an odds ratio less than 1 favors the stratum to the right of the
ratio symbol. Significance levels are reported to the first significant digit.
treatment (including worsening of tumor-related symptoms). The nature and frequency of adverse events were
similar for the letrozole and tamoxifen treatment arms
(Table 8).
Adverse events suspected to be related to the study drug
were reported with similar frequency (38% for letrozole and
37% for tamoxifen) and were similar in nature for both
treatments. Adverse events with suspected causality reported for more than 5% of patients were hot flushes,
nausea, and hair thinning (Table 8). Thromboembolic
events irrespective of drug relationship were reported in 1%
(six patients) of the letrozole arm and in 2% (11 patients) of
the tamoxifen arm. Pulmonary embolism irrespective of
study drug relationship was reported in two patients, one in
each treatment arm.
The frequency of discontinuation due to an adverse event,
withdrawal of consent, or death was similar in both groups,
with 7% overall discontinuing for these reasons. Most
discontinuations for adverse events were associated with

progression of disease.
The nature and frequency of laboratory abnormalities
were similar for the letrozole and tamoxifen arms, and no
clinically meaningful trends were observed.
Table 5.
DISCUSSION
This is the largest single study to date conducted with an

aromatase inhibitor in the first-line endocrine treatment of
advanced breast cancer. The results clearly show letrozole
to be more effective than the established first-line endocrine
therapy, tamoxifen, in the treatment of advanced breast
cancer in postmenopausal women. Letrozole was superior
to tamoxifen in TTP, reducing the risk of progression by
30% (hazards ratio, 0.70; 95% CI, 0.60 to 0.82; P .0001)
compared with tamoxifen. Median TTP was prolonged by
57%, 41 weeks for letrozole and 26 weeks for tamoxifen.
Letrozole was also significantly superior for the secondary
TTP: Detailed Stratified Analysis (key baseline covariates)

Progressions
Covariate

No
Yes
Receptor status
At least one receptor positive
Unknown/negative
Dominant site
Soft tissue only
Bone / soft tissue
Viscera / other sites
Treatment
No.
Median
(weeks)
Hazards
Ratio
95% CI
Letrozole
Tamoxifen
Letrozole
Tamoxifen
369
371
84
83
250
284
58
66
68
77
69
80
42
26
38
26
0.71
0.60-0.84
.0001
0.68
0.48-0.98
.04
Letrozole
Tamoxifen
Letrozole
Tamoxifen
294
305
159
149
199
235
109
115
68
77
69
77
42
26
40
26
0.70
0.58-0.84
.0002
0.73
0.56-0.95
.02
Letrozole
Tamoxifen
Letrozole
Tamoxifen
Letrozole
Tamoxifen
113
116
146
130
194
208
68
84
100
97
140
169
60
72
68
75
72
81
56
28
42
27
36
20
0.73
0.53-1.00
.05
0.70
0.53-0.93
.01
0.69
0.55-0.87
.001
NOTE. A hazards ratio of less than 1 favors letrozole, while a hazards ratio of greater than 1 favors tamoxifen. Significance levels are reported to the first
significant digit.
2603

Table 7.
Objective Tumor Response: Detailed Stratified Analysis (key baseline covariates)

CRPR
Covariate

No
Yes
Receptor status
At least one receptor positive
Unknown/negative
Dominant site
Soft tissue only
Bone / soft tissue
Viscera / other sites
95% CI
Treatment
No.
Odds Ratio
Letrozole
Tamoxifen
Letrozole
Tamoxifen
369
371
84
83
113
85
24
7
31
23
29
8
1.49
1.07-2.06
.02
4.34
1.75-10.76
.002
Letrozole
Tamoxifen
Letrozole
Tamoxifen
294
305
159
149
92
63
45
29
31
21
28
19
1.75
1.21-2.54
.003
1.63
0.96-2.78
.07
Letrozole
Tamoxifen
Letrozole
Tamoxifen
Letrozole
Tamoxifen
113
116
146
130
194
208
54
40
32
18
51
34
48
34
22
14
26
16
1.74
1.02-2.96
.04
1.75
0.93-3.29
.08
1.83
1.12-2.97
.02
NOTE. An odds ratio of greater than 1 favors letrozole, while an odds ratio of less than 1 favors tamoxifen. Significance levels are reported to the first significant
digit.
end points TTF, ORR, and rate of clinical benefit, with a

similar median duration of objective response and similar
duration of clinical benefit. The robustness of this result is
supported by the consistency of results among different
subgroups within the trial. Although approximately one
third of patients had tumors of unknown receptor status, the
consistency of results with ER and/or PgR positivity supports the sensitivity of these patients to endocrine treatment.
Table 8.
Adverse Events
Letrozole
(n 455)
Event
Most frequent adverse events ( 10%)

irrespective of relationship
Any adverse event
Bone pain
Hot flushes (NOS)
Back pain
Nausea
Arthralgia
Dyspnea
Cough
Fatigue
Related adverse events with frequency
of 5%
Hot flushes
Nausea
Hair thinning
Tamoxifen
(n 455)
No. of
Patients
No. of
Patients
408
89
81
77
66
63
62
49
48
90
20
18
17
15
14
14
11
11
394
83
70
79
72
58
66
47
51
87
18
15
17
16
13
15
10
11
76
30
23
16
6
5
64
29
15
13
6
3
Abbreviation: NOS, not otherwise specified.
The safety and tolerability of the two drugs were quite

similar, and there was no evidence that the greater efficacy
of letrozole was associated with any increase in the number
or seriousness of adverse events compared with tamoxifen.
The two recently published trials with anastrozole versus
tamoxifen conducted in North America14 and mainly European countries15 were designed with very similar inclusion/
exclusion criteria. However, the demographics of the two
studies were different, mainly in receptor status (proportion
of receptor-unknown patients, 11% v 55%), prior adjuvant
endocrine therapy (20% v 11% of the patients), and site of
disease. The patient population of the present study appeared to resemble that of the combined study, which
showed comparable efficacy of anastrozole and tamoxifen.16 Our study was analyzed by geographic area (prespecified analysis), namely Europe, North America, and rest
of the world. Letrozole was significantly superior to tamoxifen in TTP in all three areas, with closely similar hazards
ratios for each region (approximately 0.7).19
An important feature of the results from the letrozole
study reported here, which is also supported by recently
published trials,16,20,21 is the consistently lower response
rate for tamoxifen of approximately 20% (despite a similar
and consistently reported median TTP of approximately 6
months for tamoxifen) compared with that reported previously in the literature for a similar population.22 This
divergence in tamoxifen response rates may possibly be a
consequence of the stricter criteria used to confirm response
in this study. Another feature of the current study that needs
2604
MOURIDSEN ET AL
comment and that is of importance for the future use of

letrozole is the fact that less than 20% of the patients had
received adjuvant tamoxifen. This is similar to the 18%
to 21% reported in the anastrozole studies.16 As more and
more patients receive adjuvant tamoxifen, it is to be
expected that in the future a much larger proportion of
patients will relapse after adjuvant tamoxifen, thus possibly making them less responsive to tamoxifen in the
advanced setting. Consequently, an agent like letrozole
for use in first-line advanced breast cancer is a significant
therapeutic advance.
A recently completed, randomized, double-blind, multicenter study comparing the efficacy of 4 months of therapy
with letrozole and tamoxifen as primary treatment in the
preoperative setting confirms the superior efficacy of letrozole over tamoxifen.23 Response rate assessed by clinical
palpation (primary end point) was 55% for letrozole compared with 36% for tamoxifen (P .001). Response rates
were similarly significantly in favor of letrozole when
assessed by ultrasound or mammography. A study in the
adjuvant setting comparing letrozole and tamoxifen is
underway at the present time.
Preclinical data in vitro and in vivo comparing letrozole

with anastrozole and tamoxifen show that letrozole is
significantly more potent in vitro and more efficacious in
vivo.24-27 The effects of letrozole, anastrozole, and tamoxifen have been compared in a tumor xenograft nude mouse
model described by Brodie et al. In this model, letrozole
was the most efficacious agent in reducing tumor size.28-30
The preclinical data lend support to the improved efficacy of
letrozole seen in the clinical setting.
In conclusion, the data reported here document the
superior efficacy of letrozole compared with tamoxifen and
strongly support the use of letrozole in the first-line endocrine treatment of advanced breast cancer in postmenopausal women.
ACKNOWLEDGMENT
We acknowledge Ajay Bhatnagar for preparing an early draft of the
manuscript, as well as for his continuous support; Franzanne Vreeland,
MD, for study design; Elizabeth Baguley and her team for data
management; Carolyn Brady and Carol Gano for study management;
Malek Belmatoug for programming; Katrina Masih for statistical
analysis; and all study investigators and study monitors worldwide. In
addition, we acknowledge Lakeland Clinical for technical support.
APPENDIX
Principal investigators for the Letrozole International Letrozole Breast Cancer Group (in addition to listed authors) were as follows:
Argentina: L. Balbiani, C. Castillo, F. Coppola, R. De Angelis, L. Fein, L. Freue, C. Lopez, J. Martinez, E. Mickiewicz, E. Palazzo, H. Requejo,
L. Silberman, M. Torello, R. Viroglio, and R. Wainstein.
Australia: E. Abdi, R. Bell, P. Craft, D. Dalley, M. Green, D. Grimes, P. Harnett, R. Kimber, J. McKendrick, J. Stewart, and J. Trotter.
Austria: M. Stierer and V. Wette.
Belgium: F. Bastin, L. Dirix, L. Marcelis, and D. Vanstraelen.
Canada: M. Blackstein, F. Couture, C. Germond, and S. Legault-Poisson.
Chile: L. Prieto and L. Soto Diaz.
Denmark: E. Andersen, J. Andersen, S. Cold, C. Gadeberg, P. Grundtvig, C. Kamby, N. Keldsen, M. Kjaer, E. Madsen, K. Mo
ller, P. Philip, and
E. Sandberg.
Egypt: M. Hamza and O. Zaki.
Finland: G. Blanco and V. Kataja.
France: B. Audhuy, A. Daban, T. Delozier, P. Fargeot, O. LeFloch, A. Lortholary, E. Malaurie, M. Marty, L. Mauriac, L. Mignot, F. Morvan,
M. Namer, G. Netter-Pinon, P. Quetin, G. Romieu, M. Spielmann, N. Tubiana-Mathieu, and B. Weber.
Germany: W. Abenhardt, M. Brandtner, R. Dengler, G. von Minckwitz, P. Reichardt, F. Opri, K. Possinger, and S. Volkl.
Great Britain: S. Chan, N. Davidson, TRJ Evans, T. Iveson, R. Leonard, R. Mansel, C. Price, and J. Robertson.
Greece: G. Arvantinos, V-A Georgoulias, and N. Pavlidis.
Hungary: Z. Faluhelyi, M. Kispal, T. Nagykalnai, and J. Szanto.
Iceland: H. Sigurdsson.
India: I. Mittra and V. Raina.
Israel: B. Kaufman, T. Tichler, and N. Wigler.
Italy: P. Carlini, M. Cremonesi, M. DAprile, F. Di Costanzo, M. Fornasiero G. Francini, M. Indelli, A. Molino, G. Monti, A. Pacagnella, R. Silva,
and E. Villa.
Netherlands: E. Balk, J. Coenen, E. Maartense, J. Nortier, D. Richel, W. van Deijk, S. van der Vegt, F. van Nierop, and H. van Veelen.
New Zealand: S. Costello.
Poland: P. Koralewski.
Portugal: M. Pinto.
Russia: A. Garin, V. Gorbunova, and M. Litchinitser.
South Africa: N. Cronje, C. Falkson, L. Goedhals, C. Jacobs, J. Jordaan, J. Raats, I. Werner, and A. Zietsman.
Spain: A. Balil, R. Bastus, J. Illarramendi, and A. Llombart-Cussac.
Sweden: M. Albertsson and A. Malmstrom.
2605
APPENDIX (Contd)
United States: M. Alden, R. Asbury, C. Badolato, E. Balcueva, J. Bitran, R. Blachly, D. Blayney, T. Brotherton, R. Brown, L. Campos, R.
Chapman, F. Cummings, M. Ellis, R. Fredric, J. Hainsworth, G. Harrer, S. Jubelirer, L. Kalman, J. Kroener, M. Levin, M. Lewis, J. Liebmann,
R. Marsh, J. McCann, S. McCachren, J. McCracken, B. OConnor, R. Odders, D. Osborn, K. Pendergrass, B. Pruitt, R. Rodriguez, M. Rubin,
T. Shiftan, P. Silverman, S. Tchekmedyian, W. Waterfield, K. Weichert, R. Yanagihara, B. Yanes, F. Yunus, and M. Zimmer.
Uruguay: C. Garbino and G. Sabini.
REFERENCES
1. Legha SS: Tamoxifen in the treatment of breast cancer. Ann
Intern Med 109:219-228, 1988
2. Santen RJ, Manni A, Harvey H, et al: Endocrine treatment of
breast cancer in women. Endocr Rev 11:1-45, 1990 (suppl 2)
3. Rose C, Mouridsen HT: Endocrine therapy of advanced breast
cancer. Acta Oncol 27:721-728, 1988
4. Muss HB, Wells HB, Paschold EH, et al: Megestrol acetate
versus tamoxifen in advanced breast cancer: 5-year analysisA phase
III trial of the Piedmont Oncology Association. J Clin Oncol 6:10981106, 1988
5. Gill PG, Gebski V, Snyder R, et al: Randomized comparison of
the effects of tamoxifen, megestrol acetate, or tamoxifen plus megestrol
acetate on treatment response and survival in patients with metastatic
breast cancer. Ann Oncol 4:741-744, 1993
6. Castiglione-Gertsch M, Pampallona S, Varini M, et al: Primary
endocrine therapy for advanced breast cancer: To start with tamoxifen
or with medroxyprogesterone acetate? Ann Oncol 4:735-740, 1993
7. Gale KE, Anderson JW, Tormey DC, et al: Hormonal treatment
for metastatic breast cancer: An Eastern Cooperative Oncology Group
phase III trial comparing aminoglutethimide to tamoxifen. Cancer
73:354-361, 1994
8. Muss HB, Case DL, Atkins JN, et al: Tamoxifen versus high-dose
oral medroxyprogesterone acetate as initial endocrine therapy for
patients with metastatic breast cancer: A Piedmont Oncology Association study. J Clin Oncol 12:1630-1638, 1994
9. Buzdar A, Jonat W, Howell A, et al: Anastrozole, a potent and
selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: Results of overview analysis of two phase III trials. J Clin Oncol 14:2000-2011,
1996
10. Dombernowsky P, Smith I, Falkson G, et al: Letrozole, a new
oral aromatase inhibitor for advanced breast cancer: Double-blind
randomized trial showing a dose effect and improved efficacy and
tolerability compared with megestrol acetate. J Clin Oncol 16:453-461,
1998
11. Gershanovich M, Chaudri HA, Campos D, et al: Letrozole, a
new oral aromatase inhibitor: Randomised trial comparing 2.5 mg
daily, 0.5 mg daily and aminoglutethimide in postmenopausal women
with advanced breast cancer. Ann Oncol 9:639-645, 1998
12. Kaufmann M, Bajetta E, Dirix LY, et al: Exemestane is superior
to megestrol acetate after tamoxifen failure in postmenopausal women
with advanced breast cancer: Results of a phase III randomized
double-blind trial. J Clin Oncol 18:1399-1411, 2000
13. Hamilton A, Piccart M: The third-generation non-steroidal
aromatase inhibitors: A review of their clinical benefits in the secondline hormonal treatment of advanced breast cancer. Ann Oncol 10:377384, 1999
14. Nabholtz A, Buzdar A, Pollak M, et al: Anastrozole is superior

to tamoxifen as first-line therapy for advanced breast cancer in
postmenopausal women: Results of a North American multicenter
randomized trial. J Clin Oncol 18:3758-3767, 2000
15. Bonneterre J, Thurlimann B, Robertson JFR, et al: Anastrozole
versus tamoxifen as first-line therapy for advanced breast cancer in 668
postmenopausal women: Results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol 18:37483757, 2000
16. Nabholtz JM, Bonneterre J, Buzdar AU, et al: Preliminary
results of two multicenter trials comparing the efficacy and tolerability
of Arimidex (anastrozole) and tamoxifen (TAM) in postmenopausal
(PM) women with advanced breast cancer (ABC). Breast Cancer Res
Treat 57:A27, 1999 (abstr)
17. Dowsett M, Pfister C, Johnston SRD, et al: Impact of tamoxifen
on the pharmacokinetics and endocrine effects of the aromatase
inhibitor letrozole in postmenopausal women with breast cancer. Clin
Cancer Res 5:2338-2343, 1999
18. UICCManual of Adult and Pediatric Medical Oncology, in
Monfardini S, Brunner K, Crowther D, et al (eds): Evaluation of the
Cancer Patient and the Response to Treatment. Berlin, Germany,
Springer, 1987, pp 22-38
19. Mouridsen H, Perez-Carrion R, Becquart D, et al: Letrozole
(Femara) versus tamoxifen: Preliminary data of a first-line clinical trial
in postmenopausal women with locally advanced or metastatic breast
cancer. Eur J Cancer 36:S88, 2000 (suppl 5, abstr 220)
20. Paridaens R, Dirix L, Beex L, et al: Exemestane (Aromasin) is
active and well tolerated as first-line hormonal therapy (HT) of
metastatic breast cancer (BC) patients (Pts): Results of a randomized
phase II trial. J Clin Oncol 19:83a, 2000 (abstr 316)
21. Ellmen J, Hakulinen P, Edwards M, et al: Hormonal effects of
three toremifene (Fareston) doses in postmenopausal women with
breast cancer. J Clin Oncol 19:102a, 2000 (abstr 395)
22. Ingle JN, Twito ID, Schaid DJ, et al: Randomized clinical trial
of tamoxifen alone or combined with fluoxymesterone in postmenopausal women with metastatic breast cancer. J Clin Oncol 6:825-831,
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24. Miller WR: Biology of aromatase inhibitors: Pharmacology/
endocrinology within the breast. Endocr Relat Cancer 6:187-195,
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25. Bhatnagar AS, Miller WR: Pharmacology of inhibitors of
estrogen synthesis, in Oettel M, Schillinger E (Eds), Handbook of
Experimental Pharmacology, Vol. 135/II: Estrogens and Antiestrogens
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II, Pharmacology and Clinical Application of Estrogens and Antiestrogens. Berlin, Germany, Springer Verlag, 1999, pp 223-230
26. Long BJ, Tilghman SL, Yue W, et al: The steroidal antiestrogen
ICI 182,780 is an inhibitor of cellular aromatase activity. J Steroid
Biochem Molec Biol 67:293-304, 1998
27. Bhatnagar AS, Hausler A, Schieweck K, et al: Oestrogen
depletion in advanced breast cancer: Why, how and where are we
going?, in Advanced Breast Cancer: Reassessing Hormonal Therapy.
Ciba Int Symp Ser 2:21-30, 1996
28. Lu Q, Yue W, Wang J, et al: The effects of aromatase inhibitors

and antiestrogens in the nude mouse model. Breast Cancer Res Treat
50:63-71, 1998
29. Lu Q, Liu Y, Long BJ, et al: The effect of combining aromatase
inhibitors with antiestrogens on tumor growth in a nude mouse model
for breast cancer. Breast Cancer Res Treat 57:183-192, 1999
30. Brodie A, Lu Q, Liu Y, et al: Aromatase inhibitors and their
antitumor effects in model systems. Endocr Relat Cancer 6:205-210,
1999
CORRESPONDENCE
Meningeal Carcinomatosis From Breast Carcinoma

Responsive to Trastuzumab
To the Editor: A recent letter in the Journal of Clinical Oncology
reported simultaneously measured CSF and serum levels of trastuzumab in a breast cancer patient with meningeal carcinomatosis (MC)
in whom the levels of trastuzumab in the CSF were 300 times lower
than they were in serum.1 The letter therefore suggested that trastuzumab is unlikely to be useful in the treatment of MC from breast
cancer because of its poor CSF penetration.
We report the case of a 38-year-old woman with breast cancer,
brain metastases, and MC who was treated with intravenous
trastuzumab and demonstrated a partial response of her MC, as
shown by follow-up imaging of the brain and spinal cord. She was
diagnosed with infiltrating ductal breast carcinoma in 1998 and
underwent lumpectomy. The tumor was estrogen receptor (ER)
negative, and she was treated adjuvantly with docetaxel, doxorubicin, and cyclophosphamide, followed by radiotherapy to the left
breast. In November 1999, severe headaches developed and magnetic resonance imaging (MRI) of the brain revealed a 2-cm
metastatic tumor in the right temporal lobe that was totally resected
in January 2000. The metastatic lesion was ER- and progesterone
receptornegative but strongly HER-2/neupositive. The patient
was treated with whole-brain radiotherapy to a dose of 30 Gy, which
was completed in April 2000. No additional treatment was administered until July 2000, when at that time low-back pain, leg
weakness and bowel and bladder dysfunction developed. Spine MRI

at that time demonstrated leptomeningeal metastatic deposits. Brain
MRI also showed leptomeningeal seeding in the posterior fossa.
Lumbar puncture revealed malignant cells. The patient was then
treated with radiotherapy to the lumbosacral spine. In August 2000,
treatment with intravenous trastuzumab (2 mg/kg, given weekly)
was begun. Repeat MRI of the brain and spine, after four and five
trastuzumab treatments, respectively, showed marked abatement in
the leptomeningeal deposits in the posterior fossa and in the thoracic
and lumbar regions (Fig 1). The patient received intravenous
steroids during and after radiotherapy, and before her first three
doses of trastuzumab. No other treatment was given that might have
contributed to this patients response. Clinically, the patient remained in stable condition, being paraplegic with lack of bowel and
bladder control. At that time, treatment with intrathecal cytarabine
was added, but progression of the MC was detected 6 weeks later.
The patient subsequently failed to respond to an experimental
intrathecal agent and is now being treated with high-dose systemic
chemotherapy for her MC.
This patients case demonstrates a possible response of MC from
breast carcinoma to intravenous trastuzumab, despite its poor penetration into the CSF. The effect of steroids on the blood-brain barrier
confounds the interpretation of this response, but the MRI changes seen
suggest an effect beyond that of steroids alone. Whether patients such
as ours might derive greater benefit from early combination treatment
Fig 1. (A, B, C, D) Postcontrast images of the brain and spine before treatment show leptomeningeal metastases (white arrows). (E, F, G, H) Postcontrast
images of the brain and spine after treatment reveal significant abatement in leptomeningeal metastases (white arrows).
Journal of Clinical Oncology, Vol 19, No 13 (July 1), 2001: pp 3297-3302
3297
3298
CORRESPONDENCE
consisting of chemotherapy or radiotherapy with trastuzumab or

whether intrathecal trastuzumab might be of benefit in this setting
requires further investigation.
Randi H. Baculi
Samer Suki
John Nisbett
Norman Leeds
Morris Groves
The University of Texas M.D. Anderson Cancer Center
Houston Cancer Clinics
Houston, TX
REFERENCE
1. Pestalozzi BC, Brignoli S: Trastuzumab in CSF. J Clin Oncol
18:2350-2351, 2000 (letter)
In Reply: Baculi et al describe a case of meningeal carcinomatosis
(MC) owing to metastatic breast cancer treated with radiotherapy to the
lumbosacral spine and with intravenous trastuzumab. Interestingly, this
patient had previously received the combination of docetaxel with an
anthracycline, which has been shown to be associated with a high
incidence (30%) of CNS metastases.1 Given the marked abatement in
the leptomeningeal deposits in the posterior fossa and in the thoracic
and lumbar regions, the authors claim that this case demonstrates a
response of MC to intravenous trastuzumab. This statement deserves
some comment. First, response criteria in leptomeningeal metastasis
are not standardized. Most studies define complete response as the
normalization of CSF and improvement of clinical symptoms. In this
case there was no clinical improvement: the patient remained paraplegic with a lack of bowel and bladder control. Although later in the
course intrathecal cytarabine was given, the authors do not report on
CSF findings at that time. Were there still malignant cells? At what cell
count? Second, the radiologic response to single-agent intravenous
trastuzumab was found after only 3 weekly treatments, which is much
earlier than the usual 8 to 12 weeks used for reassessment in
trastuzumab trials.2 At that time intrathecal cytarabine was added and
(presumably) intravenous trastuzumab was continued. Progression of
MC was noted 6 weeks later. Therefore, this response to trastuzumab
was a very transient improvement limited to radiologic findings. Third,
although not mentioned by the authors, it is likely that this patient was
given corticosteroids after the diagnosis of MC. Could they have
contributed to the radiologic improvement?
It is well known that the intact blood-brain barrier limits CNS
penetration to molecules with molecular weights up to 200 da.
Nevertheless, some cytotoxic agents of larger size have shown efficacy
against CNS tumors, presumably because the latter disrupt the bloodbrain barrier. In conclusion, it is not impossible that large molecules
like trastuzumab (molecular weight: 145,000 da) might have efficacy in
CNS metastases, although this has not been demonstrated very convincingly in this case.
Bernhard C. Pestalozzi
University Hospital
Zurich, Switzerland
REFERENCES
1. Crivellari D, Pagani O, Veronesi A, et al: High incidence of
central nervous system involvement in patients with metastatic or
locally advanced breast cancer treated with epirubicin and docetaxel.

Ann Oncol 12:353-356, 2001
2. Slamon D, Leyland-Jones B, Shak S, et al: Use of chemotherapy
plus a monoclonal antibody against HER2 for metastatic breast cancer
that overexpresses HER2. N Engl J Med 344:783-792, 2001
Early-Stage Hodgkins Disease: To Mantle or Not

to Mantle?
To the Editor: I read with interest the recent article by Backstrand
et al1 in the February 1, 2001, issue of the Journal of Clinical
Oncology. In this single-arm prospective study of 87 selected
patients with early-stage (pathologic stage IA to IIA and clinical
stage IA), favorable Hodgkins disease, the authors sought to
evaluate the efficacy of mantle irradiation alone. They reported that
mantle irradiation alone in selected patients with pathologic confirmation of absence of disease below the diaphragm and in patients
with low risk of occult disease in the abdomen resulted in disease
control rates comparable to those with extended-field irradiation.
Therefore, they concluded, those patients can be spared chemotherapy-induced toxicity and thereby benefit from a higher probability
of successful salvage if a relapse were to occur.
I do not agree with their conclusion for two reasons. First, even
if there is evidence that, after staging laparotomy, mantle irradiation
alone could be a sufficient treatment in terms of local control or
survival,2 there is also evidence that without staging laparotomy,
even in selected patients with very favorable disease (women
younger than 40 years with clinical stage IA and elevated sedimentation rates 50 mm with lymphocyte-predominant or nodular
sclerosis histology) treated with mantle irradiation alone, relapse is
still considered an important problem. The April 1997 update of the
European Organization of Research and Treatment of Cancer
(EORTC) H7-VF and H8-VF trials revealed a 32% relapse rate with
a 97% survival rate at 6 years thanks to the efficacy of salvage
treatments.3,4 Several reports have documented the increased risk of
second malignancy following salvage treatment; therefore, it is
important to minimize any recurrence of Hodgkins disease. 5,6 In
the beginning of the millennium, staging laparotomy is no longer
justified given its morbidity, despite the progress in surgery.7 In the
article by Backstrand et al,1 only 7% of the patients were clinically
staged, and no information was given in terms of sex distribution,
which is also an important prognostic factor.8
Second, even if we accept the efficacy of mantle irradiation alone
in early-stage, nonlaparotomized Hodgkins disease, we do not
know if the therapeutic index of mantle alone is better or worse than
a combination of anthracycline-based chemotherapy and involvedfield radiation therapy. In terms of disease control, it is hoped that
this issue will be resolved by the ongoing EORTC H9 (20982)
randomized phase III trial to assess the role of adjuvant involvedfield radiation (0 v 20 v 36 Gy) in favorable patients (including the
above-mentioned very favorable patients) with a complete response
after chemotherapy. In terms of morbidity, anthracycline-based
chemotherapy alone or combined with involved-field radiation
therapy should, theoretically, induce fewer second cancers than
mantle irradiation alone, especially for very favorable patients for
whom involved-field irradiation includes relatively smaller normaltissue volumes than mantle irradiation does.9-12 Moreover, mantle
irradiationinduced breast cancer is reported to be biologically more
3299
CORRESPONDENCE
aggressive and results in worse overall survival compared with the
matched control population.13
Mahmut Ozsahin
Centre Hospitalier Universitaire Vaudois
Lausanne, Switzerland
REFERENCES
1. Backstrand KH, Ng AK, Takvorian RW, et al: Results of a
prospective trial of mantle irradiation alone for selected patients with
early-stage Hodgkins disease. J Clin Oncol 19:736-741, 2001
2. Tubiana M, Henry-Amar M, Carde P, et al: Toward comprehensive management tailored to prognostic factors of patients with clinical
stages of I and II in Hodgkins disease: The EORTC Lymphoma Group
controlled clinical trials1964-1987. Blood 73:47-56, 1989
3. Noordijk EM, Carde P, Hagenbeek A, et al: Combination of
radiotherapy is advisable in all patients with clinical stage I-II
Hodgkins disease: Six-year results of EORTC-GPMC controlled
clinical trials H7-VF, H7-F and H7-U. Int J Radiat Oncol Biol Phys
39:173, 1997 (suppl, abstr)
4. Cosset JM, Ferme C, Henry-Amar M, et al: Le role de la
radiotherapie dans les formes localisees de maladie de Hodgkin en
1999: Limitations et perspectives. Cancer Radiother 3:112-118, 1999
5. Doria R, Holford T, Farber L, et al: Second solid malignancies
after combined modality therapy for Hodgkins disease. J Clin Oncol
13:2016-2022, 1995
6. Donaldson SS, Hancock SL, Hoppe RT: Hodgkins disease:
Finding the balance between cure and late effects. Cancer J Sci Am
5:325-333, 1999
7. Carde P, Hagenbeek A, Hayat M, et al: Clinical staging versus
laparotomy and combined with MOPP versus ABVD in early-stage
Hodgkins disease: The H6 twin randomized trials from the European
Organization for Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol 11:2258-2272, 1993
8. Cosset JM, Henry-Amar M, Meerwaldt JH, et al: The EORTC
trials for limited stage Hodgkins disease: The EORTC Lymphoma
Cooperative Group. Eur J Cancer 28A:1847-1850, 1992
9. van Leeuwen FE, Klokman WJ, Hagenbeek A, et al: Second
cancer risk following Hodgkins disease: A 20-year follow-up study.
J Clin Oncol 12:312-325, 1994
10. Bhatia S, Robinson LL, Oberlin O, et al: Breast cancer and other
second neoplasms after childhood Hodgkins disease. N Engl J Med
334:745-751, 1996
11. Aisenberg AC, Finkelstein DM, Doppke KP, et al: High risk of
breast carcinoma after irradiation of young women with Hodgkins
disease. Cancer 79:1203-1210, 1997
12. Swerdlow AJ, Barber JA, Vaughan-Hudson G, et al: Risk of
second malignancy after Hodgkins disease in a collaborative British
cohort: The relation to age at treatment. J Clin Oncol 18:498-509, 2000
13. Gaffney DK, Hemmersmeier J, Holden J, et al: Breast cancer
after mantle irradiation for Hodgkins disease: Correlation of
clinical, pathologic, and molecular features including loss of heterozygosity at BRCA1 and BRCA2. Int J Radiat Oncol Biol Phys
49:539-546, 2001
Angiogenesis in Cancer
To the Editor: Two stimulating reviews1,2 on angiogenesis in cancer
were published in the February 15, 2001, issue of the Journal of
Clinical Oncology, which we read with great interest. Miller et al1

pointed out that microvessel density returned to normal after remission
in acute myeloid leukemia and myeloma. In multiple myeloma we
reported for the first time that a significant decrease in the microvessel
density occurred in patients who achieved a complete or partial
remission after chemotherapy in comparison to their pretreatment
values (P .01).3,4 On the contrary, in patients who did not achieve a
remission, no significant change in the bone marrow microvessel
density could be detected. In the article cited by Miller et al, a
significant difference in bone marrow angiogenesis was found in
patients with active versus nonactive myeloma, but this was a comparison of two different patient groups.5
Poon et al2 concluded in the abstract of their review that circulating
vascular endothelial growth factor (VEGF) levels were a reliable
surrogate marker of angiogenic activity in cancer patients, but this
conclusion seems premature before a correlation between tumor angiogenesis and circulating VEGF levels has been shown for a variety of
malignant tumors. Although the number of publications on tumor
angiogenesis or circulating VEGF levels is comparatively high, studies
showing a correlation between circulating VEGF levels and tumor
angiogenesis are extremely rare. Furthermore, in some of these studies
a significant difference in dichotomized groups was shown but not a
correlation on an individual level. The clinical value of microvessel
density has been established, for example, in breast cancer.6,7 VEGF is
known to be released by several types of blood cells. Circulating VEGF
was shown not to be correlated with microvessel density or VEGF
expression in breast cancer in recent studies.8,9 In another report, tumor
vascularity was correlated directly with VEGF production by the
tumor, but once again no correlation was found either between the
number of vessels in the tumor or the production of VEGF by tumor
cells and the level of serum VEGF.10 In the study11 that was cited by
Poon et al as having shown a positive correlation between serum VEGF
levels and tumor VEGF expression in breast cancer, only 19% of
patients with VEGF expression in the tumor tissue had elevated VEGF
serum levels, so that the sensitivity of the serum VEGF in this study
seems to be too low for calling it a reliable marker. To give another
example among malignant diseases, in multiple myeloma we were
unable to find a correlation between serum VEGF levels12 and bone
marrow microvessel density, which has been shown to be a prognostic
factor for survival.13 Thus prognostic significance of circulating VEGF
in cancer patients as reviewed by Poon et al does not necessarily mean
that circulating VEGF level is a good reflection of tumor angiogenic
activity. This issue may be important in the context of future
antiangiogenic treatment strategies that should be aimed against tumor
angiogenesis rather than circulating VEGF levels.
Orhan Sezer
Christian Jakob
Kathrin Niemoller
Universitatsklinikum Charite
Berlin, Germany
REFERENCES
1. Miller KD, Sweeney CJ, Sledge GW: Redefining the Target:
Chemotherapeutics as antiangiogenics. J Clin Oncol 19:1195-1206,
2001
2. Poon RT, Fan ST, Wong J: Clinical implications of circulating
angiogenic factors in cancer patients. J Clin Oncol 19:1207-1225, 2001
3. Sezer O, Niemoller K, Schweigert M, et al: Bone marrow
microvessel density is a prognostic factor for survival in multiple
3300
myeloma and a significant decrease in microvessel density occurs in
patients who achieve a remission after chemotherapy. Blood 96:363a,
2000 (abstr, suppl)
4. Sezer O, Niemoller K, Kaufmann O, et al: Decrease of bone
marrow angiogenesis in myeloma patients achieving a remission after
chemotherapy. Eur J Haematol 66:238-244, 2001
5. Vacca A, Ribatti D, Presta M, et al: Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma. Blood
93:3064-3073, 1999
6. Weidner N, Semple JP, Welch WR, et al: Tumor angiogenesis
and metastasis: Correlation in invasive breast carcinoma. N Engl J Med
324:1-8, 1991
7. Gasparini G, Harris AL: Clinical importance of the determination
of tumor angiogenesis in breast carcinoma: Much more than a new
prognostic tool. J Clin Oncol 13:765-782, 1995
8. Adams J, Carder PJ, Downey S, et al: Vascular endothelial
growth factor (VEGF) in breast cancer: Comparison of plasma, serum,
and tissue VEGF and microvessel density and effects of tamoxifen.
Cancer Res 60:2898-2905, 2000
9. Byrne GJ, Bundred NJ: Surrogate markers of tumoral angiogenesis. Int J Biol Markers 15:334-339, 2000
10. Balsari A, Maier JA, Colnaghi MI, et al: Correlation between
tumor vascularity, vascular endothelial growth factor production by
tumor cells, serum vascular endothelial growth factor levels, and serum
angiogenic activity in patients with breast carcinoma. Lab Invest
79:897-902, 1999
11. Yamamoto Y, Toi M, Kondo S, et al: Concentrations of vascular
endothelial growth factor in the sera of normal controls and cancer
patients. Clin Cancer Res 2:821-826, 1996
12. Sezer O, Jakob C, Eucker J, et al: Serum levels of the angiogenic
cytokines basic fibroblast growth factor (bFGF), vascular endothelial
growth factor (VEGF) and hepatocyte growth factor (HGF) in multiple
myeloma. Eur J Haematol 66:83-88, 2001
13. Sezer O, Niemoller K, Eucker J, et al: Bone marrow microvessel
density is a prognostic factor for survival in patients with multiple
myeloma. Ann Hematol 79:574-577, 2000
In Reply: We thank Drs Sezer, Jakob, and Niemoller for their
comments. We agree that circulating VEGF level may not reflect tumor
microvessel density. However, there is quite compelling evidence that
circulating VEGF level is of prognostic significance in cancer patients.
In our review article, we included 32 studies published up to July 2000
that demonstrated a positive correlation between circulating VEGF
level and tumor stage or prognosis.1 At least six additional studies
published subsequent to our review have demonstrated the prognostic
value of circulating VEGF level in cancer patients.2-7 Sezer et al have
also reported that serum VEGF level increased with more advanced
stage of multiple myeloma, and that tumor response to chemotherapy
was associated with a decrease in the serum VEGF level.8 The most
important biologic effect of VEGF known so far is its angiogenic
effect, and it has been demonstrated to contribute to tumor angiogenesis
in almost every type of cancer. Hence we conclude that circulating
VEGF seems to be a reliable surrogate marker of angiogenic activity
and tumor progression in cancer patients. We have indicated in the
text that the source and biologic significance of circulating VEGF
remains uncertain, and it is not yet clear whether the circulating VEGF
is derived mainly from tumor secretion of VEGF. We have been
cautious in not being assertive in our conclusion.
We use the term angiogenic activity in a broader sense than do Sezer
et al. Tumor microvessel density has been demonstrated to be of
CORRESPONDENCE
prognostic value in many cancers and thus has been widely used as an
index of tumor angiogenesis. It is one but not the only one indicator of
tumor angiogenic activity. The widespread clinical use of microvessel
density has so far been hindered by the difficulty in obtaining objective
measurement, which may partly explain why some studies failed to
demonstrate its prognostic significance. For example, as opposed to the
finding of Sezer et al, a recent study demonstrated no prognostic
influence of bone marrow microvessel density in multiple myeloma
patients.9 Tumor expression of angiogenic factors is another measure of
angiogenic activity. In fact, some studies have demonstrated that tumor
expression of VEGF was not correlated with tumor microvessel
density, and the former but not the latter was prognostic of outcome in
cancer patients.10,11 The main issue regarding circulating VEGF is not
whether it is correlated with tumor microvessel density but whether it
reflects tumor expression of VEGF. Thus far the evidence for this is
limited and controversial. Some studies demonstrated a correlation
between serum VEGF and tumor expression of VEGF,12,13 whereas
other did not show a significant correlation.14,15 However, these studies
used immunohistochemical staining for evaluating tumor expression of
VEGF, which is a semiquantitative method. It is important to have a
direct quantitative correlation between circulating VEGF and tumor
expression of VEGF. We are currently conducting a study of quantitative evaluation of tumor expression of VEGF mRNA by quantitative
polymerase chain reaction and serum VEGF level by enzyme-linked
immunosorbent assay in hepatocellular carcinoma patients, and we
hope that such a study will provide a better clue to the relationship
between tumor VEGF expression and circulating VEGF.
The relationship between circulating VEGF level and tumor
angiogenesis may be more complicated than a simple linear correlation. As pointed out in our article, tumor angiogenesis is the
overall result of balanced activity of several angiogenic and antiangiogenic factors, and thus it may be necessary to evaluate multiple
factors in the circulation to provide a true reflection of tumor
angiogenic activity. Of course, it is possible that circulating VEGF
may have other unknown biologic significance that explains its
prognostic value. Rather than providing a definite conclusion, our
review article summarized the current findings related to circulating
angiogenic factors in cancer patients with the aim of providing
insights into future directions of research in this area.
Ronnie T.P. Poon
Sheung-Tat Fan
John Wong
University of Hong Kong Medical Center
Hong Kong, China
REFERENCES
1. Poon RT, Fan ST, Wong J: Clinical implications of circulating
angiogenic factors in cancer patients. J Clin Oncol 19:1195-1206, 2001
2. Chin KF, Greenman J, Gardiner E, et al: Pre-operative serum
vascular endothelial growth factor can select patients for adjuvant
treatment after curative resection in colorectal cancer. Br J Cancer
83:1425-1431, 2000
3. Werther K, Christensen IJ, Brunner N, et al: Soluble vascular
endothelial growth factor levels in patients with primary colorectal
carcinoma: The Danish RANX05 Colorectal Cancer Study Group. Eur
J Surg Oncol 26:657-662, 2000
4. Salven P, Orpana A, Teerenhovi L, et al: Simultaneous elevation
in the serum concentrations of the angiogenic growth factors VEGF
and bFGF is an independent predictor of poor prognosis in non-
3301
CORRESPONDENCE
Hodgkin lymphoma: A single-institution study of 200 patients. Blood
96:3712-3718, 2000
5. Tabone MD, Landman-Parker J, et al: Are basic fibroblast growth
factor and vascular endothelial growth factor prognostic indicators in
pediatric patients with malignant solid tumors? Clin Cancer Res
7:538-543, 2001
6. Broll R, Erdmann H, Duchrow M, et al: Vascular endothelial
growth factor (VEGF): A valuable serum tumour marker in patients
with colorectal cancer? Eur J Surg Oncol 27:37-42, 2001
7. Ugurel S, Rappl G, Tilgen W, et al: Increased serum concentration of angiogenic factors in malignant melanoma patients correlates
with tumor progression and survival. J Clin Oncol 19:577-583, 2001
8. Sezer O, Jakob C, Eucker J, et al: Serum levels of the angiogenic
cytokines basic fibroblast growth factor (bFGF), vascular endothelial
growth factor (VEGF) and hepatocyte growth factor (HGF) in multiple
myeloma. Eur J Haematol 66:83-88, 2001
9. Ahn MJ, Park CK, Choi JH, et al: Clinical significance of
microvessel density in multiple myeloma patients. J Korean Med Sci
16:45-50, 2001
10. Shen GH, Ghazizadeh M, Kawanami O, et al: Prognostic
significance of vascular endothelial growth factor expression in human
ovarian carcinoma. Br J Cancer 83:196-203, 2000
11. Konno H, Baba M, Tanaka T, et al: Overexpression of vascular
endothelial growth factor is responsible for the hematogenous recurrence of early-stage gastric carcinoma. Eur Surg Res 32:177-181, 2000
12. Li XM, Tang ZY, Qin LX, et al: Serum vascular endothelial
growth factor is a predictor of metastasis in hepatocellular carcinoma.
J Exp Clin Cancer Res 18:511-517, 1999
13. Cascinu S, Del Ferro E, Ligi M, et al: Inhibition of vascular
endothelial growth factor by octreotide in colorectal cancer patients.
Cancer Invest 19:8-12, 2001
14. Balsari A, Maier JA, Colnaghi MI, et al: Correlation between
tumor vascularity, vascular endothelial growth factor production by
tumor cells, serum vascular endothelial growth factor levels, and serum
angiogenic activity in patients with breast carcinoma. Lab Invest
79:897-902, 1999
15. Adams J, Carder PJ, Downey S, et al: Vascular endothelial
growth factor (VEGF) in breast cancer: Comparison of plasma, serum,
and tissue VEGF and microvessel density and effects of tamoxifen.
Cancer Res 60:2898-2905, 2000
Discussing Do-Not-Resuscitate Status: Furthering

the Discourse
To the Editor: We read with great interest von Guntens article
addressing the art of do-not-resuscitate discussions.1 von Guntens
discourse nicely illustrates the essential elements of a successful
discussion on resuscitation status. By successful, we would mean a
discussion that adequately conveys pertinent medical information to the
patient and/or family, provides realistic expectations and goals of care,
and allows enough time for the patient or family to assimilate this
information so as to make a cogent end-of-life decision. von Gunten
has put in concrete terms those factors that facilitate a discussion;
namely, an appropriate setting, empathy from the physician, asking
open-ended questions, determining patient understanding, and providing sufficient information in a caring manner. This is an excellent
model for instructing physicians-in-training in the art of end-of-life
discussions.
There are additional complexities involved that should be discussed.
von Gunten touches briefly on the issue of patients who persist in their
request for resuscitation despite appropriate discussion as outlined in

his article. Resuscitation is not a suitable option for all patients, and if
not, is it proper to discuss this procedure for patients in whom it is not
indicated? Patients with acute, reversible medical conditions should
have the prerogative of resuscitation. Patients dying of progressive
malignancies for whom there is no expectation of benefit should not be
subject to futile procedures. These patients will not achieve significant
survival benefit from cardiopulmonary resuscitation.2 Physicians are
forced to violate the principle of Do No Harm and their own
conscience when patients are unrelenting in their requests for resuscitation despite its futility. Certainly, dying and end-of-life decisions
should be discussed in these situations, but should resuscitation be
offered?3
There are cultural differences that alter end-of-life discussions.
African-American physicians and patients are more likely than Caucasians to request artificial feeding, mechanical ventilation, or cardiopulmonary resuscitation if the patient is in a persistent vegetative state or
is terminally ill.4 The Islamic perspective on do-not-resuscitate orders
has been described and is complex.5 A do-not-resuscitate order is
consistent with the tenets of Islam. The withdrawal of support in the
setting of a persistent vegetative state is less clear, as Islam requires that
no life be taken and does not formally recognize brain death as death.6
von Guntens presentation involved a patient with progressive
malignancy, a situation about which most physicians would agree
resuscitation is not appropriate, and a situation in which the trajectory
of disease is predicted with relative accuracy. Terminally ill patients
whose disease course entails periods of severe exacerbation followed
by plateaus, as occurs in congestive heart failure, have distinctly
different views. Congestive heart failure patients frequently have a
significantly different preference from the treating physicians. Patients
also change their minds regarding resuscitation during stable periods.7
We greatly appreciate von Guntens sensible and empathic approach
to discussions of resuscitation status, but we do wish to point out that
even a sensible, compassionate physician may encounter significant
challenges regarding resuscitation. These challenges often transcend
the physicians ability to engage in a discourse centered on end-of-life
decisions. A different approach will be necessary when faced with
cultural and ethnic differences and nonmalignant terminal illnesses. A
clear policy is necessary to resolve differences centered on medical
futility.
Michael Naughton
Mellar Davis
Cleveland Clinic Foundation
Cleveland, OH
REFERENCES
1. von Gunten CF: Discussing do-not-resuscitate status. J Clin
Oncol 19:1576-1581, 2001
2. Faber-Langendorf K: Resuscitation of patients with metastatic
cancer is transient benefit still futile? Arch Intern Med 151:235-239,
1991
3. Tomilson T, Brody H: Refusing demands for attempted resuscitation: Ethics and hospital policy. JAMA 264:1276-1280, 1990
4. Mebane EW, Oman RF, Kroonen LT, et al: The influence of
physician race, age, and gender on physician attitudes toward advance
care directives and preferences for end-of-life decision-making. J Am
Geriatr Soc 47:579-591, 1999
5. Rehman KL: Cardio-pulmonary resuscitation and life support:
The current laws and the Muslim perspective. JIMA 25:20-22, 1993
3302
CORRESPONDENCE
6. Sarhill N, LeGrand S, Islambouli R, et al: The terminally ill

Muslim: Death and dying from the Muslim perspective. Am J Hosp
Palliat Care (in press)
7. Krumholz HM, Phillips RS, Hamel MB, et al: Resuscitation
preferences among patients with severe congestive heart failure:
Results from the SUPPORT project. Circulation 98:648-655, 1998
In Reply: Drs Naughton and Davis have written approvingly about
the overall approach to discussing do-not-resuscitate (DNR) status that
I presented.1 They accurately describe some of the additional complexities that may arise in the care of some patients.
My goal in writing the article was to describe a basic structure for
the clinical conversation about DNR status. I intended it for
beginners or those who feel in need of help with the common
challenges encountered in practice. Too many clinicians know all
about DNR but have no practical guidance to develop the necessary
clinical skills. I was anxious not to obscure the usual and ordinary
with the unusual and extraordinary. Neither did I want to present so

many exceptions and complications that the novice would feel
discouraged.
Consequently, I appreciate the discussion of complexities and
exceptions presented by these thoughtful expert clinicians. As for so
many aspects of oncology, complexities and exceptions require
additional knowledge and expertise. Naughton and Davis describe
excellent insights for clinicians who have mastered the basics.
Charles F. von Gunten
Center for Palliative Studies
San Diego, CA
REFERENCE
1. von Gunten CF: Discussing do-not-resuscitate status. J Clin
Oncol 19:1576-1581, 2001
ERRATUM
In the Rapid Publication by Mouridsen et al that appeared in the May 15, 2001, issue entitled Superior Efficacy of
Letrozole Versus Tamoxifen as First-Line Therapy for Postmenopausal Women With Advanced Breast Cancer: Results of
a Phase III Study of the International Letrozole Breast Cancer Group (J Clin Oncol 19:2596-2606, 2001), the locations for
the independent consultant and Novartis Pharma AG given in the footnote section were incorrect. The correct locations are
as follows: Independent Consultant, Milan, Italy; Novartis Pharma AG, Basel, Switzerland.
The publisher regrets this error.

JCO 2001 Mouridsen 2596 606

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RAPID PUBLICATION

Results: TTP was significantly longer for letrozole than

NITIAL PALLIATIVE treatment for postmenopausal

slowing tumor growth. Tamoxifen, the current agent of

From the Rigshospitalet, Copenhagen, Denmark; Petrov Research

Journal of Clinical Oncology, Vol 19, No 10 (May 15), 2001: pp 2596-2606

SUPERIOR EFFICACY OF LETROZOLE

of anastrozole, but in the larger, mainly European study,

compliance was monitored by tablet count at each patient visit. All

than one third of the liver defined by sonogram and/or computed

Clinical and Radiologic Assessments

Primary Efficacy Assessments

Secondary Efficacy Assessments

SUPERIOR EFFICACY OF LETROZOLE

A total of 939 postmenopausal women with advanced

are not reported here. Two patients (one letrozole, one

Patient Demographics and Baseline Characteristics

*Two patients, ER unknown/PgR negative; one patient, ER negative/PgR negative.

Table 2). Letrozole was superior to tamoxifen in TTF (P

SUPERIOR EFFICACY OF LETROZOLE

Results: End Point

*Calculated from date of randomization.

analysis indicated that the covariates that influenced overall

TTP: Multivariate Analysis (key baseline covariates)

Objective Tumor Response: Multivariate Analysis

discontinuations for adverse events were associated with

This is the largest single study to date conducted with an

TTP: Detailed Stratified Analysis (key baseline covariates)

Prior adjuvant antiestrogen therapy

SUPERIOR EFFICACY OF LETROZOLE

Objective Tumor Response: Detailed Stratified Analysis (key baseline covariates)

Prior adjuvant antiestrogen therapy

end points TTF, ORR, and rate of clinical benefit, with a

Most frequent adverse events ( 10%)

Abbreviation: NOS, not otherwise specified.

The safety and tolerability of the two drugs were quite

comment and that is of importance for the future use of

Preclinical data in vitro and in vivo comparing letrozole

SUPERIOR EFFICACY OF LETROZOLE

14. Nabholtz A, Buzdar A, Pollak M, et al: Anastrozole is superior

28. Lu Q, Yue W, Wang J, et al: The effects of aromatase inhibitors

Meningeal Carcinomatosis From Breast Carcinoma

weakness and bowel and bladder dysfunction developed. Spine MRI

Journal of Clinical Oncology, Vol 19, No 13 (July 1), 2001: pp 3297-3302

consisting of chemotherapy or radiotherapy with trastuzumab or

locally advanced breast cancer treated with epirubicin and docetaxel.

Early-Stage Hodgkins Disease: To Mantle or Not

Clinical Oncology, which we read with great interest. Miller et al1

Discussing Do-Not-Resuscitate Status: Furthering

request for resuscitation despite appropriate discussion as outlined in

6. Sarhill N, LeGrand S, Islambouli R, et al: The terminally ill

with the unusual and extraordinary. Neither did I want to present so

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