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.
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Fig 1.
Study design.
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
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
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2598
MOURIDSEN ET AL
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
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2599
RESULTS
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MOURIDSEN ET AL
Table 1.
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
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).
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2601
Median
Median
Median
Median
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*
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
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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2602
MOURIDSEN ET AL
Table 4.
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
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
Table 5.
DISCUSSION
Covariate
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.
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2603
Covariate
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.
Table 8.
Adverse Events
Letrozole
(n 455)
Event
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
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2604
MOURIDSEN ET AL
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.
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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.
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2. Santen RJ, Manni A, Harvey H, et al: Endocrine treatment of
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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,
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oral aromatase inhibitor for advanced breast cancer: Double-blind
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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
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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
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2606
MOURIDSEN ET AL
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
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27. Bhatnagar AS, Hausler A, Schieweck K, et al: Oestrogen
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CORRESPONDENCE
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).
3297
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CORRESPONDENCE
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
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
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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
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3300
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13. Sezer O, Niemoller K, Eucker J, et al: Bone marrow microvessel
density is a prognostic factor for survival in patients with multiple
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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
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3301
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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
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14. Balsari A, Maier JA, Colnaghi MI, et al: Correlation between
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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
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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.