Estimating the risks and benefits of tamoxifen for prophylactic breast cancer chemoprevention in Korea.

Abstract

According to the National Surgical Adjuvant Breast and Bowel Project P1 (NSABP-P1) study, tamoxifen can prevent 49% of invasive breast cancers in patients who have a 5-year risk of 1.67% or more. Because tamoxifen is associated with both adverse effects (endometrial cancer, stroke, pulmonary embolism) and protective effect (fracture prevention), it is necessary to weigh the risks and benefits of using tamoxifen for prevention in Korean women. This study weighed those risks and benefits.
Data were reviewed on the incidences of breast cancer, hip fracture, endometrial cancer and stroke in the absence of tamoxifen treatment in Korean women. We also reviewed NSABP-P1 data on the effects of tamoxifen on these outcomes. A risk-benefit index was calculated according to age and specific risk of breast cancer. Sensitivity analyses were performed with assumptions regarding the effects of tamoxifen.
Compared to U.S. women, the numbers of hip fractures and endometrial cancers were lower, but the number of strokes was much higher. The net benefit of tamoxifen was reduced with increasing age because of a high risk of stroke in older women. Older Korean women had more risk than benefit from tamoxifen chemoprevention. Only women younger than age 40 had a positive risk-benefit index with an average 5-year risk of breast cancer in Korea. Sensitivity analysis showed that this result was robust.
Women under the age 40 had more benefit than risk from tamoxifen chemoprevention. Tamoxifen chemoprevention should be limited to Korean women younger than age 40.

Full text

Page 1

© 2012 Korean Breast Cancer Society. All rights reserved.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/
licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
http://ejbc.kr | pISSN 1738-6756
eISSN 2092-9900
INTRODUCTION
According to the National Surgical Adjuvant Breast and Bowel
Project P1 (NSABP-P1) study [1], tamoxifen can prevent 49%
of invasive breast cancer in patients who have a 5-year risk of
1.67% or more. Based on this study, the U.S. Food and Drug
Administration (FDA) approved tamoxifen as a preventive
agent for breast cancer. However, many doctors and patients
are reluctant to take tamoxifen for prevention because of its
life threatening side effects. Tamoxifen increases the risk of
endometrial cancer by 2.53 times, the risk of ischemic stroke by
1.59 times and the risk of pulmonary embolism by 3.01 times
[1]. Tamoxifen also has the beneficial effects of preventing
osteoporosis, and decreasing the risk of hip fracture by 0.55
times [1].
Gail et al. [2] proposed a risk-benefit index to weigh the risks
and benefits of tamoxifen chemoprevention. They showed that
tamoxifen was most beneficial for younger women with an
elevated risk of breast cancer. They also showed that tamoxifen
was not suitable for low-risk older patients.
Korean women have different breast cancer probabilities
compared to Western counties [3]. It is not certain that tamox-
ifen is beneficial to Korean women as a chemopreventive agent.
Therefore, we estimated the risks and benefits of tamoxifen
using a Korean database in order to evaluate the feasibility of
using tamoxifen for chemoprevention in Korean women.
METHODS
Data sources
To calculate a risk-benefit index of preventive tamoxifen, we
used different data sources. For the preventive effects of tamox-
ifen, we could not know the exact chemopreventive effects of
tamoxifen for Korean women because there were no prospec-
tive randomized controlled studies about tamoxifen chemo-
prevention in Korea. Therefore, we assumed that the effect of
Estimating the Risks and Benefits of Tamoxifen for Prophylactic Breast
Cancer Chemoprevention in Korea
Dong Uk Kim, Jun Won Min, You-Me Kim1, Myung-Chul Chang
Departments of Surgery and 1Radiology, Dankook University College of Medicine, Cheonan, Korea
ORIGINAL ARTICLE
J Breast Cancer 2012 March; 15(1): 51-56 http://dx.doi.org/10.4048/jbc.2012.15.1.51
Purpose: According to the National Surgical Adjuvant Breast and
Bowel Project P1 (NSABP-P1) study, tamoxifen can prevent
49% of invasive breast cancers in patients who have a 5-year
risk of 1.67% or more. Because tamoxifen is associated with
both adverse effects (endometrial cancer, stroke, pulmonary em-
bolism) and protective effect (fracture prevention), it is necessary
to weigh the risks and benefits of using tamoxifen for prevention
in Korean women. This study weighed those risks and benefits.
Methods: Data were reviewed on the incidences of breast can-
cer, hip fracture, endometrial cancer and stroke in the absence
of tamoxifen treatment in Korean women. We also reviewed
NSABP-P1 data on the effects of tamoxifen on these outcomes.
A risk-benefit index was calculated according to age and specif-
ic risk of breast cancer. Sensitivity analyses were performed with
assumptions regarding the effects of tamoxifen. Results: Com-
pared to U.S. women, the numbers of hip fractures and endo-
metrial cancers were lower, but the number of strokes was much
higher. The net benefit of tamoxifen was reduced with increasing
age because of a high risk of stroke in older women. Older Korean
women had more risk than benefit from tamoxifen chemopre-
vention. Only women younger than age 40 had a positive risk-
benefit index with an average 5-year risk of breast cancer in Korea.
Sensitivity analysis showed that this result was robust. Conclusion:
Women under the age 40 had more benefit than risk from tamox-
ifen chemoprevention. Tamoxifen chemoprevention should be
limited to Korean women younger than age 40.
Key Words: Breast, Chemoprevention, Tamoxifen
Correspondence: Myung-Chul Chang
Department of Surgery, Dankook University College of Medicine,
119 Dandae-ro, Dongnam-gu, Cheonan 330-714, Korea
Tel: +82-41-550-3930, Fax: +82-41-556-3878
E-mail: changmc@dankook.ac.kr
The present research was conducted by the research fund of Dankook
University in 2009.
Received: September 8, 2011 Accepted: December 7, 2011
Journal of
Breast
Cancer

Page 2

52
? Dong?Uk?Kim,?et?al.
http://ejbc.kr http://dx.doi.org/10.4048/jbc.2012.15.1.51
tamoxifen on Korean women was the same as on U.S. women.
We used the relative risks of breast cancer, hip fracture, endo-
metrial cancer and ischemic stroke from the NSABP-P1 study
[1]. We summarized assumed relative risks with 95% confi-
dence intervals in Table 1.
The incidence rates of hip fracture for Korean women were
obtained from the study [4] that used the Korean National
Health Insurance database. We re-calculated the incidence
rate of female hip fractures according to 10-year age intervals
[4]. There was no data under the age of 50, but a hip fracture
at a young age is a rare event. So we assumed that the incidence
is zero for those under age 50.
The incidence rates of stroke were obtained from another
study [5] that also used the Korean National Health Insurance
database. That study showed the 10-year probability of stroke
per hundred individuals calculated for five-year age intervals.
We re-calculated the incidence rate of female stroke according
to the 10 year age intervals. Among those with cerebrovascular
stroke, tamoxifen increases the incidence of ischemic stroke,
but not hemorrhagic stroke. In the same study [5], the propor-
tion of patients with an ischemic stroke was 58.9% of all females
who had strokes. So we multiplied 0.589 by the incidence of
strokes.
For the incidence rates of endometrial cancer, we used age-
specific endometrial cancer incidence rates from the Korea
Central Cancer Registry data [6].
The overall mortality rates and cause-specific mortality rates
for patients with endometrial cancer and ischemic stroke were
obtained from statistics on cause-specific death from the Korea
National Statistical Office [7]. We searched the web-based
Korea National Statistical Office’s database by the International
Classification of Disease (ICD)-10 diagnostic codes I63 for
ischemic stroke and C54, C55 for endometrial cancer. The mor-
tality rates for hip fracture were obtained from the hip fracture
study [4]. The incidence rates and the mortality rates of hip
fracture, endometrial cancer and ischemic stroke are summa-
rized in Table 2.
Expected number of breast cancer prevented
To calculate the expected number of invasive breast cancer
prevented over a 5-year period, we multiplied the estimated
5-year risk of invasive breast cancer by the relative risk reduced
by tamoxifen. For example, if the 5-year risk of invasive breast
cancer is 1%, it means that 100 breast cancers will occur among
10,000 people over a 5-year period. If they take a tamoxifen
for prevention, 49 breast cancers will be prevented because the
assumed relative risk of breast cancer is 0.51. The 5-year risk
of invasive breast cancer was calculated by the Korean breast
cancer risk assessment tool [3], a web-based breast cancer risk
assessment tool for Korean women. In the tool, the risk factors
for breast cancer (age, family history, body mass index, age of
first delivery, breast feeding history and breast biopsy history)
are entered, and breast cancer risk in the following 5 years and
10 years, and up to ages 64 and 74 years are calculated.
Expected number of non-breast cancer events with and
without tamoxifen
To calculate the expected number of hip fractures, endome-
trial cancers and ischemic strokes, we used Equation 1 which
is the same method as that of Gail et al. [2]. In equation 1, the
hazard rate means the incidence rate multiplied by the relative
risk in Table 1. In tamoxifen untreated people, the relative risk
is one, so the hazard rate is the same as the incidence rate. Mor-
tality rates from other causes were calculated by subtraction of
cause-specific mortality rates from overall mortality rates. In
Table 1. Assumed relative risks from NSABP-P1 study
Type of event Relative risk 95% CI
Breast cancer
Hip fracture
Endometrial cancer
Ischemic stroke
0.51
0.55
2.53
1.59
0.39-0.66
0.25-1.15
1.35-4.97
0.93-2.77
NSABP-P1=National Surgical Adjuvant Breast and Bowel Project P1; CI=
confidence interval.
Table 2. Incidence and mortality rates per 1,000 women-years in Korea
Reference
Age group (yr)
35-3940-49 50-5960-6970-79
Incidence rates
Hip fracture
Endometrial cancer
Ischemic stroke
Mortality rates
Hip fracture
Endometrial cancer
Ischemic stroke
Overall mortality
Kang HY et al. [4]
Korean Central Cancer Registry [6]
Jee SH et al. [5]
0.00
0.03
0.22
0.00
0.06
0.79
0.12
0.11
2.38
0.66
0.08
5.23
2.45
0.05
7.63
Kang HY et al. [4]
Korean Statistical Information Service [7]
Korean Statistical Information Service [7]
Korean Statistical Information Service [7]
0.00
0.00
0.00
0.75
0.00
0.01
0.01
1.35
0.01
0.02
0.07
2.95
0.06
0.03
0.43
8.09
0.32
0.07
2.33
28.45

Page 3

Tamoxifen?for?Breast?Cancer?Chemoprevention
53
http://dx.doi.org/10.4048/jbc.2012.15.1.51
http://ejbc.kr
Table 3, we summarized the calculated number of hip fractures,
endometrial cancers and ischemic strokes in the tamoxifen
untreated and treated groups. The differences between tamox-
ifen treated and untreated cases also summarized. We compared
these results with the results of Gail et al. [2] for U.S. women.
(Equation 1)
Expected number of non-breast event over 5 years
= hazard rate / (hazard rate + mortality rate from other
causes) × [1 – exp{-5 × (hazard rate + mortality rate
from other causes)}]
Risk-benefit index
To estimate the risks and benefits of tamoxifen chemopre-
vention, we followed the methods of Gail et al. [2]. Life-threat-
ening events related to tamoxifen are invasive breast cancer,
hip fracture, endometrial cancer and stroke. The benefits of
tamoxifen are prevention of both invasive breast cancer and
hip fracture. The risks of tamoxifen are endometrial cancer
and stroke (Figure 1). To summarize the risks and benefits of
tamoxifen in a single number, we defined the risk-benefit index
as follows:
(Equation 2)
Risk-benefit index
= expected number of invasive breast cancer prevented
+ expected number of hip fracture prevented
– expected number of endometrial cancer
– expected number of stroke
As the study of Gail et al. [2] suggested, we assumed that the
magnitude of each event of breast cancer, hip fracture, endo-
metrial cancer and stroke was the same. For example, one case
of endometrial cancer that occurs is equivalent to one case of
breast cancer prevented. If the risk-benefit index is negative, it
shows that tamoxifen has more risk than benefit. For women
with a previous history of hysterectomy, there is no risk of
endometrial cancer. So we calculated this separately for women
with a hysterectomy without adding the risk of endometrial
cancer. We calculated the risk-benefit index for average 5-year
risk of breast cancer according to the study of Kim et al. [3].
Sensitivity analysis
We assumed that the effect of tamoxifen on Koreans was
the same as on the U.S. women and used the relative risks of
breast cancer, hip fracture, endometrial cancer and ischemic
stroke from NSABP-P1. But it was not certain that the effect of
tamoxifen on Korean women was the same as for U.S. women.
So we conducted sensitivity analyses in which we varied our
assumptions regarding the relative risks of breast cancer, hip
fracture, endometrial cancer and ischemic stroke. We calcu-
lated the 5-year risk of breast cancer for specific age groups
when the risk-benefit index was zero, which meant that the
risk and the benefit for tamoxifen was the same. In one-way
sensitivity analysis, each parameter of relative risk of breast
cancer, hip fracture, endometrial cancer and ischemic stroke
was varied separately from the lower limit to the upper limit
of the 95% confidence interval. Then, we conducted sensitivity
analysis including all relative risks in the same way.
RESULTS
Expected number of non-breast cancer events without
tamoxifen chemoprevention
The expected numbers of hip fractures, endometrial cancers
and ischemic strokes were calculated using Equation 1. The
expected numbers of hip fractures and ischemic strokes increased
with age (Table 3). The expected number of endometrial cancers
is highest in the sixth decade of life.
From the results of the study of Gail et al. [2], the expected
numbers of hip fractures per 10,000 in tamoxifen untreated
U.S. white women were 50 for women in their 50s, 116 for
women in their 60s and 339 those in their 70s. For endome-
Table 3. Calculated numbers of non-breast cancer events expected in
5 years among 10,000 tamoxifen untreated and treated Korean women
Age group
35-39 40-4950-5960-6970-79
Tamoxifen untreated
Hip fracture
Endometrial cancer
Ischemic stroke
Tamoxifen treated
Hip fracture
Endometrial cancer
Ischemic stroke
Difference between treated
and untreated
Hip fracture
Endometrial cancer
Ischemic stroke
0.0
1.3
10.9
0.0
3.2
39.1
5.8
5.6
32.5
3.8
253.2
113.7
2.5
351.1 117.4
0.0
3.3
17.4
0.0
8.1
62.0
3.2
14.2
186.0
17.9
9.7
399.5
62.7
6.3
552.1
0.0
2.0
6.4
0.0
4.9
23.0
-2.6
8.6
68.6
-14.6
5.9
146.3
-51.0
3.8
201.1
Figure 1. Weighing the life-threatening risks and benefits of tamoxifen
chemoprevention for Korean women.
Benefits
Breast cancer
Hip fracture
Risks
Endometrial cancer
Stroke
Tamoxifen Chemoprevention

Page 4

54
? Dong?Uk?Kim,?et?al.
http://ejbc.kr http://dx.doi.org/10.4048/jbc.2012.15.1.51
trial cancers, the expected numbers of the same U.S. white
women were 10 for those in their 40s, 40 for those in their 50s,
70 for their 60s and 75 for their 70s. For ischemic strokes, the
expected numbers of the same U.S. white women were 22 for
ages 40-49, 54 for 50-59, 156 for 60-69, and 342 for age 70 and
over. Expected numbers of hip fractures and endometrial can-
cers were lower in Korean women than in U.S. white women,
but the expected number of ischemic strokes was much higher
in Korean women.
Expected number of non-breast cancer events with tamoxifen
chemoprevention
The expected number of hip fractures was decreased by
tamoxifen, but the expected numbers of endometrial cancers
and ischemic strokes were increased by tamoxifen (Table 3). The
number of ischemic strokes dramatically increased with age.
This increase was exaggerated with tamoxifen treatment (Table
3). The magnitude of endometrial cancer was smaller than that
of hip fractures or ischemic strokes induced by tamoxifen.
Risk-benefit index of tamoxifen chemoprevention
The risk-benefit index was calculated using Equation 2. In
Tables 4 and 5, the shaded area shows a positive risk-benefit
index that has more benefits than risks. For the specific 5-year
risk of breast cancer, the net benefit of tamoxifen was reduced
according to increases with age because of the high risk of
stroke in older women. So older Korean women had more
risk than benefit from tamoxifen chemoprevention.
Comparing non-hysterectomy (Table 4) and hysterectomy
(Table 5) women, there was little difference in the risk-benefit
index because the incidence of endometrial cancer was low.
The effect of endometrial cancer is smaller than effects of hip
fracture or ischemic stroke induced by tamoxifen.
According to the study of Kim et al. [3], the average 5-year
risk of breast cancer in Korea was 0.18% for age 35, 0.38% for
age 45, and 0.28% for age 55. At that average risk of breast
cancer, the risk-benefit index was 0.4, -9.3, and -61.0 for ages
35, 45, and 55, respectively. Therefore, only women younger
than age 40 had a positive risk-benefit index for average 5-year
risk of breast cancer.
Sensitivity analysis regarding the effects of tamoxifen
We calculated the 5-year risk of breast cancer at each specific
age group when the risk-benefit index was zero, which meant
that the risk and benefit from tamoxifen was the same. The
numbers were 0.17% for women in their 30s, 0.57% in their
40s, 1.52% in their 50s, 2.81% in their 60s, and 3.14% for women
in their 70s. Sensitivity analysis regarding the 95% confidence
interval of breast cancer relative risk as parameters, the point
was converged as the age decreased. Sensitivity analyses regard-
Table 4. Without history of hysterectomy, risk-benefit indices for tamoxi-
fen chemoprevention by level of 5-year risk of breast cancer and age
group among 10,000 Korean women
5-yr risk (%) 35-3940-49 50-5960-6970-79
0.05
0.1
0.2
0.3
0.4
0.5
1.0
1.5
2.0
2.5
3.0
3.5
-6.0
-3.5
1.4
6.3
11.2
16.1
40.6
65.1
89.6
114.1
138.6
163.1
-25.4
-23.0
-18.1
-13.2
-8.3
-3.4
21.1
45.6
70.1
94.6
119.1
143.6
-72.1
-69.7
-64.8
-59.9
-55.0
-50.1
-25.6
-1.1
23.4
47.9
72.4
96.9
-135.1
-132.7
-127.8
-122.9
-118.0
-113.1
-88.6
-64.1
-39.6
-15.1
9.4
33.9
-151.5
-149.0
-144.1
-139.2
-134.3
-129.4
-104.9
-80.4
-55.9
-31.4
-6.9
17.6
Table 5. With history of hysterectomy, risk-benefit indices for tamoxifen
chemoprevention by level of 5-year risk of breast cancer and age group
among 10,000 Korean women
5-yr risk (%)35-3940-4950-5960-6970-79
0.05
0.1
0.2
0.3
0.4
0.5
1.0
1.5
2.0
2.5
3.0
3.5
-4.0
-1.5
3.4
8.3
13.2
18.1
42.6
67.1
91.6
116.1
140.6
165.1
-20.5
-18.1
-13.2
-8.3
-3.4
1.5
26.0
50.5
75.0
99.5
124.0
148.5
-63.5
-61.1
-56.2
-51.3
-46.4
-41.5
-17.0
7.5
32.0
56.5
81.0
105.5
-129.2
-126.8
-121.9
-117.0
-112.1
-107.2
-82.7
-58.2
-33.7
-9.2
15.3
39.8
-147.6
-145.2
-140.3
-135.4
-130.5
-125.6
-101.1
-76.6
-52.1
-27.6
-3.1
21.4
Figure 2. Sensitivity analysis regarding the 95% confidence interval of
relative risk as parameters in the women with and without hysterectomy.
5-yr breast cancer risk (%) at
zero risk-benefit index
Age
35-39 40-49 50-59 60-69 70-79
20.00
15.00
10.00
5.00
0.00
-5.00
Upper limit, without
hysterectomy
Upper limit, with
hysterectomy
Lower limit, without
hysterectomy
Lower limit, with
hysterectomy

Page 5

Tamoxifen?for?Breast?Cancer?Chemoprevention
55
http://dx.doi.org/10.4048/jbc.2012.15.1.51
http://ejbc.kr
ing relative risk of hip fracture, endometrial cancer and isch-
emic stroke showed similar results. Sensitivity analysis that
included all relative risks in the same way, also showed similar
results (Figure 2). It showed that the result of this study regard-
ing women younger than age 40 is robust.
DISCUSSION
Since 1999, tamoxifen has been recommended in the U.S. to
prevent breast cancer. Of 10 million U.S. women, it was esti-
mated that 2.4 million would benefit from taking tamoxifen
for chemoprevention [8]. However, only 0.2% of U.S. women
took tamoxifen for chemoprevention in 2000, and only 0.08%
of U.S. women took tamoxifen for chemoprevention in 2005
[9]. The decline was due to life-threatening effects of tamoxifen:
endometrial cancer, stroke and pulmonary embolism. There-
fore, Gail et al. [2] proposed a risk-benefit index of tamoxifen
chemoprevention. According to that study, women younger
than 50 years old had more benefits than risks. If women had
a hysterectomy, there was no risk of endometrial cancer. There-
fore, women younger than 60 years old had more benefits than
risks.
In Korea, tamoxifen is popular as a therapeutic agent but
not as a preventive agent. The incidence of breast cancer in
Korean women is much lower than in U.S. women. Therefore,
the benefit of tamoxifen for prevention would also be low.
This study showed that only Korean women younger than age
40 had a positive risk-benefit index for average 5-year risk of
breast cancer.
In this study, we used the relative risks of NSABP-P1 for
breast cancer, hip fracture, endometrial cancer and stroke,
assuming that the effect of tamoxifen prevention for Korean
women was the same as for U.S. women. This point is the most
important drawback in this study. In the NSABP-P1 study, Asian
Americans were rarely enrolled and there was no evidence of
tamoxifen chemoprevention in Korea until now. So we agree
on the necessity of doing a tamoxifen chemopreventive trial
for Korean women. This study will be useful to suggest enroll-
ment criteria for a future tamoxifen prevention trial.
Although there is no evidence of tamoxifen preventing breast
cancer in Korean women, some high-risk patients are taking
tamoxifen for preventive purpose. So a presumptive guideline
of preventive tamoxifen is thought to be needed. This study
will be useful to guide the use of preventive tamoxifen.
The relative risk of Korean women can be calculated by large
sized case-control study. It is possible that using tamoxifen for
prevention in Korean women will have different effects than
this study. If the relative risks of Korean women are different
from those of U.S. women, the results of this study will be wrong.
Therefore, we did sensitivity analyses to overcome the uncer-
tainty due to the assumed relative risks. We used the upper
and lower limit of the 95% confidence interval of relative risk
as input variables. It showed wide ranges of variation among
older women, but the range converged for younger women.
For women under age 40, there was little change with variation
in relative risks. So, we thought that the conclusion of this study
regarding women under the age of 40 is reliable.
We did not count pulmonary embolism as a life-threatening
effect. Until now, there has been no data on pulmonary embo-
lism incidence in Korea. There is some hospital based data,
none from the general population. The incidence of pulmo-
nary embolism in Korea is much lower than in the U.S. popu-
lation [10]. Therefore, we assumed that pulmonary embolism
had little effect on the risk of tamoxifen.
Gail et al. [2] divided the effects of tamoxifen into three cat-
egories: life-threatening events, severe events and other events.
Invasive breast cancer, hip fracture, endometrial cancer, stroke
and pulmonary embolism were included in life-threatening
events. They assumed that life-threatening events had the same
magnitude of effect on the risk-benefit index. Strictly speaking,
each event has different mortality and cost. Furthermore the
magnitude of each event is subjective and each woman has dif-
ferent concerns regarding the same event. As they mentioned
[2], no standard index would be particularly appropriate. How-
ever, they found the benefit of tamoxifen was insensitive to the
particular weights used. In particular, breast cancer and endo-
metrial cancer had similar survival rates. So we thought that it
was appropriate to use a risk-benefit index of the same magni-
tude.
Korean women had much higher risk of ischemic stroke
than women in the U.S. The risk of stoke increased with age.
Therefore, older Korean women had more risk than benefit
from tamoxifen chemoprevention. Although this study had
some drawbacks, we found that Korean women under age 40
had more benefit than risk from tamoxifen chemoprevention.
Tamoxifen chemoprevention should be limited to Korean
women younger than age 40.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
REFERENCES
1.?Fisher?B,?Costantino?JP,?Wickerham?DL,?Redmond?CK,?Kavanah?M,?
Cronin?WM,?et?al.?Tamoxifen?for?prevention?of?breast?cancer:?report?of?
the?National?Surgical?Adjuvant?Breast?and?Bowel?Project?P-1?Study.??????????
J?Natl?Cancer?Inst?1998;90:1371-88.