D R UG TH ER A PY
Drug Therapy
A L A S T A I R J . J . W O O D , M. D. , Editor
S IDE E FFECTS
OF A DJUVANT
T REATMENT OF B REAST C ANCER
CHARLES L. SHAPIRO, M.D., AND ABRAM RECHT, M.D.
W
OMEN with primary invasive breast cancer
receive both local and systemic treatment.
Surgery and radiation therapy are local
treatments given to reduce the risk of recurrent can-
cer in the breast, chest wall, and regional lymph nodes.
In some cases, these local treatments may prevent the
dissemination of cancer and may reduce mortality
from breast cancer. Cytotoxic chemotherapy and hor-
monal therapy are systemic treatments given after lo-
cal treatment to reduce systemic recurrences and over-
all mortality from breast cancer. Recent guidelines
from the National Institutes of Health Consensus
Conference, the National Comprehensive Cancer
Center Network, and other groups recommend ad-
juvant chemotherapy, tamoxifen, or both for women
with invasive breast tumors greater than 1 cm in di-
ameter, irrespective of whether axillary lymph nodes
are involved.1-3 In this article, we review what is known
about the side effects of adjuvant treatment of pri-
mary invasive breast cancer.
NATURAL HISTORY OF BREAST CANCER
Among women with breast cancer who have pri-
mary tumors less than 2.0 cm in diameter (T1 in the
tumor–node–metastasis [TNM] staging system) or
2.0 to 5.0 cm in diameter (T2) and no axillary-node
metastases (N0), the rates of recurrence-free survival
at 20 years are 74 to 79 percent and 63 to 64 per-
cent, respectively, and most of these long-term survi-
vors are cured (Fig. 1).4-6 Likewise, there are long-term
survivors among women with axillary-node metasta-
ses. In most of the women in these studies, the breast
cancer was not detected by mammographic screen-
ing, and systemic adjuvant therapy was not given. In
more recent studies,7 the rates of long-term survival
among women with invasive breast cancer that was
detected by mammographic screening and treated
with adjuvant therapy have been higher than those
shown in Figure 1.
From the Department of Hematology and Oncology, Arthur G. James
Cancer Hospital and Richard J. Solove Research Institute, Ohio State Uni-
versity, Columbus, Ohio (C.L.S.); and the Department of Radiation On-
cology, Beth Israel Deaconess Medical Center and Harvard Medical
School, Boston (A.R.). Address reprint requests to Dr. Shapiro at Ohio
State University, Arthur G. James Cancer Hospital and Richard J. Solove Re-
search Institute, 320 W. 10th St., Columbus, OH 43210, or at shapiro-1@
medctr.osu.edu.
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100
Primary tumor <2.0 cm
Recurrence-free7
80
Survival (%)
60 Primary tumor 2.0–5.0 cm
40
20
0
0 5 10 15 20
Time (yr)
Figure 1. Rate of Recurrence-free Survival among Women Who
Had Breast Cancer without Involvement of Axillary Nodes.
A total of 852 women had primary tumors that were less than
2.0 cm in diameter, and a total of 674 had tumors that were 2.0 to
5.0 cm in diameter. Data are from Rosen et al.4,5 and Quiet et al.6
BENEFITS OF ADJUVANT TREATMENT
OF BREAST CANCER
The benefits of adjuvant treatment of primary breast
cancer can be estimated from the meta-analyses of
worldwide randomized trials reported by the Early
Breast Cancer Trialists’ Collaborative Group (Table
1).8,9 The benefits of adjuvant chemotherapy are great-
er in women under 50 years of age, the majority of
whom are premenopausal. In contrast, treatment with
tamoxifen appears to benefit women of all ages who
have estrogen-receptor–positive tumors. Adjuvant
chemotherapy and tamoxifen have additive benefits,
and many women with estrogen-receptor–positive tu-
mors receive both treatments.
PROBLEMS IN STUDYING
TREATMENT-RELATED SIDE EFFECTS
There are several problems in identifying and es-
timating the frequency of treatment-related side ef-
fects. Information about side effects is often derived
from retrospective case–control and registry studies
that have been subject to several biases.10 Some treat-
ment-related side effects resemble diseases prevalent
in older women. The effects of radiation or anthra-
cyclines on the heart may be difficult to detect, given
the increasing rates of cardiovascular disease as wom-
en age.11 The most reliable information about side
effects comes from clinical trials conducted decades
ago. However, the treatments in those trials may no
longer be relevant to current practice. For example,
between 1972 and 1981, the alkylating agent mel-
phalan was used in National Surgical Adjuvant Breast
and Bowel Project trials and resulted in an increase by
a factor of 24 in the risk of acute myeloid leukemia.12
Melphalan was subsequently replaced by cyclophos-
phamide, a much less potent leukemogenic drug.
 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

TABLE 1. BENEFITS OF ADJUVANT TREATMENT FOR WOMEN WITH BREAST CANCER.

PROPORTIONAL PROPORTIONAL
REDUCTION IN REDUCTION IN
AGE TREATMENT RECURRENCE* RECURRENCE-FREE SURVIVAL AT 10 YR DEATHS* OVERALL SURVIVAL AT 10 YR
NODE-NEGATIVE NODE-POSITIVE NODE-NEGATIVE NODE-POSITIVE

Without With Without With Without With Without With

Treatment Treatment Treatment Treatment Treatment Treatment Treatment Treatment

percent

<50 Yr Combination 35 58 68 32 48 27 72 78 41 54
chemotherapy†
50–69 Yr Combination 20 60 66 38 43 11 65 71 46 49
chemotherapy†
All ages Tamoxifen‡ 47 64 79 45 60 26 73 79 51 61

*Proportional reductions (percent reductions) were derived from the overview analysis of the Early Breast Cancer Trialists’ Collaborative Group 8,9 and
refer to both the women with node-negative disease and the women with node-positive disease.
†Combination chemotherapy consists of cyclophosphamide, methotrexate, and fluorouracil or a doxorubicin-containing regimen.
‡Tamoxifen is given for five years to women with estrogen-receptor–positive tumors.

ADJUVANT CHEMOTHERAPY and recently completed randomized trials. At this time,

The adjuvant regimens of chemotherapy used in
the United States are shown in Table 2, and the side
effects of these regimens are shown in Table 3.13-18
The most frequently used regimen is doxorubicin and
cyclophosphamide given for three months or cyclo-
phosphamide, methotrexate, and fluorouracil given for
six months. The efficacy of the two regimens is sim-
ilar13,19; they differ in that doxorubicin and cyclophos-
phamide are more likely to cause alopecia and vom-
iting, whereas cyclophosphamide, methotrexate, and
fluorouracil are more likely to cause nausea, myelosup-
pression, and ovarian failure. A meta-analysis of ran-
domized trials of adjuvant chemotherapy showed that
regimens containing doxorubicin were slightly superi-
or to regimens consisting of cyclophosphamide, meth-
otrexate, and fluorouracil.8
Taxanes such as paclitaxel and docetaxel are being
incorporated into adjuvant regimens on the basis of
their antitumor activity in advanced breast cancer and
the absence of cross-resistance with doxorubicin.20,21
Both of these taxanes can cause hypersensitivity reac-
tions, peripheral neuropathy, myalgias, and arthralgias,
and docetaxel can cause fluid accumulation. Glucocor-
ticoids and histamine-receptor antagonists adminis-
tered before the taxane can ameliorate these side ef-
fects. The administration of four cycles of paclitaxel
after doxorubicin and cyclophosphamide was associat-
ed with a statistically significant survival advantage in a
study involving women with node-positive breast can-
cer,17 and the Food and Drug Administration (FDA)
has recently approved paclitaxel for this indication.
Further information on the efficacy and side effects of
taxanes will be available from the results of ongoing
there are insufficient data to recommend the use of
taxanes in women with node-negative breast cancer.1
Myelosuppression
A small-to-moderate reduction in the white-cell
count often occurs 10 to 14 days after each cycle of
adjuvant chemotherapy. In most women, the white-
cell count improves before the next treatment cycle.
The incidences of fever, absolute neutrophil counts
below 500 per cubic millimeter, and life-threatening
infections are 2 percent or less, and no deaths have
been reported. Guidelines for the administration of
hematopoietic growth factors do not support their
routine use to prevent febrile neutropenia or to al-
low an increase in the dose intensity of the chemo-
therapeutic regimen in women with breast cancer who
are receiving adjuvant chemotherapy.22
Nausea and Vomiting
The majority of women with breast cancer treated
with adjuvant chemotherapy have mild or moderate
nausea and vomiting, but these symptoms are severe
in less than 5 percent of women (Table 3). Drugs that
prevent nausea and vomiting include serotonin-recep-
tor antagonists, such as ondansetron, metoclopramide,
glucocorticoids, and phenothiazines; new drugs (e.g.,
an antagonist to substance P) are being developed.23
Lorazepam, a benzodiazepine, is given to reduce anxi-
ety during adjuvant chemotherapy and is often help-
ful in women with anticipatory nausea and vomiting.
Oral delta-9-tetrahydrocannabinol (dronabinol), the
active ingredient in marijuana, is more effective in con-
trolling nausea than placebo or phenothiazines. It

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 D R UG TH ER A PY

TABLE 2. COMMON REGIMENS OF ADJUVANT CHEMOTHERAPY FOR WOMEN WITH BREAST CANCER.

TOTAL
CYCLE NO. OF
STUDY REGIMEN DURATION CYCLES DOSE (mg/m2)
CYCLOPHOS-
PHAMIDE METHOTREXATE FLUOROURACIL DOXORUBICIN PACLITAXEL

days

Fisher et al.13 Oral cyclophosphamide, 28 6 100, days 40, days 600, days — —
intravenous methotrex- 1–14 1 and 8 1 and 8
ate and fluorouracil
Zambetti et al.14 Intravenous cyclophos- 21 8–12 600, day 1 40, day 1 600, day 1 — —
phamide, methotrex-
ate, and fluorouracil
Buzdar et al.15 Intravenous fluorouracil, 28 6 400, day 1 — 400, days 40, day 1 —
doxorubicin, and 1 and 8
cyclophosphamide
Wood et al.16 Intravenous cyclophos- 21 4 600, day 1 — 600, day 1 60, day 1 —
phamide, doxorubicin,
and fluorouracil
Fisher et al.13 Intravenous doxorubicin 21 4 600, day 1 — — 60, day 1 —
and cyclophosphamide
Henderson Intravenous doxorubicin 21 4, 4* 600, day 1 — — 60, day 1 175, day 1
et al.17 and cyclophosphamide,
then paclitaxel
Bonadonna Intravenous doxorubicin, 21 4, 8* 600, day 1 40, day 1 600, day 1 75, day 1 —
et al.18 then cyclophospha-
mide, methotrexate,
and fluorouracil

*The first number refers to the number of cycles of the first part of the regimen, and the second number to the number of cycles of the
second part of the regimen.

causes hallucinations, depression, or intoxication in Weight Gain

23 percent to 81 percent of patients with cancer, and
surveys of oncologists suggest that they prefer other
antiemetic drugs and rarely prescribe dronabinol.24
There are few data on the antiemetic efficacy of smok-
ing marijuana; anecdotal reports suggest it is effective,
particularly among those who have previously smoked
it. The incidences of severe oropharyngeal mucositis
or stomatitis and of diarrhea requiring intravenous-
fluid therapy or hospitalization are low for regimens
of cyclophosphamide and doxorubicin but may be
higher when the regimen includes fluorouracil.
Neurologic Toxicity
The taxanes cause both sensory and motor periph-
eral neuropathy. The neuropathy is usually mild to
moderate, and the severity is related to the individ-
ual dose, cumulative dose, and schedule of adminis-
tration (Table 3). There are currently no effective
means to prevent or treat taxane-induced neuropa-
thy, but early recognition and a subsequent delay or
reduction in the dose improve the symptoms in most
cases. Taxanes often cause mild-to-moderate myalgias
and arthralgias that usually respond to nonsteroidal
antiinflammatory drugs or codeine-containing anal-
gesic drugs. In severe cases, a short course of gluco-
corticoids may be helpful.
The majority of women with breast cancer who are
treated with cyclophosphamide, methotrexate, and
fluorouracil gain weight. The average weight gain
ranges from 2 to 6 kg; the gain tends to be at the up-
per end of this range in women who are premenopaus-
al, those who are treated with a prolonged regimen
(12 months vs. 6 months), and those who are also re-
ceiving prednisone.25,26 Women treated with doxorubi-
cin and cyclophosphamide gain less weight than those
given cyclophosphamide, methotrexate, and fluorour-
acil (Table 3). The postulated causes of weight gain
include decreased physical activity, ovarian failure, in-
creased food consumption, and a reduced basal met-
abolic rate.25,27 Weight gain may adversely affect the
quality of life and has been associated with higher rates
of recurrent cancer in some,28 but not all, studies.
Ovarian Failure
Age and the duration of adjuvant chemotherapy are
the primary determinants of ovarian failure.29,30 Treat-
ment with cyclophosphamide, methotrexate, and
fluorouracil for six months results in permanent ovar-
ian failure in 70 percent of women over 40 years of age
and in 40 percent of younger women.29 The median
time to the onset of ovarian failure is shorter in older
women than in younger women (2 to 4 months vs.

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 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

TABLE 3. SERIOUS SIDE EFFECTS OF ADJUVANT CHEMOTHERAPY FOR WOMEN WITH BREAST CANCER.*

ORAL CYCLOPHOSPHAMIDE, INTRAVENOUS CYCLO- INTRAVENOUS FLUORO- INTRAVENOUS CYCLO-

INTRAVENOUS METH- PHOSPHAMIDE, METH- URACIL, DOXORUBICIN, PHOSPHAMIDE, DOXO-
OTREXATE AND FLUOR- OTREXATE, AND FLUOR- AND CYCLOPHOSPHA- RUBICIN, AND FLUORO-
SIDE EFFECT OURACIL (N=739)13 OURACIL (N=45)14 MIDE (N=222)15 URACIL (N=516)16

percentage of women

Reduced white-cell count

1–1999/mm3 9 27‡ — —§
<1000/mm3 0.3 — 22
Reduced platelet count
25,000–50,000/mm3 0.3 0 0 16
<25,000/mm3 0 0 0 2
Infection
Severe systemic infection requiring intravenous antibiotics 0.3 — 1 9
Life-threatening infection requiring intravenous antibiotics, 0.9 — — 2
antifungal drugs, or hospitalization
Death 0 — 0 0
Nausea
Moderate: oral intake substantially reduced 43¿ — — 39
Severe: patient unable to eat, requiring intravenous fluids — — 3
Vomiting
Moderate: 6–10 episodes/24 hr 37 — —
Severe: >10 episodes/24 hr, intravenous fluids required 5 — —
Stomatitis
Severe: patient unable to eat, requiring intravenous fluids — — — 9
Diarrhea
Severe: >7 stools/day, fecal incontinence, or intravenous 4.5** — — 5
fluids required
Life-threatening: >10 stools/day, grossly bloody stools, or 0.3 — — 0
intravenous fluids required
Neurologic: sensory
Severe: objective sensory loss or paresthesias that interfere — — — —
with function
Neurologic: motor
Severe: objective weakness that interferes with function — — — —
Bone or muscle pain
Severe — — — 0.6
Weight gain
10%–20% 12 —†† — —
>20% 2.3 — —
Ovarian failure
Permanent 70 65 81 —
Cardiac
Congestive heart failure that is responsive to therapy 0 — 0.9 0.4
Severe congestive heart failure that is refractory to therapy 0 — 0.5 0.2
Death 0 — 0 0.2
Thrombosis
Deep-vein thrombosis 0.3 — — 0.6¶¶
Pulmonary embolism 0.3 — —
Death 0 — — 0
Alopecia
Pronounced or total hair loss 40 67 95 57

*Dashes indicate values not reported.

†The first value is for doxorubicin plus cyclophosphamide, and the second is for paclitaxel.
‡The value is the percentage of women with white-cell counts below 2500 per cubic millimeter.
§The nadir white-cell count was 45 per cubic millimeter.
¶The nadir white-cell counts were 27 and 8 per cubic millimeter, respectively.
¿The value is the percentage of women with mild, moderate, or severe nausea but without vomiting.
**The value is the percentage of women with more than four stools per day.
††The mean absolute weight gain was 2.0 kg.
‡‡The mean absolute weight gain was 2.5 kg.
§§Doxorubicin was administered at a dose of 75 mg per square meter of body-surface area, with concurrent radiation therapy.
¶¶The value is the total number of cases of thrombophlebitis.

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 D RUG TH ER A PY

nal dryness, dyspareunia, depression, and sleep dis-

TABLE 3. CONTINUED. turbances, are often reported by women with breast
cancer and are severe in up to one third of them.33
INTRAVENOUS DOXO- INTRAVENOUS DOXORU- INTRAVENOUS DOXORUBICIN, Ovarian failure may increase the risk of osteoporosis
RUBICIN AND CYCLO- BICIN AND CYCLOPHOS- THEN CYCLOPHOSPHAMIDE,
PHOSPHAMIDE PHAMIDE, THEN PACLI- METHOTREXATE, AND FLUOR- and possibly of cardiovascular disease. Long-term data
(N=1492)13 TAXEL (N=533)17† OURACIL (N=201)18 on fractures in women with chemotherapy-induced
percentage of women ovarian failure are unavailable. However, early meno-
pause is a risk factor for osteoporosis. Treatment with
3 —¶ 7‡
bisphosphonates mitigates bone loss in women with
0.3 13, 2 breast cancer and chemotherapy-induced ovarian fail-
ure.34-36 Women who have chemotherapy-induced
0 1, 0 0
0.1 0, 0 0 ovarian failure should have adequate dietary intakes of
calcium and vitamin D and should perform weight-
0.9 3, 2 — bearing exercise regularly and have their bone den-
1.5 0, 0 —
sity evaluated.
0 0, 0 — The administration of estrogen to women with
15¿ 8, 0 —
breast cancer for the relief of menopausal symptoms
1, 0 — and for the long-term prevention of osteoporosis and
possibly heart disease is controversial, because sup-
12 4, 0 —
1.6 2, 0 — plemental estrogen may increase the risk of disease
progression or the development of a new primary
— 1, 0 — breast cancer. However, an increasing body of data
2.6** 1, 0 — highlights the potential benefits and absence of ad-
verse effects of estrogen in women who have had
0.3 0, 0 —
breast cancer.37-39 Until the results of randomized tri-
als are available, caution should be exercised in pre-
— 0, 5 — scribing estrogen for such women, and nonhormonal
treatments for hot flashes, such as selective serotonin-
— 0, 2 — reuptake inhibitors or bisphosphonates for the pre-
vention of osteoporosis, should be considered.40,41
— 0, 3 —

2.1 0, 0 —‡‡ Cardiac Toxicity

1.7 0, 0
— —
0.1 0, 0
0 0, 0
0 0, 0
0.1 0, 0
0.1 0, 0
0 0, 0
91 100
6 to 16 months), and ovarian failure is less likely to be
reversible in older women (in about 10 percent vs. up
to 50 percent). The rate of permanent ovarian failure
is lower with regimens of doxorubicin and cyclophos-
phamide than with cyclophosphamide, methotrex-
ate, and fluorouracil.31,32 The rate of ovarian failure
among women treated with taxane-containing regi-
mens is not known.
Chemotherapy-induced ovarian failure may have
short-term and long-term consequences for health.
Menopausal symptoms, including hot flashes, vagi-
Doxorubicin directly damages the myocardium and
60 can cause cardiomyopathy. Risk factors for doxoru-
bicin-related myocardial damage include a high cu-
0.5§§
0.5 mulative dose of the drug, an older age at the time of
0.2 treatment, preexisting heart disease, a history of me-
diastinal (cardiac) irradiation, and the coadministration
—
— of paclitaxel or trastuzumab.42-44 Continuous infusions
— or low-dose weekly infusions are associated with a
96
lower risk of damage than are bolus infusions. When
the total dose of doxorubicin is limited to 240 to 300
mg per square meter of body-surface area, the inci-
dence of clinically important cardiomyopathy is less
than 1 percent (Table 3).
Congestive heart failure, ventricular tachycardia,
and sudden death have been reported in survivors of
childhood cancer years after treatment with doxoru-
bicin or other anthracyclines. Thus far, no such de-
layed cardiac events have been noted in women in
whom the cumulative dose of doxorubicin was less
than 300 mg per square meter.44-47 In one study of
women with breast cancer, however, 8 percent of those
previously treated with doxorubicin had echocardio-
graphic evidence of systolic dysfunction or a reduced
left ventricular ejection fraction without cardiac dil-
atation, as compared with less than 1 percent of wom-
en previously treated with cyclophosphamide, meth-

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 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
otrexate, and fluorouracil.48 Whether such subclinical
systolic dysfunction eventually results in clinically overt
cardiac problems is unknown.
Cardiomyopathy develops in approximately 3 per-
cent of women with advanced breast cancer who are
treated with trastuzumab.44 When trastuzumab is giv-
en concurrently with doxorubicin, the incidence of
cardiac toxicity increases to 18 percent.49
Second Cancers
There is little evidence that the risk of second can-
cers is increased among women who receive cyclo-
phosphamide, methotrexate, and fluorouracil (Table
4).50-54 There is less information on the risk of sec-
ond cancers among women treated with doxorubicin-
containing regimens, and there is no information on
the risk with regimens that contain taxanes. The risks
of chemotherapy-induced acute myeloid leukemia and
myelodysplasia are dependent on the specific alkylat-
ing drug, the cumulative dose, and the duration of
treatment. Registry data show that treatment with
cyclophosphamide, methotrexate, and fluorouracil for
6 months is associated with a risk of acute myeloid
leukemia or myelodysplasia that is increased by a fac-
tor of approximately two, or about 5 excess cases per
10,000 treated patients at 10 years.55 The risk of
acute myeloid leukemia or myelodysplasia with stand-
ard doses of doxorubicin-containing adjuvant chemo-
therapy is no higher or is only slightly higher than
that in the general population.56,57 However, among
women receiving both chemotherapy and radiation
treatment, the risk of leukemia may be higher.55,57
TABLE 4. SECOND CANCERS AFTER
TYPE OF NO. OF
STUDY STUDY WOMEN
Holdener et al.50 Randomized 2458
Herring et al.51 Cohort 797
Arriagada and Randomized 1113
Rutqvist52
Valagussa et al.53 Randomized 2465
Rubagotti et al. 54 Cohort 1696
*Contralateral breast cancers are excluded; leukemia is included.
†The control group was not randomized.
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Unlike the leukemia associated with alkylating
agents, that associated with doxorubicin is monocytic,
involves a specific cytogenetic abnormality (11q23),
and develops within a few years after treatment, with-
out prior myelodysplasia in some cases.58
Fatigue and Quality of Life
Many women with breast cancer who are receiv-
ing adjuvant chemotherapy have fatigue, and about
two thirds of them rate the level of fatigue as mod-
erate or severe.59,60 The cause of the fatigue is poorly
understood; possible contributing factors include ane-
mia, vasomotor symptoms that cause sleep disturb-
ance, and depression. There are insufficient data to
support the use of erythropoietin to relieve fatigue
in women receiving adjuvant chemotherapy. The fa-
tigue appears to resolve after treatment. In a survey
of nearly 2000 women with breast cancer who were
evaluated three years after adjuvant treatment, the lev-
el of fatigue was similar to that of age-matched nor-
mal women.60
Measurements of the quality of life also worsen
during adjuvant chemotherapy but improve after the
cessation of treatment.61 In several studies, the overall
quality of life, the presence or absence of depression,
and body image did not differ significantly between
women with breast cancer who had been treated with
adjuvant chemotherapy, tamoxifen, or both and wom-
en who had not received such treatment or age-
matched normal women.62,63 In addition, ethnicity was
not associated with significant differences in the over-
all quality of life.64 However, specific symptoms are
ADJUVANT CHEMOTHERAPY IN WOMEN WITH BREAST CANCER.*
YEARS OF CHEMO-
FOLLOW-UP REGIMEN THERAPY CONTROL
% of women with
second cancer
4–14 Cyclophosphamide; cyclophospha- 2.7 3.1
mide, methotrexate, and fluorour-
acil; chlorambucil, methotrexate,
and fluorouracil; melphalan
10 Fluorouracil, doxorubicin, and 1.3 4.8
cyclophosphamide
10 Chlorambucil, methotrexate, and 1.0 5.0†
fluorouracil; cyclophosphamide,
methotrexate, and fluorouracil
15 Cyclophosphamide, methotrexate, 6.4 8.4
and fluorouracil
Cyclophosphamide, methotrexate, 5.1
fluorouracil, and doxorubicin
5 Cyclophosphamide, methotrexate, 2.6 2.0
and fluorouracil
Cyclophosphamide, methotrexate, 1.7
fluorouracil, and tamoxifen
 D RUG TH ER A PY
associated with specific treatments. In one study, for
example, the frequency of sexual dysfunction was
higher in women who received chemotherapy, where-
as vasomotor symptoms occurred more often in wom-
en who received tamoxifen.62
Vaginal dryness and dyspareunia are common in
breast-cancer survivors, especially among women who
receive chemotherapy. Topical estrogen therapy re-
lieves these symptoms, but its use is associated with
the same issues as oral estrogen therapy in these wom-
en. In one study, polycarbophil-based vaginal lubri-
cant and placebo were equally effective in relieving
vaginal dryness and dyspareunia.65
Cognitive Dysfunction
Preliminary studies suggest that cognitive dysfunc-
tion may occur after adjuvant chemotherapy. Two or
three years after treatment, problems with memory,
concentration, and language were more frequent in
women who had received chemotherapy than in sim-
ilar women who had not received such treatment or
in women without breast cancer.66-68 These cognitive
problems did not appear to be associated with a wor-
sening of the quality of life, fatigue, or depression.
The mechanism of cognitive dysfunction is unknown,
but it has been postulated that a direct effect of che-
motherapy or diminished estrogen secretion result-
ing from ovarian failure has a role.
TAMOXIFEN
Depending on the target tissue, tamoxifen acts as
an agonist or an antagonist of estrogen. Tamoxifen has
estrogen-like effects on the endometrium, the skele-
ton, the coagulation system, and lipid metabolism. In
women with estrogen-receptor–positive breast can-
cers, tamoxifen acts as an estrogen antagonist, thus
reducing the risks of systemic recurrence and contra-
lateral breast cancer and the overall mortality rate.
Serum Lipids and Cardiovascular Mortality
In postmenopausal women treated with tamoxifen,
serum concentrations of total and low-density lipo-
protein cholesterol fall by about 10 percent.69 Wheth-
er tamoxifen reduces the rate of cardiovascular disease
remains to be determined. Retrospective analyses of
two randomized trials showed that the risks of my-
ocardial infarction and death from cardiac causes were
lower among women who received tamoxifen than
among those who did not.70,71 However, an analysis
of data from the National Surgical Adjuvant Breast and
Bowel Project P-1 prevention trial showed that the
rates of cardiovascular disease and of death from car-
diovascular causes did not differ significantly between
the group of women treated with tamoxifen and the
group given placebo.72
Coagulation and Thrombosis
Women treated with tamoxifen have small decreas-
es in plasma concentrations of antithrombin III, pro-
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tein S, and fibrinogen.73-75 The relevance of these
findings to the very small excess risks of deep-vein
thrombosis, pulmonary embolus, and stroke among
postmenopausal women taking tamoxifen is uncer-
tain (Fig. 2).9,72,76,77 Whether the risk of tamoxifen-
associated thrombosis is higher among women with
underlying thrombotic disorders than among those
without such disorders is unknown. Concurrent ad-
ministration of tamoxifen and chemotherapy may re-
sult in a higher incidence of venous and arterial throm-
bosis than either treatment alone.78,79
Second Cancers
Like estrogen, tamoxifen is associated with an ap-
proximate doubling of the risk of endometrial cancer,
or about 80 excess cases per 10,000 tamoxifen-treated
women at 10 years.9,72,77,80 This increase occurs pri-
marily in women over the age of 50 years.72 There is
no evidence that tamoxifen increases the risk of oth-
er cancers.9,81
The value of periodic screening with transvaginal
ultrasonography or endometrial biopsy in asympto-
matic women taking tamoxifen has not been estab-
lished. The incidence of tamoxifen-associated endo-
metrial cancer is low, and most cases are low-grade,
early-stage cancers that are curable with surgery alone.
Women should undergo an annual pelvic examina-
tion while taking tamoxifen, and they should be ad-
vised to see a gynecologist if irregular bleeding oc-
curs.82 For women who have not received routine
gynecologic care, a pelvic examination should be per-
formed before treatment with tamoxifen is started.
Raloxifene is a selective estrogen-receptor modu-
lator that may prevent breast cancer. The drug was
developed to treat osteoporosis in postmenopausal
Average Annual Rate7
20 Tamoxifen7
(per 10,000 women)
Placebo
10
0
si n7
lu y7
er 7
ke
nc ial
bo ei
bo nar
ro
s
s
Ca etr
m -V
St
Em mo
ro ep
m
Th De
do
l
Pu
En
Figure 2. Average Annual Rates of Endometrial Cancer, Deep-
Vein Thrombosis, Pulmonary Embolus, and Stroke among Wom-
en Given Tamoxifen or Placebo in National Surgical Adjuvant
Breast and Bowel Project Trials B-14, B-24, and P1.
A total of 8793 women received tamoxifen, and a total of 8824
received placebo. Data are from Fisher et al.72,76,77
 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
women83 and was recently approved by the FDA for
this indication. In the Multiple Outcomes of Ralox-
ifene Evaluation trial, there were fewer primary breast
cancers in the group of women who received ralox-
ifene than in the group of women who received pla-
cebo.84 Raloxifene is associated with hot flashes and
an increased risk of thromboembolic events, but un-
like tamoxifen, it has not been associated with an in-
creased risk of endometrial cancer thus far. Until more
data are available, raloxifene should not be substitut-
ed for tamoxifen or estrogen outside a clinical trial.
Skeletal Effects
Tamoxifen preserves bone mineral density in post-
menopausal women,85,86 but whether it reduces the
risk of vertebral or hip fractures is uncertain. One
report suggested that tamoxifen does not provide pro-
tection against fractures,87 but there was a nonsignif-
icant decrease in the rate of fractures among tamox-
ifen-treated women in the National Surgical Adjuvant
Breast and Bowel Project P-1 prevention trial.72 In
contrast, tamoxifen may increase bone loss in pre-
menopausal women because of its estrogen-antago-
nist activity.86
Vaginal and Vasomotor Symptoms, Depression,
Weight Gain, and Ocular Toxicity
Hot flashes, vaginal discharge, and irregular men-
ses are all more common in women given tamoxifen
than in those given placebo (Fig. 3). In trials of me-
gestrol acetate,88 transdermal clonidine,89 oral cloni-
dine,90 and venlafaxine,91 each of these agents was
more effective than placebo in relieving hot flashes in
women taking tamoxifen. However, the effects of me-
gestrol acetate, a progestational agent, on breast cancer
are uncertain, and clonidine has several unpleasant
side effects, including dry mouth, constipation, drows-
iness, and dizziness. Vitamin E is associated with a
marginal reduction in the incidence of hot flashes,
and soy phytoestrogens have no effect on them.92,93
Comparisons of tamoxifen and placebo have re-
vealed no significant differences in measurements of
the quality of life, although tamoxifen was more likely
to be associated with sexual dysfunction and vaginal
symptoms.94,95 Tamoxifen is frequently thought to
cause depression and weight gain, but both the inci-
dence and the severity of depression and weight gain
were similar in the tamoxifen and placebo groups in
several trials.78,94 In rare cases, tamoxifen is associated
with reversible retinopathy 96 and a slight increase in
cataracts and cataract surgery (about 0.3 and 0.1 ex-
cess cases per 10,000 women per year, respectively).72
RADIATION THERAPY
The side effects of irradiation of the breast, chest
wall, and regional lymph nodes are listed in Table 5.
As with chemotherapy, much of the information on
the side effects of radiation therapy, such as cardiac
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100
Average Incidence (%)
Tamoxifen7
Placebo
80
60
40
20
0
Hot7 Vaginal7 Irregular7
Flashes Discharge Menses
Figure 3. Average Incidence of Hot Flashes, Vaginal Discharge,
and Irregular Menses in Women Treated with Tamoxifen or Pla-
cebo in National Surgical Adjuvant Breast and Bowel Project
Trials B-24 and P1.
A total of 7475 women received tamoxifen, and a total of 7498
received placebo. Data are from Fisher et al.72,77
toxic effects and second cancers, is confounded by
treatment received decades ago with outmoded ra-
diation techniques. Current radiation therapy, admin-
istered with the use of higher-energy sources, lower
daily doses (or smaller fractions), and field arrange-
ments that limit the exposure of normal tissue, is as-
sociated with lower rates of toxic effects.
Cardiac Toxicity
Acute and subacute cardiac complications of radi-
ation therapy for breast cancer, such as pericarditis
and cardiac failure, are rare. Meta-analyses97 and reg-
istry-based studies98 have shown small long-term in-
creases in mortality from cardiac causes, probably in-
volving coronary artery disease; however, most of the
women in these studies received radiation therapy
with outmoded techniques that exposed the heart to
high doses of radiation. Studies with a median follow-
up time of 10 to 20 years have not found an increased
risk of cardiac disease in women treated with mod-
ern techniques that limit the exposure of the heart to
radiation.99-102 However, even when radiation fields
are limited to the breast, there still may be a risk of
cardiac toxicity when the daily doses are high.103
Many women with breast cancer are treated with
both doxorubicin and irradiation of the breast or chest
wall, but few long-term data are available on the in-
teraction between chemotherapy and radiation ther-
apy administered with current techniques. In several
studies, there was no additional short- or long-term
cardiac toxicity in women who received radiation ther-
apy in combination with a standard dose of doxoru-
bicin (60 mg per square meter) given for four cy-
cles.46,104,105 However, treatment by radiation with a
higher dose of doxorubicin (75 mg per square meter)
given for four cycles administered concurrently,19 or
by higher cumulative doses of doxorubicin (450 mg

TABLE 5. SIDE EFFECTS OF LOCAL RADIATION THERAPY
FOR BREAST CANCER.
EFFECT INCIDENCE
% of women
Long term
Second cancer
Myocardial infarction
Pneumonitis
Lymphedema (after nodal irradiation)
Mild to moderate
Severe
Brachial plexopathy (after nodal irradiation)
Skin (breast or chest wall)
Mild shrinkage or induration
Severe shrinkage or induration
Short term
Skin (breast or chest wall)
Hyperpigmentation, dry desquamation, or erythema
Moist desquamation
Mild fatigue
Mild myelosuppression
per square meter) with sequentially administered ra-
diation,46 increased the risk of cardiac toxicity.
Second Cancers
Several registry-based case–control studies found
that the risk of contralateral breast cancer was slight-
ly increased among women who had been treated
with radiation after mastectomy, probably as a result
of the small dose of “scatter” radiation to the other
breast.106-108 The increased risk seems to be confined
to women younger than 40 to 45 years of age at the
time of treatment, a finding that is consistent with
increased risks among women with other types of
radiation-associated breast cancer, such as survivors
of the atomic explosions in Hiroshima and Nagasaki
and women who have been treated for Hodgkin’s
disease.10 The dose of radiation to the contralateral
breast can be reduced by technical measures when
young women receive radiation treatment.109
Sarcomas are very rarely caused by radiation. The
10-, 20-, and 30-year actuarial incidences of soft-tis-
sue sarcomas in patients who have undergone chest-
wall irradiation after mastectomy are 0.2 percent,
0.4 percent, and 0.8 percent, respectively.110 Like-
wise, angiosarcoma of the skin of the irradiated breast
occurs in 0.1 percent to 0.5 percent of patients.111
The risks of acute myeloid leukemia and myelodys-
plasia are related to the total dose of radiation, the
volume of bone marrow irradiated, and the use or
nonuse of alkylating agents. Very small increases in the
rate of acute myeloid leukemia after chest-wall and
nodal irradiation have been noted in some, but not
all, studies.12,112 In case–control studies that were
mainly limited to smokers, there were very small ex-
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D RUG TH ER A PY
cess risks of ipsilateral lung cancer and possibly of
esophageal cancer among women treated with now-
outmoded radiation techniques.113,114
Pneumonitis
Symptomatic radiation pneumonitis is character-
ized by cough, fever, and shortness of breath occur-
<1
ring two to nine months after the completion of ra-
<1 diation therapy. The condition occurs in less than
<1 1 percent of women who undergo irradiation of the
6–10
breast or chest wall alone; however, the incidence is
1–5 higher when chemotherapy and radiation therapy are
<1 given concurrently or when a supraclavicular or full
10–50 axillary field is treated in addition to breast tangential
6–10 fields.115 The symptoms of radiation pneumonitis
usually resolve without treatment in a few weeks or
>50 months, and most patients do not require glucocor-
6–10 ticoid therapy.
>50
>50
Lymphedema, Brachial Plexopathy, and Rib Fractures
The incidence of lymphedema ranges from 5 per-
cent to 25 percent, depending on the extent of axillary
irradiation and surgery.116 Lymphedema is a distressing
side effect that should be treated early. Effective
treatments include specialized massage (called com-
plete decongestive physiotherapy) and elastic pres-
sure sleeves.117
The total and daily doses of radiation, as well as the
use of chemotherapy, affect the development of bra-
chial plexopathy. The risk of brachial plexopathy and
rib fractures is 1 to 2 percent in series of women
treated with modern radiation techniques.118
CONCLUSIONS
Adjuvant treatment reduces mortality from breast
cancer. Most of the side effects of treatment are re-
versible, and there is little or no detectable increase
in the long-term risk of cardiac toxic effects or sec-
ond cancers with the use of current regimens. Thus,
the benefit-to-risk ratio favors adjuvant treatment in
women with primary invasive breast tumors that are
larger than 1 cm in diameter. However, the optimal
adjuvant treatment has yet to be determined. Research
is under way to improve the identification of women
who are likely to benefit from adjuvant treatment,119
to increase the efficacy of such treatment, and to re-
duce its toxic effects on normal tissue.120-127
The development of trastuzumab was based on an
understanding of growth factors and signal-transduc-
tion pathways in breast cancers that overexpress hu-
man epidermal growth factor receptor (HER2). Like
trastuzumab, antiangiogenesis agents, mixed metal-
loproteinase inhibitors, tyrosine kinase inhibitors, and
farnesyl transferase inhibitors target the mechanisms
that distinguish cancer cells from normal ones. These
drugs, in combination with chemotherapy, are cur-
rently being evaluated in women with advanced breast
cancer. If such regimens are found to be effective for
N Engl J Med, Vol. 344, No. 26 · June 28, 2001 · www.nejm.org · 2005
 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
the treatment of advanced breast cancer, they are like-
ly to be even more beneficial as adjuvant treatment for
earlier stages of disease.
Dr. Shapiro has received grants from Aventis, Genentech, and Novartis.
We are indebted to Dr. Priscilla Bresler, Deborah Scherder, and
Constance Cirricionne for their assistance in the preparation of the
manuscript.
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