C A C a n c e r J C l i n 1 9 9 5 ; 4 5 : 1 9 9 - 2 2 6
Current Status of Adjuvant Systemic
Therapy for Primary Breast Cancer:
Progress and Controversy
Gabriel N. Hortobagyi, MD
Aman U. Buzdar, MD
Introduction
Because of its high incidence, breast can-
cer is a substantial public health problem
throughout the Western industrialized
world.1 In the United States, breast can-
cer is the most common malignant neo-
plasm in women, accounting for 32 per-
cent of malignancies in females.2 For
1995, it is estimated that 183,400 new
cases of breast cancer will be diagnosed in
the United States. Of these, 182,000 will
occur in women, and 1,400 in men. The
incidence rate for breast cancer has been
increasing steadily since the 1960s at a
rate of one to two percent per year in the
United States.
Breast cancer is the second leading
cause of cancer-related death in women
in the United States. For 1995, it is esti-
mated that 46,240 deaths will occur as a
result of breast cancer.2 For women be-
tween the ages of 15 and 54 years, breast
cancer is the most common cause of can-
cer-related death. In spite of increasing
Dr. Hortobagyi is Professor of Medicine in the De-
partment of Breast and Gynecologic Medical
Oncology at The University of Texas M.D. An-
derson Center in Houston, Texas.
Dr. Buzdar is Professor of Medicine in the Depart-
ment of Breast and Gynecologic Medical Oncology
at The University of Texas M.D. Anderson Center
in Houston, Texas.
The authors thank Melissa G. Burkett for reviewing
the manuscript and Deborah Crowe for her assis-
tance in preparing the manuscript.
Vol. 45 No. 4 July/august 1995
incidence rates, the mortality rates for
breast cancer have remained stable for
the last 50 years. However, between 1973
and 1987, the mortality rate decreased by
4.9 percent for women younger than 65
years, while it increased by 10.7 percent
for women aged 65 years and older.
Similar incidence and death rates are
applicable to western and northern Eu-
rope.1 In Asian countries, where the inci-
dence and mortality rates for breast can-
cer have been historically low, both rates
have been increasing at a greater pace
than in the industrialized West.
In 1985, it was estimated that about
700,000 new cases of breast cancer were
diagnosed worldwide.3 Because most
countries have no comprehensive tumor
registries, this is probably an underesti-
mate. By 1990, this figure had increased
to between 800,000 and 900,000 new cases
of breast cancer. Breast cancer is usually
diagnosed in later stages in developing
countries; thus, the mortality rates are
much higher than in the United States or
western Europe.
Because of the high incidence of
breast cancer, even small improvements
in the efficacy of treatment may repre-
sent tens of thousands of lives saved
every year. The high failure rate after lo-
cal/regional therapies prompted, several
decades ago, the search for more effec-
tive treatments, or combinations of
treatments, to increase the cure rates of
199
 A d j u v a n t s y s t e m i c t h e r a p y
primary therapy. In this article, we will
review the current status of adjuvant sys-
temic therapies and areas of persistent
controversy.
Background
The acceptance of the radical mastecto-
my as the treatment of choice for prima-
ry breast cancer around the turn of the
century served several very useful pur-
poses. First, it established a standard of
care by which other treatments could be
measured. Second, it established some
order in the reigning chaotic approach to
this highly lethal disease. Third, it stimu-
lated the systematic evaluation of treat-
ment outcomes and the assessment of
the natural history of the disease follow-
ing surgical therapy, including the identi-
fication of now commonly accepted
prognostic indicators.
The first series of challenges to the
use of radical mastectomy as the standard
treatment did not occur until the mid-
1930s.4-6 In fact, major conceptual chal-
lenges to the Halstedian hypothesis did
not appear until the 1950s.7 It was in the
second half of the 20th century that suffi-
cient biologic knowledge accumulated
about the long-term results of radical lo-
cal/regional therapy to establish the limi-
tations of the radical mastectomy.
Based on elegant work by several in-
vestigators, it became apparent that mi-
crometastases existed at the time of diag-
nosis in many patients and that despite
aggressive radical resection or radiation
therapy, cure was possible only in the mi-
nority of patients who did not harbor
such subclinical metastases.8-10 This led to
a gradual conceptual change in the ap-
proach to breast cancer that dictated the
need for combined modality therapy that
included both regional and systemic
treatments.11
The initial trials of adjuvant systemic
therapy involved studies of surgical or ra-
diation oophorectomy12-15 and the pio-
neering work of Nissen-Meyer et al16 and
200
F o r B r e a s t C a n c e r
Fisher et al17 with single-agent chemo-
therapy. However, these trials were, in
retrospect, poorly designed. They includ-
ed insufficient numbers of patients, and
the statistical power of the observations
was quite limited.
It wasn’t until the early 1970s that
adjuvant chemotherapy began to under-
go systematic evaluation according to
sound modern scientific principles.18,19
Within the next two decades, an enor-
mous body of information was generated,
based mostly on prospective, randomized
clinical trials.20 It was established, in rapid
succession, that adjuvant chemotherapy
improved disease-free and overall sur-
vival rates,18,19 that adjuvant tamoxifen
also improved disease-free and overall
survival rates,21 and that ovarian ablation
prolonged disease-free and, sometimes,
overall survival for premenopausal
women.22,23
Evaluation of Benefit in Adjuvant
Systemic Therapy Trials
Patients treated with surgery and adju-
vant systemic therapy can be divided into
three groups (Fig. 1): (A) those cured by
surgical resection (shown between the
horizontal axis and the lower survival
curve of patients treated with local/re-
gional therapy only); (B) those not cured
by surgical resection but with tumors re-
sponsive to adjuvant systemic therapy
(shown between the two survival curves);
and (C) those not cured with surgical re-
section and with tumors resistant to the
adjuvant systemic therapy used (the area
above the upper survival curve).
Adjuvant systemic therapy cannot
improve the outcome of patients already
cured by surgery, nor can it be effective if
the tumor is resistant to chemotherapy or
hormone therapy. Therefore, adjuvant
therapy can help only patients in group B.
The beneficial effects found in clinical tri-
als are thus diluted by the inclusion of pa-
tients in the other two groups, because
the three groups cannot be identified be-
Ca—A cancer Journal for Clinicians
 C A
100
90
80
70
Percent Disease-Free
60
50
40
30
20
10
0
0 1
Fig. 1. Hypothetical representation of potential benefit from adjuvant systemic therapy in patients
with primary breast cancer: (A) patients cured after local/regional therapy; (B) patients with resid-
ual micrometastases after local/regional therapy whose tumor cells are responsive to the adjuvant
therapy used; (C) patients with resistant residual micrometastases after local/regional therapy.
fore the initiation of adjuvant therapy.
Several methods are used to quanti-
fy the benefits of adjuvant systemic treat-
ments. One compares the median time to
treatment failure between the surgical
control and the adjuvant-treated groups
(Fig. 2A) This method shows the benefit
for patients with intermediate risk of re-
currence but does not reflect the effect of
adjuvant therapy on patients expected to
relapse early or patients with late treat-
ment failure, usually represented at the
“tail” end of the survival curves.
A second method uses vertical dif-
ferences between treated and control
groups at a specific point in time (Fig.
2B).20,24 This method fails to assess the
overall benefit for the entire group and
may provide markedly different answers
at different points during follow-up.
A third method assesses benefit by
calculating the area between the survival
curves for the treated and control groups.
In essence, this method averages the dif-
Vol. 45 No. 4 July/august 1995
C a n c e r J C l i n 1 9 9 5 ; 4 5 : 1 9 9 - 2 2 6
C
B
A
2 3 4 5 6 7 8 9 10
Years
ference between the two curves at multi-
ple points in time. While this method fails
to detect time-dependent variations in
benefit, it may provide the most accurate
determination of the relative and ab-
solute benefits over the entire length of
follow-up. This method probably pro-
vides a fairly accurate basis for cost-bene-
fit calculations.
Variations on this method include
calculations that correct for the toxic ef-
fects of adjuvant systemic therapy25 and
take into consideration the duration of
such toxic effects as well as the duration
of the benefit.26
In addition to the graphic methods
described above, the benefit from adju-
vant systemic therapies can be expressed
numerically in several ways. One of the
most commonly used methods is the one
employed in the Early Breast Cancer Tri-
alists’ Collaborative Group (EBCTCG)
meta-analysis, described below.22 Table 1
illustrates this concept using two hypo-
201
 A d j u v a n t s y s t e m i c t h e r a p y F o r B r e a s t C a n c e r

100
90
80
70
Percent Disease-Free

60
50
40
30
20
10
0
0 1 2 3 4 5 6 7 8 9 10 11
A Years
100
90
80
70
Percent Disease-Free

60
50
40
30
20
10
0
0 1 2 3 4 5 6 7 8 9 10 11
Years
B
Fig. 2. Evaluation of the benefits obtained from adjuvant systemic therapies. (A) Comparison of
median times to treatment failure of patients treated with and without adjuvant systemic therapy.
(B) Comparison of failure-free survival (or overall survival) rates at specific time intervals (five
years, 10 years) of patients treated with and without adjuvant systemic therapies.

thetical situations and assuming an over-
all reduction in the odds of death of 20
percent in treated patients, a figure similar
to the results with adjuvant tamoxifen in
the meta-analysis. The example demon-
strates that although the relative benefit
does not change (20 percent), the absolute
benefit, in terms of number of deaths and
five-year survival rate, changes according
to the baseline risk of death. Thus, pa-

202 Ca—A cancer Journal for Clinicians

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Table 1
Calculation of Relative and Absolute Benefits from
Adjuvant Systemic Therapies*

No. of Patients Five-Year Survival

Adjuvant
Adjuvant Systemic Surgery Percent Benefit
Systemic Surgery Therapy Alone
Therapy Alone (percent) (percent) Absolute Relative

Node-Positive Group
(Risk of Death = 45 percent)
Patients randomized 500 500 64 55 9 20
Deaths 180 225

Node-Negative Group
(Risk of Death = 8 percent)
Patients randomized 500 500 94 92 2 20
Deaths 32 40

*Assuming a reduction of 20 percent in odds of death.

tients at higher risk for recurrence and
death obtain a greater absolute benefit
than those with a smaller initial risk. Un-
derstanding these differences is important
in calculating risk:benefit ratios for adju-
vant systemic treatments.
World Overview of Randomized
Trials of Adjuvant Therapy
In 1985, the EBCTCG pooled the data
from all available prospective, random-
ized clinical trials of adjuvant systemic
therapy for operable breast cancer and
performed an overview, or meta-anal-
ysis.22 This meta-analysis, because of the
large number of patients included, pro-
vided much greater statistical power than
could be obtained from any individual
clinical trial and established that adju-
vant chemotherapy or adjuvant tamox-
ifen produced significant reductions in
the annual odds of recurrence and annu-
al odds of death compared with no adju-
vant systemic treatment. The overview
also confirmed that combination chemo-
therapy was superior to single-agent
chemotherapy.
In addition, the EBCTCG meta-
analysis strongly suggested that the effi-
cacy of chemotherapy was greater in
women younger than 50 years, while the
benefit of tamoxifen was most pro-
nounced in women aged 50 years and old-
er. It also documented that the relative
benefits obtained from tamoxifen, ovari-
an ablation, or polychemotherapy were
consistent regardless of the number of in-
volved nodes, although they varied ac-
cording to age and estrogen-receptor
(ER) status.
The EBCTCG meta-analysis was

Vol. 45 No. 4 July/august 1995 203

 A d j u v a n t s y s t e m i c t h e r a p y
updated and reanalyzed in 1990.23 For the
update, data from 77,000 women includ-
ed in 133 randomized clinical trials were
available. At the time of analysis, there
had been 31,000 recurrences and 24,000
deaths. The conclusions of the first world
overview were confirmed by the second
meta-analysis. Highly significant reduc-
tions in the annual odds of recurrence
and death were observed in trials using
tamoxifen alone, polychemotherapy
alone, ovarian ablation alone, or combi-
nations of hormone therapy and chemo-
therapy. The estimated reductions in
odds of recurrence and mortality after ad-
juvant tamoxifen, polychemotherapy, or
ovarian ablation are demonstrated in
Table 2.
RESULTS OF TAMOXIFEN TRIALS
The overall relative reduction in annual
odds of recurrence with adjuvant tamox-
Women with ER-rich tumors derived a
greater benefit from adjuvant tamoxifen
than did those with ER-poor tumors
ifen was 25 percent, while the relative
reduction in odds of death was 17 per-
cent.27-46 These findings were highly sta-
tistically significant (P<0.00001). Analysis
of these results by age suggested that
while the reduction in odds of recurrence
was significant in all age groups, the re-
duction in odds of death was significant
only in women older than 50 years.
The EBCTCG meta-analysis also
suggested that the efficacy of tamoxifen
in older women (aged 50 years and older)
was similar whether it was given alone or
in association with chemotherapy.22 On
the other hand, for women younger than
50 years, the benefit from tamoxifen was
apparent only if it was administered
alone. However, these conclusions result-
204
F o r B r e a s t C a n c e r
ed from indirect comparisons.
The efficacy of adjuvant tamoxifen
was also related to the ER content of
the tumor. Women with ER-rich tumors
derived a greater benefit from adjuvant
tamoxifen than did those with ER-poor
tumors.
RESULTS OF OVARIAN ABLATION
TRIALS
The EBCTCG meta-analysis demon-
strated a significant benefit from adju-
vant ovarian ablation. Twelve random-
ized trials of ovarian ablation begun
before 1985 and involving a total of 4,000
women were examined.12-14,22,23 The
overview analyzed only the results in the
1,817 premenopausal women (934 of
whom had ovarian ablation). Follow-up
of up to 15 years was available for these
trials, which demonstrated overall reduc-
tions in odds of recurrence and death of
26 percent and 25 percent, respectively,
with ovarian ablation.
The effects of ovarian ablation ap-
peared greater when it was the only adju-
vant therapy (30 percent and 28 percent
reductions in odds of recurrence and
death, respectively) than when it was
used in association with cytotoxic thera-
py (21 percent and 19 percent, respec-
tively). These differences were highly
statistically significant despite the rela-
tively small number of patients included
in these trials (in comparison with those
who participated in trials of adjuvant ta-
moxifen or chemotherapy). Further-
more, the differences between the treat-
ed and the control groups continued to
increase with time.
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 C A C a n c e r J C l i n 1 9 9 5 ; 4 5 : 1 9 9 - 2 2 6

Table 2
Results of Adjuvant Hormone Therapy
and Chemotherapy in Randomized Trials*

Reduction in Annual Odds of

No. of Patients Recurrence Death
Treatment Patient Group Randomized (percent) (percent)

Tamoxifen All 30,081 25±2 16±2

<50 years 8,612 12±4 6±5
≥50 years 21,280 29±2 20±2

Ovarian ablation <50 years 1,817 26±6 25±7

Chemotherapy All 18,403 21±2 11±2

<50 years 6,103 28±4 17±4
≥50 years 12,300 17±3 9±3

*The results for tamoxifen were derived from 40 randomized trials;,those for ovarian ablation from 12
randomized trials, and those for chemotherapy from 90 randomized trials.
Data from the Early Breast Cancer Trialists Collaborative Group.22,23

RESULTS OF CHEMOTHERAPY TRIALS perioperative chemotherapy.

When the results of all trials of
chemotherapy versus no chemotherapy
were combined, the overall reductions in
annual odds of recurrence and death
were 21 percent and 11 percent, respec-
tively. The magnitude of these effects was
much greater in women younger than 50
years (28 percent and 17 percent) than in
those aged 50 years and older (17 percent
and nine percent), although even the re-
sults in older women were highly statisti-
cally significant. Comparing prolonged
polychemotherapy with short preopera-
tive and perioperative chemotherapy, the
reductions in annual odds of recurrence
and death were 41 percent and 32 per-
cent, respectively, demonstrating the
much greater efficacy of prolonged com-
bination chemotherapy compared with
Most chemotherapy trials included
in the first and second meta-analyses were
first-generation trials of single-agent cyto-
toxic therapy (e.g., cyclophosphamide,16
melphalan,18 or thiotepa17) or trials of
combination therapy, such as the fre-
quently used combination of cyclophos-
phamide, methotrexate, and 5-fluoro-
uracil (CMF) or less frequently used
combinations, such as cyclophosphamide,
5-fluorouracil, and prednisone (CFP)47 or
melphalan, methotrexate, and 5-fluoro-
uracil (LMF).24 Few studies of anthracy-
cline-based regimens48,49 were included,
and with the relatively short follow-up
available in those studies at the time of
the analysis, no substantial conclusions
could be reached on the relative merits of
anthracycline-based combinations.

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 A d j u v a n t s y s t e m i c t h e r a p y F o r B r e a s t C a n c e r

Table 3
Controversies in Adjuvant Systemic Therapy
for Breast Cancer

■ Optimal chemotherapy regimen

■ Role of anthracyclines
■ Timing of adjuvant chemotherapy
■ Duration of adjuvant chemotherapy
■ Duration of adjuvant hormone therapy
■ Combined chemotherapy and hormone therapy
■ Role of immunotherapy
■ Dose intensity of chemotherapy
■ Sequencing chemotherapy and radiation therapy
■ Who should and should not receive adjuvant systemic therapy

Controversies in Adjuvant Systemic standard regimen for adjuvant chemo-

Therapy for Breast Cancer
Despite the determination that the three
adjuvant systemic treatments used to
date are in fact beneficial, there are sever-
al remaining areas of controversy for
which the existing data do not provide
compelling answers (Table 3).
OPTIMAL CHEMOTHERAPY REGIMEN
It has been clearly established that poly-
chemotherapy is superior to monothera-
py in reducing odds of both recurrence
and death.22,23 Most trials included in the
EBCTCG meta-analysis described above
were based on CMF-type combinations.
Indirect comparisons in the overview sug-
gested that CMF was superior to other
polychemotherapy regimens. However,
there have been few randomized trials
that provide direct evidence of this find-
ing. Nevertheless, based on the available
information, the classic CMF combina-
tion (days one and eight, oral cyclopho-
sphamide, 28-day cycle) is an effective
therapy.50
THE ROLE OF ANTHRACYCLINES
Doxorubicin and epirubicin are consid-
ered the most effective agents against
metastatic breast cancer.51 Doxorubicin-
containing regimens have been shown in
prospective, randomized trials to produce
higher overall and complete response
rates and longer durations of response
and survival for patients with metastatic
breast cancer compared with regimens
without anthracyclines. Anthracycline-
containing regimens have been used in
the adjuvant setting since 1973, so there is
extensive experience with these agents,
and they have a long record of safety that
now extends to 20 years.48,49
With the standard dose and schedule
of administration used for doxorubicin
(or epirubicin) and a total cumulative
dose of less than 400 mg/m2, the incidence
of cardiac toxicity has been less than one
percent in published series.52 To date, late
deterioration of cardiac function in adult

206 Ca—A cancer Journal for Clinicians

 C A C a n c e r J C l i n
patients who received adjuvant anthracy-
clines has not been reported.
Although the acute toxicities of an-
thracycline-containing regimens were re-
ported in the past to be greater than those
associated with CMF, these have been re-
evaluated in the context of modern sup-
portive care. Nausea and vomiting are
better controlled with newer antiemetics,
such as ondansetron53 and granisetron,
and hematologic toxicity is not markedly
different between the two combinations.
Total alopecia is more frequent with the
anthracycline-containing regimens, but
CMF also produces marked alopecia in
more than 50 percent of patients.54
A randomized trial reported by Fish-
er et al55 compared four cycles of doxoru-
bicin and cyclophosphamide (AC) with
It has been clearly established that
polychemotherapy is superior to monotherapy in
reducing odds of both recurrence and death.
six cycles of CMF in the adjuvant treat-
ment of node-positive breast cancer. The
efficacy was similar, but treatment with
AC was preferred by patients and nurses
alike, in part because of better tolerance
and in part because of the convenience of
completing adjuvant therapy in three
months as opposed to the six months rec-
ommended for CMF.
Several prospective, randomized tri-
als have compared anthracycline-contain-
ing and non-anthracycline-containing ad-
juvant chemotherapy regimens (Table
4).55-60 Three of seven trials of direct com-
parisons56-58 showed that the anthracy-
cline-containing regimens produced sig-
nificantly superior relapse-free rates
compared with the non-anthracycline-
containing regimens, and two trials56,57
demonstrated statistically significant im-
provements in overall survival rates. No
trial suggested that the anthracycline-
containing regimen was inferior. Better
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1 9 9 5 ; 4 5 : 1 9 9 - 2 2 6
designed trials, which are likely to answer
the question of the difference in thera-
peutic ratio,59,60 have a relatively short
follow-up, so additional time will be nec-
essary to obtain a definitive answer.
Four additional randomized trials
were designed to address a different
question: whether adding an anthracy-
cline-containing regimen to CMF with
vincristine and prednisone (VP) im-
proves outcome.61-64 Two of these four
trials demonstrated a statistically signifi-
cant improvement in disease-free sur-
vival61,64 for the doxorubicin-containing
regimen. Although the major objective of
these trials was to test the Goldie-Cold-
man hypothesis using non-cross-resistant
regimens, they also support the use of
doxorubicin in this setting. Another trial,
based on the use of non-cross-resistant
regimens, tested the sequence of adminis-
tration of two regimens, one containing
doxorubicin.65 The result favored the se-
quential use of the two regimens, as op-
posed to the alternating schedule of ad-
ministration.
Additional randomized trials or a
meta-analysis of all existing trials of an-
thracycline-containing regimens will be
needed to definitively determine their
therapeutic efficacy. However, the data
discussed above suggest that anthracy-
cline-containing regimens may be superi-
or to other combinations, and the exten-
sive experience with these regimens for
both metastatic disease and adjuvant
therapy, as well as their established safety
record, makes them an excellent choice
for adjuvant therapy.
In the absence of overwhelming su-
periority of anthracyclines in the adjuvant
setting, a reasonable approach would be
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Table 4
Randomized Clinical Trials to Establish the Effect of
Anthracyclines in Adjuvant Therapy for Breast Cancer

Significant Reduction
No. of Patients (P value) in
Reference Follow-up
(Study) Treatments (months) Anthracycline Control Recurrence Mortality

Misset et al57 AVCF vs CMF 120 137 112 0.04 0.01

(Oncofrance)

Beuzeboc et al56 MMiAC vs MMiFC 96 57 64 — 0.03

Fisher et al58 PAF vs PF 88 344 353 0.01 0.11

(NSABP B-11)

Fisher et al58 PAFT vs PFT 87 539 554 No 0.15

(NSABP B-12)

Moliterni et al62 CMF→A vs CMF 60 218 215 No No

(Milan)

Abeloff et al64 CMFPrTH/VbATHT

vs CMFPrT 61 270 263 0.04 No

Fisher et al55 AC vs CMF 44 734 739 No No

(NSABP B-15)

Carpenter et al59 CAF vs CMF 60 — 528* — No No

Marty et al60 FEC vs CMF 54 319

Perloff et al61 CMFVPr→VATH

vs CMFVPr 23 — 897* — 0.01 No

Chaitchik et al63 CMF/VA vs CMF — 202* — — No

(Israel)

*Study only reported in abstract form: the abstracts did not provide numbers of patients in each arm.

A = doxorubicin P = melphalan
V = vincristine T = tamoxifen
C = cyclophosphamide Pr= prednisone
F = 5-fluorouracil H = Halotestin (fluoxymesterone)
M = methotrexate Vb = vinblastine
Mi = mitomycin E = epirubicin

208 Ca—A cancer Journal for Clinicians

 C A C a n c e r J C l i n
to use CMF for low-risk patients (node-
negative), and 5-fluorouracil, doxoru-
bicin, and cyclophosphamide (FAC) or
AC for higher-risk groups.
TIMING OF ADJUVANT THERAPY
Preclinical experiments suggested that
early initiation of adjuvant systemic ther-
apies was important to obtain optimal
therapeutic results in terms of relapse-
free and overall survival rates.9 However,
retrospective analyses of several clinical
trials of adjuvant therapy have given con-
flicting results.27,66-69 In some,66 patients
who began adjuvant chemotherapy soon
after definitive surgery had higher re-
lapse-free and overall survival rates than
those who started their adjuvant chemo-
therapy late in the postoperative period.
However, in other retrospective analyses,
this advantage could not be confirmed.67-69
Similar data do not exist for adjuvant hor-
mone therapy, except for a recent ab-
stract that suggested that starting adju-
vant tamoxifen even more than two years
after the diagnosis of primary breast can-
cer is of some therapeutic benefit, result-
ing in prolonged disease-free survival.70
The only prospective trial ever de-
signed to determine the optimal timing of
postoperative adjuvant systemic therapy
was performed by the Ludwig Breast
Cancer Study Group27,71 and suggested
no additional benefit from the initiation
of adjuvant chemotherapy immediately
after the surgical procedure (periopera-
tive and postoperative cyclophospha-
mide, methotrexate, 5-fluorouracil, and
prednisone [CMFP]) compared with a
delay of three to four weeks (standard
postoperative CMFP).
In most reported adjuvant systemic
therapy trials, chemotherapy or hormone
therapy was required to start within 30 or
60 days after diagnosis or surgery. There-
fore, we have limited information about
the efficacy of adjuvant systemic treat-
ment initiated beyond 60 days after
surgery for primary breast cancer. In a
Vol. 45 No. 4 July/august 1995
1 9 9 5 ; 4 5 : 1 9 9 - 2 2 6
few controlled trials, chemotherapy was
started at different times after diagnosis.
However, this was done to avoid antago-
nistic or toxic interactions between radia-
tion therapy and anthracyclines, and in
addition to the timing of chemotherapy,
the type of chemotherapy used also
changed. Therefore, these studies cannot
help define the optimal time for initiating
adjuvant chemotherapy.
Several ongoing randomized trials
compare simultaneous chemotherapy and
hormone therapy with sequential chemo-
therapy and hormone therapy in the ad-
juvant setting. While this may give an in-
dication of the importance of timing of
initiation of adjuvant hormone therapy,
the question may be confounded by is-
sues of drug interactions between simul-
taneous chemotherapy and tamoxifen or
chemotherapy and ovarian ablation. In
addition, chemotherapy starts early in all
these trials, so no information about the
timing of cytotoxic therapy can be expect-
ed from them.
DURATION OF ADJUVANT
CHEMOTHERAPY
The initial programs of adjuvant chemo-
therapy called for treatment durations of
one or two years.18,19,48 This was accompa-
nied by problems with patient compli-
ance and increasing or cumulative side
effects, as well as concerns about the ad-
ministration of very large cumulative
doses of cytotoxic agents, some of which
have mutagenic effects. Several prospec-
tive, randomized trials have addressed
the issue of duration of adjuvant chemo-
therapy (Table 5).71-80
Both indirect and direct compar-
isons suggest that polychemotherapy ad-
ministered for about six months (or six
cycles) is as effective as chemotherapy
(with the same regimen) administered for
a longer time.20,24 There are a few reports
suggesting equivalent efficacy of adjuvant
chemotherapy given for three cycles com-
pared with adjuvant chemotherapy with
209
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Table 5
Randomized Clinical Trials of the Effect of Duration of
Adjuvant Chemotherapy on Disease-Free and Overall Survival

Longer Treatment Improved

Durations Disease-Free Overall
Reference Regimen of Therapy Survival Survival

Tancini et al72 CMF 6 vs 12 months No No

Jungi et al73 LeuMF 6 vs 24 months No No
Henderson et al74 AC 15 vs 30 weeks No No
Velez-Garcia et al75 CMF 6 vs 24 months. No No
Rivkin et al76 CMFVP 12 vs 24 months No No
Scheurlen77 CMF 3 vs 6 months No No
Falkson et al80 CMFPT 4 vs 12 months No No
Nissen-Meyer et al78 CMFV 1 vs 12 months Yes No
Ludwig Breast Cancer
Study Group71 CMFL 1 vs 6 months Yes Yes
79
Levine et al CMFVP ± AT 12 vs 36 weeks Yes Yes

C = cyclophosphamide V = vincristine
M = methotrexate P = prednisone
F = 5-fluorouracil L = leucovorin
Leu = chlorambucil (Leukeran) T = tamoxifen
A = doxorubicin (Adriamycin) NS = not stated

the same regimen for six cycles.74,77 How-
ever, one cycle of perioperative chemo-
therapy was inferior to six cycles of post-
operative chemotherapy, and at least one
report suggested that adjuvant chemo-
therapy for periods substantially shorter
than six months (or six cycles) produced
inferior disease-free and overall survival
rates compared with the standard six cy-
cles of chemotherapy.79
Therefore, until further evidence de-
velops, we believe that six cycles of adju-
vant chemotherapy (CMF, FAC, or 5-flu-
orouracil, epirubicin, cyclophosphamide
[FEC]) is an appropriate standard. Based
on the comparison of six cycles of adju-
vant CMF to four cycles of AC, four cy-
cles of AC at the dose and schedule re-
ported by the NSABP56 also represents
appropriate treatment and is probably
more convenient for the patient.
Several second- and third-genera-
tion adjuvant chemotherapy trials are in
the process of exploring the concept of al-
ternative, non-cross-resistant chemother-
apy.61-64 In this context, after the adminis-
tration of four cycles of AC or six cycles
of CMF, intensification therapy with ei-
ther a different drug (single-agent dox-
orubicin or single-agent paclitaxel) or a

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 C A C a n c e r J C l i n
different combination (vinblastine, dox-
orubicin, thiotepa, and fluoxymesterone
[VATH] or methotrexate and vinblastine
[MVb]) is administered for a limited
number of cycles. Such approaches are
conceptually attractive, but their thera-
peutic superiority needs to be demon-
strated by appropriately designed clinical
trials.
DURATION OF ADJUVANT HORMONE
THERAPY
Preclinical experiments have demonstrat-
ed that tamoxifen has long-term suppres-
sive effects on the proliferation of breast
cancer cell lines. However, these same ex-
periments have shown that even after
long-term administration, if tamoxifen
was stopped, tumor regrowth occurred.81
Based on this experimental evidence, the
duration of adjuvant tamoxifen has in-
creased in recent adjuvant hormone ther-
apy protocols.22,23
In the initial studies, one or two
years of antiestrogen therapy was admin-
istered. In fact, most of the information
about adjuvant tamoxifen contained in
the EBCTCG meta-analysis22 relates to
the results of one or two years of adjuvant
tamoxifen. Indirect comparisons in the
meta-analysis allowed tentative conclu-
sions regarding the efficacy of tamoxifen
based on the duration of administration.
These analyses suggested that tamoxifen
administered for less than two years re-
sulted in reductions of annual odds of re-
currence and death of 16 percent and 11
percent, respectively. Tamoxifen given
for an average of two years resulted in de-
creases in recurrence and death rates by
27 percent and 18 percent, respectively.
Finally, tamoxifen given for more than
two years resulted in decreases in recur-
rence and death rates of 38 percent and
24 percent, respectively.
When only randomized trials that di-
rectly addressed the issue of duration of
tamoxifen therapy were taken into con-
sideration, there was a substantially larg-
Vol. 45 No. 4 July/august 1995
1 9 9 5 ; 4 5 : 1 9 9 - 2 2 6
er decrease in the odds of recurrence with
longer duration of administration of ta-
moxifen (22 ± 8 percent). However, these
direct comparisons did not document a
significant decrease in the odds of death
(7 ± 11 percent).23 Consequently, in view
of the increasing awareness of adverse ef-
fects related to long-term administration
of tamoxifen (some of them life threaten-
ing), it is imperative to determine wheth-
er longer administration of this agent is
necessary, beneficial, and justified.82 On-
going trials will establish whether five
years of adjuvant tamoxifen is superior to
two years and whether indefinite admin-
istration of tamoxifen improves the ther-
apeutic results compared with five years
of antiestrogen treatment.
At this time, it is apparent that two
years of tamoxifen given postoperatively
has a clear-cut therapeutic benefit in re-
ducing odds of recurrence and death.
While the administration of tamoxifen
for five years is reasonably safe, the need
for prolonged administration beyond two
to three years remains to be confirmed.
COMBINED CHEMOTHERAPY AND
HORMONE THERAPY
Several trials have compared the simul-
taneous administration of adjuvant che-
motherapy and hormone therapy with
adjuvant chemotherapy alone or adju-
vant hormone therapy alone.27,40,42,44,83-93
About half of these trials have shown an
added benefit in disease-free survival
with the combined use of hormone thera-
py and chemotherapy compared with
chemotherapy alone, but a significant
overall survival benefit was observed only
in three trials83,86,93 (in the rest the benefit
was not significant).
The EBCTCG meta-analysis sug-
gested that the addition of tamoxifen to
standard adjuvant chemotherapy provid-
ed an increased benefit, in terms of both
relapse-free and overall survival for pa-
tients aged 50 years and older.22 Similar
comparisons in women younger than 50
211
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Table 6
Indirect Estimation of the Benefit of
Polychemotherapy plus Endocrine Therapy*

Annual Reduction in Odds of

Recurrence Death
Combination (percent) (percent)
Adding tamoxifen to chemotherapy
Chemotherapy + tamoxifen vs chemotherapy
Age ≥50 years 28±3 20±4
Age <50 years 7±4 3±5

Adding chemotherapy to tamoxifen

Tamoxifen + chemotherapy vs tamoxifen
Age ≥50 years 26±5 10±7
Age <50 years 32±16 -6±23

Adding ovarian ablation to chemotherapy

Chemotherapy + ovarian ablation vs chemotherapy
Age < 50 years 29±9 19±11

*Data from Early Breast Cancer Collaborative Group.23

years failed to demonstrate an improve-
ment in relapse-free survival or a signifi-
cant overall survival benefit in this group
(Table 6).
The addition of chemotherapy to ta-
moxifen has resulted in conflicting re-
ports. In most trials, no disease-free or
overall survival advantage was observed
compared with tamoxifen alone, while in
a few,85,90,94,95 the combination gave sig-
nificantly better results. Whether these
differences in outcome are related to pa-
tient selection, the type of therapy used,
or the statistical power of the study re-
mains to be determined.
One of the shortcomings of many of
these studies is the use of combined ther-
apies in patients unselected by hormone-
receptor status. One could hypothesize
that patients most likely to benefit from
combined chemotherapy-hormone thera-
py are those with low or modest ER con-
tent. In contrast, those with clearly ER-
negative tumors would be unlikely to
benefit from the combination and should
be treated with chemotherapy, and pa-
tients with strongly ER-positive tumors
may need only tamoxifen. In the Ludwig
III trial,27,94 the overall analysis of women
aged 50 years and older demonstrated
that the combination of chemotherapy
and hormone therapy was superior to
hormone therapy alone or to no adjuvant
therapy. However, when patients were
stratified by ER status, the results with
hormone therapy alone were equivalent
to those with the combination in patients
with ER-positive tumors, while the com-
bination was superior in patients with
ER-negative tumors, a group that would
presumably derive just as much benefit
from chemotherapy alone as from the

212 Ca—A cancer Journal for Clinicians

 C A C a n c e r J C l i n
combination.94 Unfortunately, there was
no chemotherapy-alone arm in this trial.
Until additional information be-
comes available about combined-mo-
dality versus single-modality therapy, it
would be reasonable to offer tamoxifen
alone to low-risk, receptor-positive post-
menopausal patients and a combination
of both tamoxifen and chemotherapy to
those postmenopausal patients with high-
risk disease.
In unselected populations of pa-
tients, the combination of oophorectomy
and chemotherapy for premenopausal
women appears to have no benefit over
either treatment alone (Table 6). Intu-
itively, one would expect the hormone re-
ceptor-positive group to benefit; howev-
er, evidence in support of this hypothesis
is lacking.27,96,97 Therefore, it remains to
be demonstrated whether the combina-
tion is better than surgical oophorectomy
alone or chemotherapy alone.
A recently published report from the
Scottish Cancer Trials Breast Group
compared CMF alone with ovarian abla-
tion alone in premenopausal patients
with primary breast cancer.98 The overall
relapse-free and overall survival rates for
the two groups were identical. However,
when broken down by ER status,
provocative results appeared. For the
ER-poor group, CMF was significantly
superior to oophorectomy in terms of dis-
ease-free and overall survival. Converse-
ly, for ER-rich tumors, oophorectomy
appeared superior to CMF. This obser-
vation needs to be confirmed by addition-
al trials, whether using surgical ovarian
ablation or luteinizing hormone-releasing
hormone analogues.
The combination of chemotherapy
and hormone treatment in premeno-
pausal women is further complicated by
overlapping effects. For instance, about
two thirds of premenopausal women be-
come amenorrheic during adjuvant
chemotherapy.99-101 Whether amenorrhea
occurs depends on age, type of cytotoxic
agents used, and duration of treatment.
Vol. 45 No. 4 July/august 1995
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While most women younger than 30
years continue to menstruate during and
after chemotherapy, more than 90 per-
cent of women older than 40 years be-
come permanently amenorrheic after ad-
juvant CMF, AC, or FAC.
With this in mind, one questions
whether adding ovarian ablation to the
treatment of a patient who is already
amenorrheic as a consequence of adju-
vant chemotherapy would result in addi-
tional benefit. Furthermore, one would
have to question the use of ovarian abla-
tion in women with hormone-receptor-
negative tumors. This would leave only
the group of women who are premeno-
pausal, have hormone-receptor-positive
tumors, and continue to menstruate regu-
larly during and after adjuvant chemo-
therapy in whom to assess the efficacy of
ovarian ablation added to adjuvant che-
motherapy or done instead of adjuvant
chemotherapy. Large numbers of pa-
tients will need to be studied to clarify
this issue.
ROLE OF ADJUVANT IMMUNOTHERAPY
Several immunomodulators have been
investigated in the management of prima-
ry breast cancer. Among them, bacillus
Calmette-Guérin (BCG), the methanol
extracted residue of BCG (MER), lev-
amisole, Corynebacterium parvum, inter-
feron alfa, and polyadenylic-polyuridylic
acid (poly A:U) have been used in vari-
ous randomized trials.102 Of these, poly
A:U, administered postoperatively as the
only systemic adjuvant therapy, has been
reported in a single study to provide su-
perior relapse-free and overall survival
rates compared with surgery only.103 All
other trials with immunotherapy or bio-
logic therapy have failed to demonstrate
an advantage in terms of disease-free or
overall survival. In the absence of confir-
matory trials for the poly A:U study,
there are insufficient data at the present
time to justify the use of any adjuvant im-
munotherapy for breast cancer.
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DOSE INTENSITY OF CHEMOTHERAPY regimens with hematopoietic growth fac-

Retrospective analyses have suggested
that higher doses and higher dose-inten-
sity of adjuvant chemotherapy are asso-
ciated with superior disease-free and
overall survival.104 However, these ret-
rospective analyses had serious limita-
tions, including the inability to deter-
mine retrospectively whether dose
reductions were related to toxicity or
were associated with higher-risk patient
populations with a higher expected
treatment-failure rate to start with. Re-
cently, prospectively randomized trials
tors or autologous stem cell support for
the adjuvant treatment of patients with
ten or more positive axillary lymph nodes
have suggested a substantial survival ben-
efit.109,110 This is a subgroup with a notori-
ously poor prognosis after surgery alone,
or even surgery followed by standard ad-
juvant chemotherapy.111 However, the se-
lection process for entering patients in
the high-dose chemotherapy protocols
precludes any meaningful comparison
with nonrandomized controls. Ongoing
prospective, randomized trials will deter-

While the administration of tamoxifen

for five years is reasonably safe, the need for
prolonged administration beyond two to three
years remains to be confirmed.

have been reported that suggest that
dose-intensive therapy (within the stan-
dard dose range) is important in the de-
termination of outcome.105,106
A recent report from the Cancer and
Leukemia Group B suggested that doses
50 percent lower than the “standard”
dose produced inferior outcome, both in
terms of relapse-free and overall
survival.107 Another interpretation of
these data would suggest that patients
with HER-2/NEU-overexpressing tu-
mors would benefit from dose-intensive
therapies, while other patients would not.
It remains to be determined whether
doses higher than the standard dose or
the maximum tolerated dose without
growth factor support would further im-
prove the efficacy of adjuvant chemo-
therapy. Preliminary results of a random-
ized trial to evaluate the efficacy of
dose-intense adjuvant chemotherapy with
doxorubicin and cyclophosphamide failed
to support a benefit of dose increases for
cyclophosphamide above the standard
range.108
Trials of high-dose chemotherapy
mine whether high-dose chemotherapy
provides a benefit over standard-dose
chemotherapy for patients with high- or
intermediate-risk breast cancer.
SEQUENCING CHEMOTHERAPY AND
RADIATION THERAPY
Many patients with primary breast can-
cer, especially those treated with breast
conservation surgery, receive postopera-
tive radiation therapy. Most of these
patients also require adjuvant chemo-
therapy. The optimal sequence for ad-
ministering adjuvant chemotherapy and
radiation therapy has not been deter-
mined. Table 7 shows the potential sched-
ules of administration.
Some retrospective analyses have
suggested that delaying radiation therapy
may result in increased local recurrence
rates.112,113 On the other hand, there are
theoretical reasons to believe that for pa-
tients at high risk of systemic recurrence,
early institution of adjuvant chemothera-
py is imperative. There are also concerns
about the ability to deliver the full dose of

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 C A C a n c e r J C l i n
Table 7
Sequence Options for Adjuvant Chemotherapy
and Radiation Therapy
■ Chemotherapy
■ Simultaneous administration
■ Sandwich
(Chemotherapy x 3
■ Radiation therapy
chemotherapy or dose-intensive chemo-
therapy in association with or following
adjuvant radiation therapy. However, the
optimal schedule for administration of
chemotherapy and radiation therapy can
be determined only by prospective, ran-
domized trials, several of which are cur-
rently in progress. Until these results be-
come available and based on the existing
evidence, we recommend the administra-
tion of all adjuvant chemotherapy before
the administration of adjuvant radiation
therapy.
TOXICITY OF ADJUVANT HORMONE
THERAPY
In general terms adjuvant hormone ther-
apies are very well tolerated. Short-term
or acute side effects of tamoxifen include
hot flushes, nausea, vomiting, fluid reten-
tion, weight gain, and thrombocytopenia.
Although uncommon, deep venous and
arterial thromboses have been reported,
especially when tamoxifen is adminis-
tered simultaneously with chemotherapy.
Severe depressive episodes have been re-
ported in less than five percent of patients
who take tamoxifen and may require dis-
continuation of therapy. Recent reports
suggest a significant increase in the risk of
developing endometrial cancer, some-
times with fatal outcome, after prolonged
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Radiation therapy
Radiation therapy Chemotherapy x 3)
Chemotherapy
tamoxifen therapy.114-116
Ovarian ablation is accompanied by
the effects of premature menopause, in-
cluding early onset of osteoporosis117,118
and adverse changes in serum lipid pro-
file that increase the frequency and sever-
ity of adverse cardiovascular events.119
TOXICITY OF ADJUVANT
CHEMOTHERAPY
The acute side effects of chemotherapy
include nausea, vomiting, anorexia, alo-
pecia, mucositis, leukopenia, neutrope-
nia, thrombocytopenia, and infections.
Modern supportive care can render most
of these effects tolerable, especially be-
cause they are self-limited and totally re-
versible. Infectious complications must
be managed aggressively to avoid the
rare fatality.
For premenopausal women, regi-
mens that contain an alkylating agent of-
ten result in amenorrhea, which is related
to age at the time of exposure and the du-
ration (or total dose) of alkylator therapy.
For patients with irreversible amenor-
rhea, the long-term consequences might
be similar to those experienced after
ovarian ablation.
There has been no documented evi-
dence of an increased risk of second solid
malignancies after adjuvant chemothera-
215
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Table 8
Decision Points in the Selection of
Adjuvant Systemic Treatments

■ Determination of risk

■ Identification of treatment options

■ Analysis of comorbidity

■ Determination of benefits

■ Risk-benefit assessment

■ Selection of therapy

py. However, myelodysplastic syndromes COLLATERAL BENEFITS OF ADJUVANT

and acute leukemias occur with greater
frequency, and these secondary leu-
kemias are less responsive to therapy.
Thus, among 5,299 patients treated with
melphalan, there were 27 cases of acute
leukemia and seven of myelodysplastic
syndrome, for a 10-year risk of 1.68
percent.120 Cyclophosphamide-contain-
ing regimens are less leukemogenic,121
and the excess risk of leukemia associated
with adjuvant CMF is about five cases per
10,000 treated women at 10 years. Re-
cently, a newly recognized secondary
leukemia was described that seems to be
associated with the use of topoisomerase-
inhibitors (etoposide, doxorubicin, epiru-
bicin, etc.). It is usually M4/M5 in the
French-American-British classification,
and it appears during the early years of
follow-up.121,122 Its exact incidence and
clinical course are currently under assess-
ment in several prospective trials.
Both radiation therapy and chemo-
therapy are independently associated
with increased risk of secondary leu-
kemias. Preliminary evidence suggests
that when both modalities are combined,
the risk of leukemia is higher than that
observed with chemotherapy alone.123
TAMOXIFEN
As a mixed estrogen agonist-antagonist,
tamoxifen has multiple effects, some of
them clearly beneficial to the host. It has
been shown that the administration of ad-
juvant tamoxifen results in a significant re-
duction in the risk of developing a second
primary (contralateral) breast cancer.124
Presumably as a result of its agonist effect,
tamoxifen preserves bone mineral
density125 and alters favorably the blood
lipid profile traditionally associated with
cardiovascular risk factors.126 The magni-
tude of benefit, in terms of actual decrease
in coronary events or osteoporotic frac-
tures, remains to be determined.
WHO SHOULD AND SHOULD NOT
RECEIVE ADJUVANT SYSTEMIC
THERAPY?
Since the publication of the many ran-
domized trials that established the effica-
cy of adjuvant systemic treatments, and
especially since the publication of the
most recent meta-analysis of all random-
ized trials,23 it has been generally accept-
ed that all patients with node-positive pri-
mary breast cancer (except those with

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 C A C a n c e r J C l i n
Table 9
Probability of Recurrence at Five Years
Based on Tumor Characteristics in Patients with
Lymph-Node-Negative Breast Cancer
Tumor Characteristics
Noninvasive
Tumor size <1 cm
Nuclear grade 1 (good)
Low S-phase fraction
Tumor size <2 cm
Diploid
Aneuploid
Nuclear grade 2 (intermediate)
Estrogen-receptor positive
Nuclear grade 3 (poor)
High S-phase fraction
Estrogen-receptor negative
High HER-2, estrogen-receptor
positive, <3 cm in size
Aneuploid, high cathepsin D
Modified with permission from McGuire et al.128
significant coexistent morbidity) should
receive adjuvant systemic treatment. Fur-
thermore, many patients with node-nega-
tive breast cancer have adverse prognos-
tic indicators that place them in the
moderate- to high-risk category. These
patients, too, should receive adjuvant sys-
temic therapy.
Table 8 outlines the decision points
in the selection of adjuvant systemic
treatments. First, the clinician must eval-
uate histologic, biochemical, and clinical
parameters to determine the patient’s
risk of relapse/metastases. While this is
straightforward for node-positive pa-
tients, it is somewhat more complicated
Vol. 45 No. 4 July/august 1995
1 9 9 5 ; 4 5 : 1 9 9 - 2 2 6
Five-Year Probability
of Recurrence (percent)
1
6
7
10
11
12
25
26
27
28
30
33
55
60
for node-negative patients, especially
those with small primary tumors.
There is extensive literature on the
development of new prognostic fac-
tors.127-129 Many of these factors have
been highly significant prognostic indica-
tors in univariate analyses but have limit-
ed value in multivariate analyses, in
which only some of the standard prognos-
tic factors were considered. Table 9 rep-
resents the pooled results of several prog-
nostic factor analyses. Even within the
node-negative group, there is tremen-
dous prognostic heterogeneity, and such
heterogeneity can be identified by cur-
rently available prognostic indicators.128
217
 A d j u v a n t s y s t e m i c t h e r a p y F o r B r e a s t C a n c e r

30 30
Absolute Reduction in Risk of Recurrence (%)

25 25

Probability of Toxicity (%)

20 20

15 15

10 10

5 5

0 0
0 60 50 40 30 20 10 0
Probability of Recurrence at Five Years

Fig. 3. Graphic model to calculate the risk:benefit ratio of adjuvant tamoxifen therapy based on the
probability of benefit documented in the Early Breast Cancer Trialists’ Collaborative Group meta-
analysis,23 the five-year probability of recurrence described in Table 9, and the known frequency of
moderate and serious toxicity of the agent. The light shaded area represents moderate and
severe toxicity; the dark shaded area represents life-threatening toxicity.

Using such prognostic information many more partially described in the lit-
for node-negative breast cancer and in- erature should remain the subject of on-
corporating data on the reductions in the going research.
odds of recurrence derived from the re- The next important step is to evalu-
cent EBCTCG meta-analysis,23 one can ate the various treatment options avail-
demonstrate that the higher the initial able to the patient. For instance, adjuvant
risk of treatment failure, the higher the ovarian ablation would not be a reason-
absolute benefit obtained from either ad- able therapeutic option for a woman aged
juvant chemotherapy or adjuvant hor- 70 years, and adjuvant chemotherapy
mone therapy. It should be stated that would probably not be reasonable for
many of these proposed prognostic fac- someone with severe cardiovascular dis-
tors have not been fully validated, and ease or major immune deficiencies. The
their clinical usefulness remains in ques- determination of the presence and severi-
tion. However, traditional factors, such as ty of coexistent morbid conditions, as well
pathologic tumor size, histologic and nu- as their influence on the selection of thera-
clear grade, hormone-receptor status, py, is essential. Likewise, the clinician
and S-phase fraction, provide sufficient should attempt to determine whether the
information for determination of progno- life expectancy of the patient will be more
sis to determine whether adjuvant sys- limited by the coexistent morbid condi-
temic therapy is indicated and whether tions or by the risks of recurrence and
risk of recurrence and death is low, inter- death from breast cancer. A patient with
mediate, or high. In our opinion, all other severe, uncontrolled heart failure or se-
prognostic factors listed in Table 9 and vere chronic obstructive lung disease who

218 Ca—A cancer Journal for Clinicians

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Table 10
Adjuvant Systemic Therapy for Node-Negative
Breast Cancer outside Clinical Trials

Patient Group Adjuvant Therapy

Noninvasive (DCIS, LCIS) No

Microinvasive No
Invasive cancer <1 cm No
Favorable histology <2 cm
(tubular, mucinous) No
Invasive ductal/lobular ≥1 cm Yes
Favorable histology ≥2 cm Yes

DCIS = ductal carcinoma in situ

LCIS = lobular carcinoma in situ

30 30
Absolute Reduction in Risk of Recurrence (%)

25 25
Probability of Toxicity (%)

20 20

15 15

10 10

5 5

0 0
0 60 50 40 30 20 10 0
Probability of Recurrence at Five Years

Fig. 4. Graphic model to calculate the risk:benefit ratio of adjuvant chemotherapy based on the
probability of benefit documented by the Early Breast Cancer Trialists’ Collaborative Group meta-
analysis,23 the five-year probability of recurrence described in Table 9, and the frequency of mod-
erate to severe toxicities described in the literature. The light shaded area represents moderate
and severe toxicity; the dark shaded area represents life-threatening toxicity.

Vol. 45 No. 4 July/august 1995 219

 A d j u v a n t s y s t e m i c t h e r a p y
Table 11
Recommendations for Standard (Nonprotocol)
Adjuvant Systemic Therapy
The M.D. Anderson Cancer Center Approach
Patient Group
Estrogen-Receptor
Age Status
<50 Negative
<50 Positive
<50 Unknown
≥50 Negative
≥50 Positive
≥50 Unknown
has a simultaneous small, node-negative
breast cancer is much more likely to die of
the coexisting nonmalignant condition
than of breast carcinoma.
Based on the previous considera-
tions, the clinician should be able to
quantify the potential benefits of the
available treatment options. Figure 3 rep-
resents a tool for risk-benefit analysis.
The horizontal axis is the probability of
recurrence at five years. This probability
can be determined from Table 9 or simi-
lar analyses of prognostic factors. Based
on that risk, the vertical axis on the left
side marks the probability of benefit from
tamoxifen (or adjuvant chemotherapy in
Fig. 4), while the vertical axis on the right
marks the probability of severe or life-
threatening toxicity. As the probability of
recurrence decreases, so does the ab-
solute probability of benefit (derived
from the 1992 EBCTCG meta-analy-
sis23). When the benefit line crosses the
horizontal line below which life-threaten-
ing toxicity occurs, the risk of serious or
lethal toxicity exceeds the probability of
220
F o r B r e a s t C a n c e r
Adjuvant Therapy
Tamoxifen Chemotherapy
No Yes
No Yes
No Yes
No Yes
Yes No
or
Yes Yes
Yes Yes
benefit. Based on this graph, a risk-bene-
fit determination can be made with rea-
sonable certainty. A situation in which
the risk of life-threatening toxicity ex-
ceeds the calculated potential benefit pre-
cludes the administration of adjuvant sys-
temic treatment. On the other hand,
adjuvant systemic therapies are clearly in-
dicated when the probability of benefit
exceeds the risk of serious toxicity.
Once it has been determined that
the benefit of adjuvant systemic therapy
exceeds the risks, the treatment is se-
lected. Because of the many remaining
uncertainties in this area and the oppor-
tunities to develop new and more effec-
tive therapies, our choice is to encour-
age all eligible patients to participate in
an ongoing clinical trial of adjuvant
therapy. All major cooperative groups
and several comprehensive cancer cen-
ters have ongoing clinical trials. Infor-
mation about these trials is readily avail-
able through the National Cancer
Institute, the American Cancer Society,
or the Cancer Information Service at all
Ca—A cancer Journal for Clinicians
 C A C a n c e r J C l i n
comprehensive cancer centers.
Tables 10 and 11 show our institu-
tional approach to adjuvant therapy for
patients who elect not to participate in
(or are ineligible for) clinical trials. We
consider that patients with noninvasive or
microinvasive cancer of any histologic
subtype or invasive ductal or lobular car-
cinomas less than 1 cm in largest diameter
are highly curable with local/regional
therapy. Therefore, the potential benefit
from adjuvant systemic therapy is very
small and is probably exceeded by the
likelihood of serious toxic effects. For this
reason, we do not offer systemic therapy
to patients in these groups. Noninvasive
and microinvasive cancers represent 10 to
20 percent of newly diagnosed breast can-
cers. In addition, 50 percent of new breast
cancers are node-negative, and of these,
one third (about 15 percent of the total
number) have tumors less than 1 cm in di-
ameter. Therefore, 25 to 35 percent of pa-
tients with primary breast cancer would
not be offered adjuvant systemic therapy.
All patients younger than 50 years
who would benefit from adjuvant treat-
ment are given chemotherapy. Adjuvant
hormone therapy is not used in this age
group. For patients aged 50 years and
older, the ER status becomes an impor-
tant indicator. Patients with ER-positive
tumors in a low-risk category are treated
with tamoxifen alone. Patients at high
risk of recurrence are treated with com-
bined tamoxifen and chemotherapy. Pa-
tients with ER-negative tumors are treat-
ed with chemotherapy alone. Additional
clinical trials with increased statistical
power and appropriate determination of
ER status will be needed to refine these
recommendations.
Patients with stage III breast can-
cer and patients with more than 10 posi-
tive nodes represent very high-risk
groups. However, until it is determined
that high-dose chemotherapy produces
greater therapeutic benefit than stan-
dard-dose chemotherapy for these
groups, such high-dose therapies cannot
Vol. 45 No. 4 July/august 1995
1 9 9 5 ; 4 5 : 1 9 9 - 2 2 6
be recommended outside of a well-de-
signed clinical trial.
One final comment relates to the im-
portance of accurately and openly infor-
ming a patient about the available alter-
natives, the potential risks, and the
realistic likelihood of benefit. The pa-
tient’s own perceptions of the risk:benefit
ratio should be strongly considered in the
selection of adjuvant systemic treatments.
Adjuvant Therapy for Male Breast
Cancer
Adjuvant systemic therapy for male
breast cancer follows the pattern of adju-
vant systemic therapy for women with
breast cancer. Because of the relative rar-
ity of male breast cancer, all of the infor-
mation available has been obtained by
extrapolation from the results of adjuvant
therapy trials in women and from retro-
spective analyses of single-institution ex-
periences based on small numbers of pa-
tients.130-132 Because there is no evidence
that breast cancer in men behaves differ-
ently from breast cancer in women, until
additional information develops, deci-
sions about adjuvant therapy for men
should parallel those for women with
breast cancer.
Areas of Investigation
The development of new and effective
cytotoxic agents over the last three or
four years and the development of new
and exciting treatment approaches (such
as immunoconjugates, fusion toxins, and
ligand-driven therapy [targeted to the
epidermal growth factor receptor or the
HER-2/NEU oncoprotein]) promise to
add new dimensions to therapy for
metastatic breast cancer and, if success-
ful, to treatment of primary breast can-
cer.133 Paclitaxel and vinorelbine are cur-
rently in clinical trials to evaluate their
contribution to the adjuvant systemic
therapy of early breast cancer. Today, al-
though we enjoy the benefits of progress
221
 A d j u v a n t s y s t e m i c t h e r a p y
made in this field in the last 30 years, it is
ever more important to continue search-
ing for the best answers to the many re-
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