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Update on Adjuvant Chemotherapy for Early Breast Cancer

Update on Adjuvant Chemotherapy for Early Breast Cancer

ABSTRACT: Adjuvant chemotherapy represents a significant advance in the management of early-stage breast cancer and, as such, has saved many lives. Worldwide, adjuvant chemotherapy has benefitted all groups tested, including pre- and postmenopausal women, those with node-negative and node-positive disease, and those with estrogen-receptor (ER)-positive and ER-negative disease. However, the significant number of women who relapse despite adjuvant therapy provides the impetus to develop more efficacious regimens. Results from large randomized clinical trials, which will mature over the next few years, will clarify the potential benefits of the taxanes in the adjuvant setting, provide answers as to the efficacy of a dose-dense approach, and define a role, if any, for high-dose chemotherapy. A shift toward targeted therapies has also begun, with the incorporation of trastuzumab (Herceptin) into the adjuvant setting. Minimizing the long-term toxicity of adjuvant therapy for the large number of women who survive their disease is paramount. This article highlights the need to develop predictive factors to help tailor individual therapy. [ONCOLOGY 14(9):1267-1288, 2000]

Introduction

The last three decades have yielded marked progress in the diagnosis
and management of breast cancer. Not only is the disease being
detected at a much earlier stage through screening mammography and
heightened patient awareness, but the addition of systemic therapy
has also improved survival.[1] The efforts of hundreds of trials,
thousands of investigators, and tens of thousands of women with
breast cancer, have helped establish adjuvant treatment of breast
cancer as effective in prolonging both disease-free and overall
survival.

Adjuvant therapy is the only treatment for breast cancer that
currently offers the prospect of cure by eliminating micrometastases,
even with regimens that are noncurative in metastatic disease.
Adjuvant therapy was initially directed at patients with
node-positive disease; however, with the maturation of clinical trial
data, it became apparent that all patient groups would benefit
significantly from the incorporation of this modality into overall
treatment. Unfortunately, large numbers of patients still succumb to
their disease, mandating ongoing research to improve existing
treatments and incorporate new agents and novel therapies into
adjuvant regimens.

The following article provides an overview of data from adjuvant
trials evaluating chemotherapy in all groups of women with breast
cancer. Key findings from the Early Breast Cancer Trialists’
Collaborative Group are discussed. Because the margins in terms of
survival benefit can be small, toxicity issues and the need for
predictive markers are considered. The use of adjuvant endocrine
therapy was reviewed by Pritchard in the April 2000 issue of Oncology.[2]

Overview Analysis

The 1995 overview analysis of polychemotherapy by the Early Breast
Cancer Trialists’ Collaborative Group summarized the results of
any randomized trial that began before 1990 and involved treatment
groups that differed only with respect to the adjuvant chemotherapy
regimens that were being compared.[1] The analysis involved 18,000
women in 47 trials of prolonged vs no polychemotherapy, 6,000 women
in 11 trials of longer vs shorter chemotherapy, and 6,000 women in 11
trials of anthracycline-containing chemotherapy vs CMF
(cyclophosphamide [Cytoxan, Neosar], methotrexate, fluorouracil).

Polychemotherapy consisting of regimens in which two or more agents
were administered over several months produced proportional
reductions in recurrence and mortality in all groups analyzed. In
women younger than 50 years old at the time of randomization,
polychemotherapy decreased the annual risk of relapse by 35% and
mortality by 27%. In women older than age 50 at the time of
randomization, the benefits were more modest, with an annual risk
reduction of 20% for recurrence and 11% for mortality (Table
1
).

When nodal involvement was considered, the absolute reductions in
recurrence and mortality with polychemotherapy were similar in both
node-negative and node-positive disease (Table
2
). For all women under age 50 at randomization,
polychemotherapy improved 10-year survival from 71% to 78% for those
with node-negative disease and from 42% to 53% for those with
node-positive disease. This represents an absolute survival benefit
of 7% and 11% in node-negative and node-positive patients,
respectively. For women aged 50 to 69 years, polychemotherapy
improved 10-year survival from 67% to 69% for node-negative disease
and from 46% to 49% for node-positive disease, conveying an absolute
benefit of 2% and 3%, respectively.

Estrogen-receptor (ER) status had little impact on the overall
benefit of polychemotherapy in women less than 50 years. In women
aged 50 to 69 years, chemotherapy also significantly reduced
recurrence and mortality in both ER-positive and ER-negative
patients, with the reduction in recurrence being almost twice as
large for ER-negative patients as for ER-positive patients (Table
1
).

The analysis of the addition of chemotherapy to tamoxifen (Nolvadex)
in women less than 50 years old did not demonstrate a significant
reduction in recurrence or mortality compared to tamoxifen alone,
which may reflect the relatively small number of younger women in
trials of combined chemoendocrine therapy. In women aged 50 to 69
years, the proportional reductions in recurrence and mortality gained
with polychemotherapy were significant, with or without tamoxifen.
Thus, chemotherapy and hormonal therapy should be considered
complementary in the adjuvant setting (Table 3).

There was no survival advantage associated with the use of
polychemotherapy for more than 3 to 6 months. A trend toward fewer
recurrences was demonstrated with prolonged treatment (about 6 to 24
months), but this difference was not significant.

CMF vs Anthracycline-Based Regimens

The overview analysis indirectly compared chemotherapy regimens
containing CMF, CMF with additional cytotoxic drugs, and other
cytotoxic drug regimens.[1] No significant advantage was apparent
among the many variants of CMF.

The overview also compared anthracycline-containing regimens vs CMF
in approximately 6,000 women in 11 trials, where 70% of the women
evaluated were less than 50 years old. The results showed a
statistically significant 12% (standard deviation [SD], 4%) reduction
in recurrence and an 11% (SD, 5%) reduction in mortality for the
anthracycline-containing regimens. This translated into an absolute
risk reduction of 3.2% and 2.7% for recurrence and mortality,
respectively, above the advantages seen with CMF.[1] However,
confidence intervals were relatively wide.

Trials evaluating newer anthracycline-based regimens, including the
Intergroup node-negative trial (INT 0102), and the National Surgical
Adjuvant Breast and Bowel Project (NSABP) B-23 trial, were not
incorporated in this analysis, and thus, may overrepresent the use of
CMF-type combinations (Table 4).

Intergroup Trial

The Intergroup INT 0102 trial compared CMF with CAF
(cyclophosphamide, Adriamycin [doxorubicin], fluorouracil) in high-risk
node-negative patients, who were also treated with or without
tamoxifen.[3] Over 4,400 patients were enrolled in this trial and
stratified into three groups according to risk.

The high-risk group included patients with tumors measuring 2 cm or
greater and those who were hormone-receptor negative. The low-risk
group included patients with tumors too small for biochemical
hormone-receptor assay. The uncertain risk group included patients
with tumors less than 2 cm and hormone-receptor–positive
disease; these patients were further divided into low or high risk as
determined by S-phase fraction of their tumor.

All patients in the high-risk group were randomized to receive either
CAF or CMF, with or without tamoxifen, for 5 years. Low-risk patients
were followed without receiving any adjuvant therapy. Both
disease-free and overall survival were marginally better with CAF (P
= .03), although at the cost of increased toxicity including
granulocytopenias, gastrointestinal symptoms, and alopecia. The
recurrence rate was 15% in the CAF group and 18% in the CMF group,
and the mortality rate was 8% and 10%, respectively. In low-risk
patients, the relapse rate was 11% and mortality, 4%. Tamoxifen
provided additional benefit only in ER-positive patients.

NCIC Trial

The NCIC trial compared a moderately intensive regimen of CEF
(cyclophosphamide, epirubicin [Ellence], fluorouracil) with CMF.[4]
Premenopausal women with node-positive breast cancer were randomly
allocated to receive either standard CMF or cyclophosphamide (75
mg/m² orally on days 1 through 14), epirubicin (60 mg/m² on
days 1 and 8), and fluorouracil (500 mg/m² IV on days 1 and 8),
with each cycle administered monthly for 6 months. At a median
follow-up of 59 months, both relapse-free and overall survival
improved in women who received CEF compared with those who received
CMF, with a 29% relative risk reduction in recurrent breast cancer
and a 19% relative reduction in mortality.

The 5-year relapse-free survival rate was 53% for patients who
received CMF and 63% for patients who received CEF (P = .009),
and the 5-year actuarial survival rates were 70% and 77%,
respectively (P = .03). This benefit was seen in patients with
one to three positive nodes and in those with more than three
positive nodes. No patient in the CEF arm developed congestive
cardiac failure; however, five patients developed acute leukemia
including four cases of acute myelogenous leukemia.

NSABP Trial

The recently presented NSABP B-23 trial, compared four 3-week cycles
of AC (Adriamycin [doxorubicin], cyclophosphamide) with six 4-week
cycles of CMF, with or without tamoxifen, in approximately 2,000
women with ER-negative, node-negative disease.[5] No difference in
disease-free or overall survival was seen between those who received
AC or CMF or those who received tamoxifen or placebo with either
regimen.

Discussion

Thus, the literature offers a number of large, well-designed,
prospective randomized trials that show conflicting results. The
debate continues as to whether the small difference in survival
demonstrated for an anthracycline-based adjuvant regimen in the
overview analysis by the Early Breast Cancer Trialists’
Collaborative Group translates into a clinically meaningful benefit
in all patient groups. It may be that if four cycles of AC is
equivalent to six cycles of CMF, then perhaps six cycles of an
anthracycline-based regimen would show a benefit, as alluded to in
the Intergroup and NCIC studies.

Dose Intensity

A retrospective analysis of existing adjuvant trials suggested a
relationship between the dose-intensity (dose per unit time) of
adjuvant chemotherapy and clinical outcome.[1,6] Preclinical studies
have supported the concept of a steep dose-response curve for
alkylating agents in the breast cancer cell lines studied. The
expectation has been that for some drugs—especially alkylating
agents and to a lesser extent anthracyclines—doses above certain
levels will successfully overcome drug resistance.

CALGB 8541

The Cancer and Leukemia Group B (CALGB) trial 8541 compared three
dose intensities of CAF in 1,550 patients with node-positive breast
cancer.[7,8] Patients received CAF, 300/30/300 mg/m² every 4
weeks for 4 cycles (low-dose arm); CAF, 400/40/400 mg/m² every 4
weeks for 6 cycles (moderate-dose arm); or CAF, 600/60/600 mg/m²
every 4 weeks for 4 cycles (high-dose arm). The high-dose arm
received twice the drug dose given the low-dose arm at twice the dose
intensity. The moderate-dose arm received the same total drug dose as
the high-dose arm but at only two-thirds the dose intensity.

Disease-free and overall survival rates for patients in the moderate-
and high-dose arms were superior to those of the low-dose arm with no
significant difference between these measures in the high- and
intermediate-dose arms. The higher dose levels used in this study are
now considered standard therapy, so it is probable that this trial
supports the value of dose intensity or rather, supports the concept
of a threshold total cumulative dose below which treatment becomes ineffective.

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