Cooperative groups and research
groups on national and multinational levels have initiated new and innovative randomized clinical trials
designed to advance adjuvant chemotherapy for breast cancer. Following their
success in the metastatic setting, new classes of agents such as the taxanes and
trastuzumab (Herceptin) have become available to study in the adjuvant setting.
This has resulted in a large number of ongoing studies of combination or
sequential therapies, particularly focused on the anthracyclines and the
taxanes, and the incorporation of trastuzumab for patients whose tumors
In Canada, the National Cancer Institute of CanadaClinical
Trials Group (NCIC-CTG) will soon initiate a phase III randomized clinical
trial, MA.21 (the group’s 21st breast study). MA.21 is based on results of
previous clinical trials, some conducted through the NCIC-CTG and others through
other cooperative group mechanisms, and builds on results of the meta-analyses
of the Early Breast Cancer Trialists Collaborative Group (EBCTCG) as well.
The MA.21 study compares two standard therapies: CEF (cyclophosphamide [Cytoxan,
Neosar], epirubicin [Ellence], fluorouracil
[5-FU]) and AC®T (doxorubicin [Adriamycin] plus cyclophosphamide followed by
paclitaxel [Taxol]). In addition to comparing these two standard therapies, the
study tests whether it is necessary to add a taxane to an optimal anthracycline
regimen for adjuvant therapy, ie, epirubicin and cyclophosphamide (EC). The
study therefore includes a third arm consisting of a dose-dense, dose-intense
regimen of EC®T (epirubicin and cyclophosphamide followed by paclitaxel).
Reduction in Risk of Recurrence and Mortality
In its most recent publications, the EBCTCG summarized the
proportional reductions in the risk of recurrence and death associated with
ovarian ablation, tamoxifen (Nolvadex), and chemotherapy. Ovarian
ablation in premenopausal women, ie, less than 50 years old, results in a 24%
reduction in the proportional risk of death
at 10 years compared to no treatment. Tamoxifen treatment reduces the risk
compared to no treatment, by 20% to 22% in both premenopausal and postmenopausal
women, and CMF (cyclophosphamide, methotrexate, 5-FU) chemotherapy results in a
14% reduction in risk for all ages. These findings translate into an approximate
10% absolute reduction in mortality at 10 years for node-positive patients and a
5% absolute reduction in mortality for node-negative patients.
The most recent meta-analysis demonstrated that
anthracycline-based adjuvant regimens are modestly more effective than non-anthracycline-containing
regimens, with an 11% proportional reduction in mortality risk, or an
approximate 3% absolute reduction in mortality risk. Furthermore, the
combination of tamoxifen and chemotherapy is superior to either modality alone
in hormone-receptor-positive patients, while tamoxifen is of no benefit in
receptor-negative patients with respect to the primary breast cancer.
Various guidelines for adjuvant therapy have been developed,
including the 2000 National Comprehensive Cancer Network (NCCN) guidelines.[4-6]
These guidelines recommend adjuvant chemotherapy for hormone-receptor-negative
patients regardless of nodal status. For patients with hormone-receptor-positive
tumors, chemotherapy ± tamoxifen is recommended for high-risk node-negative or
node-positive patients. Those whose tumors measure 1 to 2 cm and who are node-
negative may be offered tamoxifen ± chemotherapy. For patients with tumors less
than 1 cm and no poor prognostic factors, tamoxifen or no therapy can be
Potential regimens for node-negative patients are: CMF; FAC
(5-FU, doxorubicin [Adriamycin], cyclophosphamide)/CAF (cyclophosphamide,
doxorubicin, 5-FU); or AC. In the node-positive setting,
anthracycline-containing regimens are preferred, although CMF remains an
acceptable treatment option. FAC/CAF or CEF may be recommended. AC followed by
paclitaxel is another option, as is doxorubicin followed by CMF, which has been
shown to be superior to doxorubicin alternating with CMF in women with four or
more positive lymph nodes.
Doxorubicin-based regimens have been compared to CMF-based
regimens in several studies. The National Surgical Adjuvant Breast and Bowel
Project (NSABP) B-15 and B-23 studies have demonstrated the equivalence of
four cycles of AC vs six cycles of CMF. While in one study by the Southeast
Cancer Study Group, an FAC regimen was shown to be equivalent to CMF, a more
recent intergroup study involving node-negative patients showed superiority of a
CAF regimen over CMF.
A Cancer and Leukemia Group B (CALGB)/Intergroup study
demonstrated that AC followed by paclitaxel was superior to AC alone. A more
recent study at M. D. Anderson Cancer Center did not show that paclitaxel × 4
followed by FAC × 4 was superior to FAC × 8, although the results are still
Epirubicin-containing regimens have also been compared to CMF.
The NCIC-CTG study of CEF vs CMF showed superiority for the CEF regimen. The
International Cancer Collaborative Group showed that FEC 50 was equivalent to
CMF, where 50 represents the epirubicin dose (mg/m2) in the FEC regimen. The
French Adjuvant Study Group, however, showed that FEC 100 is superior to FEC
50. Hence, direct or indirect comparisons would suggest that CEF, FEC 100,
CAF, and AC®paclitaxel may all be superior to standard AC or CMF regimens.
Choosing the Anthracycline
The anthracycline chosen by the various collaborative groups has
been based on both drug availability and associated toxicities. Epirubicin is
metabolized not only into 4-aglycone and epirubicinolsimilar to what occurs
in doxorubicin metabolismbut also is glucuronidated as epirubicin glucuronide
and epirubicinol glucuronide. This results in a shorter half-life and fewer
hematologic, nonhematologic, and cardiac toxicities than those associated with
doxorubicin; however, no decrease in efficacy is seen. The probability of
developing congestive heart failure with epirubicin treatment is less than 5% at
a total dose of 950 mg/m2, while a comparable level of risk is reached at a
total doxorubicin dose of 500 mg/m2.[18,19]
In 1998, Cancer Care Ontario (Canada) published a practice
guideline that compared doxorubicin and epirubicin in women with metastatic
breast cancer. The guideline reviewed 13 randomized controlled trials, 11
published reports and 2 abstracts. The guideline concluded that epirubicin was
as effective as doxorubicin in the metastatic setting but caused less toxicity.
Three of these randomized controlled trials compared FEC 50 to
FAC 50, where 50 represents the dose (mg/m2) of the anthracycline in the
respective regimen.[21-23] Response rates were not significantly different
within any of the trials and median survival was not affected by whether
doxorubicin or epirubicin was used. However, the FEC regimens resulted in less
cardiac toxicity as determined by ECG alterations or percent of patients with
congestive heart failure. Furthermore, less grade 3/4 leukopenia, anemia, and
nausea/vomiting occurred with the epirubicin-based regimens.
The guideline also examined randomized trials comparing
escalating doses of epirubicin in metastatic breast cancer.[24-26] These studies
demonstrated an increase in response rate with increasing doses of epirubicin at
least to 100 mg/m2. The increased response rates did not, however, translate
into increased overall survival in the metastatic setting. Increased response
rates with escalating doses of doxorubicin have also been demonstrated, but
these studies were limited by hand-foot syndrome and cardiac toxicity.
In 1987, a pilot study was conducted by the Ontario Clinical
Oncology Group and formed the basis for the NCIC-CTG clinical trial of CEF vs
CMF (MA.5). The pilot regimen was developed based on the concept that, at
that time, anthracyclines were the most active chemotherapeutic agents for
advanced breast cancer and the expectation that dose-intensive chemotherapy
would improve outcome. The study was initiated prior to the routine use of 5-HT3
antagonists as antiemetics and before recognition of the advantages of
epirubicin over doxorubicin with respect to both emesis and lack of congestive
At the optimal dose level chosen in the pilot study, the rate of
febrile neutropenia in women less than 50 years old was 17%. Several patients
were accrued at these dosages; the subsequent use of concurrent antibiotic
prophylaxis resulted in a reduction in hospital admissions for febrile
neutropenia to 5% of patients.
The Drug Regimens
In the MA.5 trial, the CEF regimen consisted of oral
cyclophosphamide at 75 mg/m2 daily on days 1 through 14, and intravenous (IV)
60 mg/m2 and IV fluorouracil at 500 mg/m2, both given on days 1 and 8
(Figure 1). Each cycle was repeated monthly for 6 months.
Based on the pilot study results with the use of antibiotics to
reduce febrile neutropenia, in the MA.5 protocol, all patients assigned to the
CEF regimen also received prophylactic antibiotics throughout the trial with
trimethoprim-sulfamethoxazole (Co-Trimoxazole, TMP-SMZ), norfloxacin (Noroxin),
or ciprofloxacin (Cipro).
Standard CMF with oral cyclophosphamide was administered in the
other study arm. Patients were stratified with respect to type of surgery
performed (total or partial mastectomy), hormone receptor status, and number of
positive lymph nodes.
Differences in Survival and
A total of 710 premenopausal node-positive patients were
registered in the study351 in the CEF arm and 359 in the CMF arm. In the two
arms, respectively, 36% and 39% of patients had T1 tumors; 55% and 49% had T2
tumors. Among all patients, 61% had one to three positive nodes and 59% were
CEF resulted in a 29% reduction in risk of recurrence and a 19%
reduction in risk of mortality compared with CMF. At 5 years, overall survival
was 77% in the CEF arm and 70% in the CMF arm, a statistically significant
difference (Figure 2).
During treatment, grade 3/4 adverse events included 8.5% of
patients with fever or infection in the CEF group and 1.1% in the CMF group. As
expected, alopecia was significantly more frequent in the CEF arm. Rates of
stomatitis were 12.3% for CEF and 1.9% for CMF, and vomiting occurred in 11.4%
of CEF and 4.1% of CMF patients. Of note, no 5-HT3 antagonists or
colony-stimulating factors were administered.
Quality of life was studied using standard European Organization
for the Research and Treatment of Cancer (EORTC) questionnaires. Except for the
higher frequency of alopecia with CEF in cycle 1, no significant differences in
quality of life indices were noted between the two treatments.
Late adverse events included congestive heart failure and acute
leukemias. In the CEF arm, four patients (1.1%) developed congestive heart
failure while one (0.3%) in the CMF arm did so. Five cases of acute leukemia
occurred on the CEF armfour acute myelocytic leukemias (AML), and one acute
lymphoblastic leukemia (ALL). One patient in the CMF group developed AML. Cases
of leukemia were reported between 18 and 40 months after study enrollment. No
cases of leukemia have been reported between years 4 and 6. Of note, mortality
secondary to leukemia is included in the overall survival statistics; thus,
overall survival benefits with respect to breast cancer outweigh this risk.
CEF Becomes Standard Treatment in Canada
Based on results of the MA.5 trial, CEF has become standard
therapy in Canada for node-positive, premenopausal women with breast cancer. In
fact, in clinical practice, high-risk, node-negative, and young postmenopausal
women, ie, less than 60 years old, are also treated with CEF.
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