Introduction
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(Drug information on 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 overexpress HER2/neu.
In Canada, the National Cancer Institute of Canada—Clinical 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.[1] The MA.21 study compares two standard therapies: CEF (cyclophosphamide [Cytoxan, Neosar], epirubicin [Ellence], fluorouracil(Drug information on fluorouracil) [5-FU]) and AC®T (doxorubicin [Adriamycin] plus cyclophosphamide(Drug information on cyclophosphamide) followed by paclitaxel(Drug information on 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(Drug information on 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).
Background and Rationale
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,[1] tamoxifen (Nolvadex),[2] and chemotherapy.[3] 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(Drug information on tamoxifen) treatment reduces the risk compared to no treatment, by 20% to 22% in both premenopausal and postmenopausal women, and CMF (cyclophosphamide, methotrexate(Drug information on 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[3] 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.
Recommended Regimens
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 recommended.
Potential regimens for node-negative patients are: CMF; FAC (5-FU, doxorubicin(Drug information on 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.[7]
Doxorubicin-based regimens have been compared to CMF-based regimens in several studies. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-15[8] and B-23[9] 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,[10] a more recent intergroup study involving node-negative patients showed superiority of a CAF regimen over CMF.[11]
A Cancer and Leukemia Group B (CALGB)/Intergroup study demonstrated that AC followed by paclitaxel[12] 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 early.[13]
Epirubicin-containing regimens have also been compared to CMF. The NCIC-CTG study of CEF vs CMF[14] showed superiority for the CEF regimen. The International Cancer Collaborative Group showed that FEC 50 was equivalent to CMF,[15] 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.[16] 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 epirubicinol—similar to what occurs in doxorubicin metabolism—but 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.[17] 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[20] 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.
Results of Clinical Trial Comparing CEF vs CMF
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).[27] 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 heart failure.
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) epirubicin at 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(Drug information on trimethoprim)-sulfamethoxazole (Co-Trimoxazole, TMP-SMZ), norfloxacin(Drug information on norfloxacin) (Noroxin), or ciprofloxacin(Drug information on 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 Adverse Events
A total of 710 premenopausal node-positive patients were registered in the study—351 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 estrogen-receptor positive.
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 arm—four 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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