Table 6. Standard Adjuvant Chemotherapy Regimens for Stage I, II, IIIA, and Operable IIICHER2/neuNon-Overexpressing Breast Cancer continued...
Dose-intensity, dose-density, and high-dose chemotherapy
Retrospective and some prospective data support the view that physicians should avoid arbitrary reductions in dose intensity.[176,177] The data for the benefit of dose escalation in breast cancer, however, are more controversial. The CLB-8541 trial compared three dose intensities of CAF in 1,550 patients with node-positive breast cancer. Patients received either CAF (300/30/300 mg/m2 every 4 weeks for four cycles; low-dose arm), CAF (400/40/400 mg/m2 every 4 weeks for six cycles; moderate-dose arm), or CAF (600/60/600 mg/m2 every 4 weeks for four cycles; high-dose arm). The high-dose arm had twice the dose intensity and twice the drug dose as the low-dose arm. The moderate-dose arm had 66% of the dose intensity as the high-dose arm but the same total drug dose. At a median follow-up of 9 years, DFS and OS on the high-dose and intermediate-dose arms were superior to the corresponding survival measures on the low-dose arm (P = .001) with no difference in these measures between the high-dose and intermediate-dose arms.[Level of evidence: 1iiA] The higher dose levels used in this trial are currently considered standard, so it is unclear whether this trial is supportive of the value of dose intensity or, rather, supportive of the concept of a threshold level below which treatment becomes ineffective.
Other trials have clearly escalated doses beyond the standard range. The NSABP-B-22 and NSABP-B-25 trials, for example, escalated the dose of cyclophosphamide to 1,200 mg/m2 (without granulocyte-colony stimulating factor [G-CSF]) and 2,400 mg/m2 (with G-CSF), respectively, with no significant advantage observed in DFS or OS compared with the standard dose of 600 mg/m2.[178,179][Level of evidence: 1iiA]
A U.S. Intergroup study (CLB-9344) randomly assigned women with node-positive tumors to three dose levels of doxorubicin (60, 75, and 90 mg/m2). Following treatment with doxorubicin, a second randomization occurred to paclitaxel or to no further therapy. After chemotherapy, patients with ER-positive tumors were offered a planned course of tamoxifen for 5 years. No difference in DFS related to the dose of doxorubicin was found. In contrast, a Canadian trial (CAN-NCIC-MA5) in which cyclophosphamide, epirubicin, and 5-FU (CEF) were given to a total dose of 720 mg/m2 for a period of six 4-week cycles demonstrated at a median follow-up of 10 years for live patients, a 10-year RFS of 52% for patients who received CEF compared with 45% for CMF patients (HR for CMF vs. CEF, 1.31; stratified log-rank, P = .007). The 10-year OS for patients who received CEF and CMF was 62% and 58%, respectively (HR for CMF vs. CEF, 1.18; stratified log-rank, P = .085). The rates of acute leukemia have not changed since the original report, whereas the rates of congestive heart failure were slightly higher (four patients [1.1%] in the CEF group vs. one patient [0.3%] in the CMF group).[Level of evidence: 1iiA] The design of the trial does not allow a determination of whether anthracycline or dose-intensity or both is responsible for the improved outcome. A French trial showed that higher doses of epirubicin led to a high survival rate in women with poor-prognosis disease. A randomized trial that increased duration of epirubicin did not lead to increased survival at 10 years in node-positive premenopausal women.