Standard combination chemotherapy with an anthracycline and taxane reduces mortality by about one-third in patients with early breast cancer; however, the optimal dosage and timing of these agents is not known. It has been hypothesized that dose-dense regimens—i.e., regimens in which an increased amount of drug is delivered per unit time—may enhance tumor-cell kill rates, decrease tumor regrowth, and improve the chances of cure.

A recent meta-analysis of 33 randomized trials published in The Lancet sought to clarify the relative benefits and risks of dose-intense compared with standard-schedule chemotherapy in early breast cancer. This collaborative meta-analysis included individual patient-level data (N = 37,298 patients) from 26 adjuvant or neoadjuvant randomized trials that compared shorter intervals between cycles (2-weekly) (i.e., dose-dense chemotherapy regimens) with identical or similar-dose regimens administered as standard 3-weekly or 4-weekly doses.

These 2-weekly regimens were administered along with granulocyte colony-stimulating factor to help prevent neutropenia. Anthracyclines studied were doxorubicin or epirubicin and the taxanes evaluated were paclitaxel or docetaxel. This dose-dense group was further divided into patients who received the same drugs, doses, and number of cycles in each arm; patients who received additional drugs in the control arm; and those who were given additional drugs in the dose-dense arm.

This meta-analysis also examined trials that employed sequential versus concurrent anthracycline and taxane therapy as another strategy for dose intensification. Sequential therapy permits the use of higher doses per cycle than could be used with concurrent or combined administration of chemotherapeutic agents. This group was further subdivided into those patients receiving sequential versus concurrent anthracycline and taxane therapy with the same drugs in each arm and those patients with some differences in drugs received between the study arms.

Two other groups included patients who had a shorter interval between cycles and sequential anthracycline and taxane use and those who received the same total chemotherapeutic doses in fewer cycles (i.e., 50% higher dose of anthracycline per cycle for four, not six, cycles).

The primary outcomes were any recurrence of invasive BC, BC mortality, death without recurrence, and all-cause mortality. Subgroup analyses were conducted based on site of recurrence, method of dose intensification, use of taxane, number of intensified cycles, hormone receptor status, nodal status, tumor diameter, grade, histology, HER2 status, proliferation index, and length of follow-up.

This study found that using a dose-intense 2-weekly schedule significantly reduced the risk of BC recurrence by 17% compared with 3-weekly regimens. The 10-year risk of recurrence was 24% in the dose-dense group compared with 28.3% in the standard-regimen group, resulting in an absolute reduction of 4.3%. The proportional reductions were similar for recurrence, breast cancer mortality, and all-cause mortality. A 2.8% decrease in 10-year risk of dying from breast cancer and no increase in nonbreast cancer deaths were also observed. Similar significant results were found when all dose-dense groups were combined compared with standard-treatment groups.

The sequential administration of the anthracycline/taxane regimens versus their concurrent administration conferred a statistically significant benefit that was similar to that of the dose-dense regimens, with recurrence rates of 28.1% versus 31.3%, respectively.

When dose intensification was achieved by combining 2-weekly regimens with sequential therapy, the recurrent rates were 30.4% versus 35% for the group receiving both shorter intervals and sequential administration of chemotherapy versus standard therapy; this difference was statistically significant. In the group that received the same total chemotherapeutic doses in fewer cycles, there was no difference in recurrence rates.

Data from all 26 dose-intensification studies revealed a 10-year risk of recurrence, breast cancer mortality, and all-cause mortality for the dose-intense treatment arm versus the standard-treatment regimens of 28% versus 31.4%, 18.9% versus 21.3%, and 22.1% versus 24.8%, respectively, which were all statistically significant.

Overall, there was a moderate 10% to 15% 10-year risk reduction of recurrence and of death from breast cancer with dose-intense adjuvant chemotherapy regimens, which occurred in addition to the approximately 33% reduction from the use of standard chemotherapy.

Further, these beneficial effects were similar regardless of hormone receptor status or other patient or tumor characteristics.

Anemia was more common in the dose-intensified regimens, but there was no evidence of increased cardiotoxicity or nonhematological toxicities between the different regimens.

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