Large adjuvant trial shows no benefit of adding a taxane

SAN ANTONIO—Sequential docetaxel (Taxotere)-based chemotherapy did not lead to better outcomes than standard anthracycline-based chemotherapy among women with resected breast cancer in the Taxotere as Adjuvant Chemotherapy Trial (TACT), the largest primary adjuvant trial of taxanes to date.

Although the CALGB 9344 and NSABP B28 adjuvant trials found better disease-free survival in patients given sequential paclitaxel, compared with AC alone, the duration of treatment was longer with the addition of paclitaxel, lead author Paul A. Ellis, MD, said at the 30th annual San Antonio Breast Cancer Symposium (abstract 78).

Controlled for duration

"In the UK at least, that led to debate: Was the benefit related to the taxane or was it related to increased duration? There was huge enthusiasm for a national adjuvant taxane trial controlling for the variable of duration," Dr. Ellis explained.

The multicenter trial enrolled women with completely resected, node-positive or high-risk node-negative invasive breast cancer, according to Dr. Ellis, an oncologist with the Guy's and St. Thomas' NHS Foundation Trust in London.

The study patients were assigned in balanced fashion to a control arm—either FEC (eight cycles) or E-CMF (four cycles of epirubicin followed by four cycles of CMF) at each center's discretion—or to an experimental arm—FEC-T (four cycles of FEC followed by four cycles of docetaxel)—with the arms having equivalent durations (eight cycles).

The median follow-up among the 4,162 women randomized was 51.8 months. About 80% received all eight cycles of treatment and 76% had a relative dose intensity exceeding 85%, with no difference between arms.

Compared with their counterparts in the control arm, patients in the FEC-T arm had significantly higher rates of grade 3-4 neutropenia (45% vs 38%), febrile neutropenia (8% vs 3%), stomatitis/mucositis (8% vs 4%), lethargy (22% vs 13%), musculoskeletal symptoms (7% vs 2%), and neuropathy (5% vs < 1%).

This treatment toxicity profile "is consistent with the profile seen in other large randomized adjuvant docetaxel trials," Dr. Ellis noted.

There was no difference with regard to the primary endpoint—disease-free survival—between the two groups, Dr. Ellis reported.

The estimated 5-year rate of disease-free survival was 74.7% for the FEC-T arm and 73.9% for the control arm (hazaard ratio [HR] 0.97). The corresponding estimated 5-year rates of overall survival were 82.0% and 81.8% (HR 0.98).

Seven patients died while receiving treatment, he noted—five from treatment-related infection (three during docetaxel, one during FEC, and one during CMF) and two from hemorrhage within a month of treatment (both following docetaxel).

In subgroup analyses of disease-free survival, the findings were similar in patients stratified by age, tumor grade, and number of nodes involved, Dr. Ellis said.

Disease-free survival was somewhat better with FEC-T than with control treatment in patients with estrogen-receptor (ER)-negative disease (HR 0.87), HER2-positive disease (HR 0.89), or the combination of ER negativity, HER2 positivity, and involved nodes (HR 0.70), but not significantly so.

Global perspective

When taxane trials are viewed from the global perspective, "you can see a number of well-known studies that clearly show benefit for taxane-based therapy over control, but I think it's also important to point out those trials where the benefit for taxane-based therapy is perhaps not quite as clear," Dr. Ellis commented (see Figure). "Into that group of trials, you can see these [TACT] data added."

In conclusion, he said, "in this trial, docetaxel-based sequential chemotherapy overall was not superior to anthracycline-based chemotherapy of equivalent duration. As expected, there were higher levels of grade 3-4 toxicity seen in the FEC-T group, compared with controls."

The results regarding HER2 and ER status are consistent with those of other studies, Dr. Ellis commented.

"There are ongoing biological substudies trying to define which subgroups may get more or less benefit from taxane-based chemotherapy," he said.