Best schedule for adjuvant taxanes Rx remains elusive

The optimal use of taxanes in the adjuvant treatment of breast cancer continues to inspire debate. Questions remain regarding the relative efficacy of sequential vs concurrent treatment, the most effective doses and schedules, and the best combinations of agents. Key studies presented at SABCS 2008 offered insight into these issues, but no definitive resolutions. In fact, two studies designed to establish optimal scheduling reached conflicting conclusions.

NSABP B-30: AC→T most effective
The definitive analysis of the large NSABP B-30 trial determined that AC→T results in better outcomes than two concurrent regimens using these standard agents, reported Sandra M. Swain, MD, of Washington Hospital Center, Washington, DC (abstract 75).

NSABP B-30 evaluated different schedules and combinations of adjuvant therapy with doxorubicin (A), cyclophosphamide (C), and docetaxel (T) in 5,351 node-positive patients. Patients were randomized to receive AC × 4→T × 4; AT × 4; or TAC × 4, and were followed for a mean of 73 months.

“The study found that AC→T is superior to four cycles of AT for overall survival, the primary endpoint of the trial, and is marginally superior to four cycles of TAC × 4,” Dr. Swain said.

“For disease-free survival, AC→T is superior to both TAC and AT.”

In the intent-to-treat analysis for overall survival, mortality was significantly reduced by 17% with AC→T, compared with AT (P = .034), and by 14% over TAC (P = .086). Results for AT and TAC were similar. Disease-free survival (DFS) events were significantly decreased by 17% with AC→T vs TAC (P = .006) and by 20% vs AT (P = .001), while AT and TAC, again, were similar.

NSABP B-30 found no treatment interactions between baseline nodal, estrogen-receptor, or menopausal status and outcome, with all subgroups benefiting most from AC→T. Interestingly, women with persistent amenorrhea had improved overall survival and DFS (see Sidebar).

BCIRG 005: TAC equivalent to AC→T
The international BCIRG 005 trial, on the other hand, found that the concurrent TAC regimen was as effective as AC→T in terms of DFS, the primary endpoint, reported Wolfgang Eiermann, MD, of the Red Cross Women’s Hospital in Munich (abstract 77).

“Despite AC→T delivering higher dose intensity for each of the three agents and requiring eight cycles vs six for TAC, it was not more effective,” he said.

The study randomized 3,298 no depositive patients to AC × 4 → T × 4, or to TAC × 6. At a median follow-up time of 65 months, DFS was 78.9% with TAC and 78.6% with AC→T, and overall survival was 88.1% and 88.9%, respectively. There were no differential treatment effects according to subgroup.

Of note, patients in this study received six cycles of TAC, compared with four cycles in NSABP B-30, suggesting that patients on TAC in B-30 may have been under-treated, according to discussion during the meeting.

EC-Doc trial: Sequential EC→T superior to FEC
In a third large trial conducted by the West German Study Group and the AGO group, Ulrike Nitz, MD, and colleagues found that four cycles of an anthracycline-based regimen (EC→T) significantly improved survival, compared with a standard regimen of fluorouracil, epirubicin, and cyclophosphamide (FEC).

The phase III EC-Doc trial involved 2,012 node-positive patients who were randomized to six cycles of FEC (500/100/500 mg/m2) or to four cycles of lower-dose epirubicin (90 mg/m2) plus cyclophosphamide (600 mg/m2) followed by four cycles of docetaxel (100 mg/m2). The five-year overall survival rate for FEC was 92.6%, but the rate for EC→T was even better at nearly 95% (P = .04).

The hazard ratio of 1.59 for FEC was statistically significant. Event-free survival was 85.8% for FEC and 90.2% for EC→T (P = .009). In all subgroups, EC→T was associated with a reduced risk of events (abstract 78).

“EC followed by docetaxel should be discussed with every patient with one to three involved lymph nodes, even if they have hormone-positive disease,” Dr. Nitz concluded.

Neoadjuvant use of taxanes
The neoadjuvant use of taxanes was also evaluated in the largest integrated meta-analysis yet of patients treated preoperatively with anthracyclines and taxanes, with or without trastuzumab (Herceptin) (n = 6,634). German investigators, led by Gunter von Minckwitz, MD, PhD, of the University of Frankfurt and German Breast Group, found certain characteristics related to pathologic complete response (pCR). Overall, 19.3% of patients achieved a pCR, with higher rates observed in patients treated most recently. Among patients treated between 1998 and 2002, the pCR rate was just 12.7%, but rose to 22.5% between 2003 and 2006.

In patients with HER2-positive tumors, the addition of trastuzumab significantly increased pCRs from 22.7% to 41.1%, Dr. von Minckwitz reported (abstract 79). Other factors related to greater chance of achieving pCR included conventional dosing (vs dose-dense approaches), young age (especially < 35), negative nodal status, negative hormone-receptor status, positive HER2 status, small tumor size, and tumor grade 3 (vs 1 or 2). Treatment eff ect was the same for both approaches, Dr. von Minckwitz reported.