Anthracycline Added to Adjuvant Therapy Trio Scores For Early Breast Cancer

BIRMINGHAM, England, Nov. 1 -- For early breast cancer, a fourth chemotherapy agent mixed in with a standard trio proved to make a superior adjuvant combination, researchers here reported.

When they added the anthracycline epirubicin to Cytoxan (cyclophosphamide), methotrexate, and fluorouracil, the risk of death without relapse or death from any cause at a median follow-up of 48 months was about 30% lower than for patients given the CMF trio alone.

The results of this analysis are applicable to most patients with breast cancer, Christopher Poole, F.R.C.P., of the University of Birmingham, and colleagues at various British centers, reported in the Nov. 2 issue of the New England Journal of Medicine.

Neither estrogen-receptor status nor tumor grade were significant influences, and even though the proportion of women younger than age 50 was larger in this study, there appeared to be no loss of efficacy among older women, he said.

The findings came from a combined analysis of two studies, the National Epirubicin Adjuvant Trial (NEAT) and the BR9601 trial, both of which examined the efficacy of anthracyclines in the adjuvant treatment of early breast cancer. Patients were recruited from 1996 to 2001.

In the NEAT trial, the researchers compared four cycles of epirubicin followed by four cycles of CMF versus six cycles of CMF alone.

In the BR9601 trial, four cycles of epirubicin followed by four cycles of CMF were compared with eight cycles of CMF alone every three weeks. Neither trial restricted adjuvant hormonal treatment. In the NEAT trial, for which data were available, 68% were to receive adjuvant tamoxifen.

In explaining the design of the drug regimens, the investigators noted that they used epirubicin instead of Adriamycin to reduce treatment-related adverse effects.

The two trials in this analysis included 2,391 women with early breast cancer. The median follow-up was 48 months, and the main cause of death was breast cancer.

Relapse-free and overall survival rates were significantly higher in the epirubicin-CMF groups than in the CMF-alone groups.

The two-year relapse-free survival was 91% vs. 85%. The five-year relapse-free survival was 76% vs. 69%.

The two-year overall survival was 95% vs. 92%, while the five-year overall survival was 82% vs. 75%. (P<0.001 by the log-rank test for all comparisons).

Hazard ratios (HR) for relapse (or death without relapse) and death from any cause favored epirubicin plus CMF over CMF alone.

The HR for relapse (or death without relapse) was 0.69 (95% confidence interval 0.58 to 0.82; P<0.001), while the HR for death from any cause was 0.67 (CI, 0.55 to 0.82; P<0.001).

Independent prognostic factors were nodal status, tumor grade, tumor size, and estrogen-receptor status (P<0.001 for all four factors) and the presence or absence of vascular or lymphatic invasion (P = 0.01). However, these factors did not significantly interact with the effect of epirubicin plus CMF, the researchers said.

Finally, they reported that the overall incidence of adverse effects was significantly higher with epirubicin plus CMF than with CMF alone, but toxic effects did not significantly compromise the delivered-dose intensity or the quality of life as rated by several standard questionnaires. An analysis of changes from baseline to two years showed no significant differences in the quality of life between the two groups.

In the NEAT study, significantly more patients in the epirubicin group reported severe alopecia, nausea, vomiting, constipation, and stomatitis. In the BR9601 trial, alopecia was significantly higher among patients getting epirubicin, However, the other adverse effects, as well as infection, fatigue, and diarrhea were similar in the two groups.

Among 2,391 patients in the two trials, 20 deaths (1%) were attributed to treatment-related adverse effects. In all groups in both studies all deaths from treatment related adverse effects occurred during the CMF phase, the investigators reported. Although treatment-related side effects were moderately higher in the epirubicin plus CMF phase, the majority of treatment related deaths occurred in the CMF group (14 versus six).

The 48-month follow-up in the two studies used in this analysis was too short to assess the incidence of secondary acute myeloid leukemia, which typically occurs two to four years after anthracycline treatment, the researchers said. However, they said they do not anticipate many late such cases because the cumulative dose of epirubicin was low.

In conclusion, Dr. Poole wrote that on the basis of the results in 75 centers, "we recommend epirubicin plus CMF as an option for anthracycline-based adjuvant chemotherapy in women with early breast cancer."

In an accompanying editorial Mark Levine, M.D., and Timothy Whelan, B.M., B.Ch., of McMaster University in Hamilton, Ontario, wrote that the experimental regimen in Dr. Poole's study was based on a trial in Milan that added Adriamycin to the CMF regimen, although in that trial the control group did not receive CMF. The current study, they said, "better reflects the advantages (or disadvantages) of adding an anthracycline to CMF."

Commenting on the use of the combined results from two independent trials (NEAT and BR90601), they said that whether differences between the two trials used in the study influenced the results is difficult to determine, but they added that it is reassuring that the benefits of adding epirubicin to CMF were seen in both trials.

The report by Dr. Poole and colleagues did not include the number of patients in each group who received adjuvant radiation therapy or tamoxifen during follow-up, they noted. While a subgroup analysis found no significant difference in outcome for women with estrogen-receptor-positive tumors, longer follow-up will show whether a difference in this subgroup emerges, they said.

Summing up the current status of adjuvant therapy, the authors wrote that although adjuvant chemotherapy reduces the risk of recurrence and increases survival, the magnitude of the benefit is modest and is associated with considerable toxic effects and cost to the heath care system.

The writers advised physicians caring for a woman with early breast cancer to consider a number of recurrence risks: the presence or absence of tumor in the axillary nodes, tumor size and grade, HER2 status, and endocrine responsiveness of the tumor. Hence high-risk patients might be offered a regimen that includes an anthracycline and a taxane, such as Taxol (paclitaxel), or an intensive anthracycline regimen, they said.

Drs. Levine and Whelan stressed recent progress in the fight against breast cancer, including the addition of Herceptin (trastuzumab) after chemotherapy and promising new agents such as Avastin (bevacizumab), and finally advances in genetic analysis for risk recurrence and for predicting a tumor's responsiveness to chemotherapy. Still, there is much to be done, they said.

Thus, they wrote, adjuvant therapy that is tailored for the patient on the basis of amplification of a particular gene or gene profile "may be just around the corner."

The study was supported by grants from Cancer Research UK and Pharmacia (now Pfizer); Pharmacia also provided epirubicin at a discount. Dr. Poole reported having received fees from Lilly, Pfizer, Amgen UK, Sanofi-Aventis, Roche, AstraZeneca, GlaxoSmithKline, Fulcrum Pharma, and Bristol- Myers Squibb, as well as consulting fees from Novartis and grant support from Pfizer and Cancer Research UK. Other investigators reported receiving lecture and consulting fees or grant support from these firms, plus Merck, Westaway Gillis, Bioenvision, European Union, and Chugai.