Longer duration of treatment for primary breast cancer was not superior to a shorter regimen in the Cancer and Leukemia Group B (CALGB) 40101 trial, whose first results were presented by Lawrence N. Shulman, MD, of Dana-Farber Cancer Institute, at the 33rd Annual San Antonio Breast Cancer Symposium.¹

Study Rationale

CALGB 40101 is a 2×2 factorial phase III trial that was initiated in 2002 to determine the equivalence of single-agent paclitaxel with doxorubicin/cyclophosphamide (AC) for relapse-free survival, and to determine if longer therapy (six cycles) is superior to shorter therapy (four cycles), regardless of the agent. Patients were randomly assigned to AC or paclitaxel for four or six cycles (usually given every 2 weeks), followed by hormone therapy if their disease was estrogen receptor (ER)-positive and trastuzumab (Herceptin) if HER2-positive.

"Taxane-containing regimens have been compared to AC, showing favorable results but increased toxicity. Studies in locally advanced disease raise the possibility of equivalence of single-agent taxane to AC-based regimens, avoiding the anthracycline and potentially reducing short- and long-term toxicity. The ideal duration of adjuvant therapy for patients with good-prognosis breast cancer is unknown, and AC × 4 and other regimens given for six cycles are frequently used," Dr. Shulman said.

In September 2010, data were released for six vs four cycles, based on 3,173 patients followed for an average of 4.6 years. Most patients had T1 tumors, 94% were node-negative, 64% were ER-positive, and 20% were HER2-positive. This analysis looked just at duration of therapy. Data for AC vs paclitaxel have not yet been released.

Survival Rates Equivalent

"Relapse-free survival was 92% in each arm. There was no superiority of six over four cycles," Dr. Shulman announced (Table 1). "Also, in ER-positive patients there was no evidence that six cycles was better, nor was there for ER-negative patients." Overall survival rates (a secondary endpoint) were also similar (95.3% vs 96.4% for six vs four cycles, respectively).

For ER-positive patients, the relapse-free survival rate at 4 years was 93.8% with four cycles and 94.4% with six cycles, and overall survival was 98.0% and 97.7%, respectively.  For ER-negative patients, relapse-free survival was 88.0% with four cycles and 85.5% with six cycles while overall survival rates were 93.3% and 91.3%, respectively  
For HER2-negative patients, relapse-free survival was 91.7% with four cycles and 91.1% with six cycles, and overall survival was 96.2% and 95.9%, respectively. For HER2-positive patients, relapse-free survival was 93.4% and 92.6%, respectively, and overall survival was 96.6% and 96.0%, respectively.

Toxicity Differences

Hematologic toxicity was greater with both AC regimens, especially with six cycles. Neuropathy was seen only in the paclitaxel arms. Cardiac toxicity occurred mainly with six cycles of AC. Among 790 patients in this arm, grade 3 left-ventricular systolic dysfunction was observed in 2 patients, grade 4 in 2 patients, and grade 5 in 1 patient, while 1 patient had grade 3 restrictive cardiomyopathy.

"AC × 6 is more cardiotoxic," Dr. Shulman emphasized.

Acute myeloid leukemia developed within 1 to 2 years in five patients treated with AC × 6 and one with AC × 4. No such cases were seen with paclitaxel.

By number of cycles, 65 of 1,593 patients have died in the four-cycle arm and 85 of 1,579 in the six-cycle arm, including 41 and 50 breast cancer deaths, respectively, and two and five treatment-related deaths. "All the treatment-related deaths were in the AC arms, and there were more deaths with six cycles of treatment," he noted.

"We conclude that six cycles of AC or paclitaxel for patients with primary breast cancer and zero to three positive axillary nodes is not superior to four cycles of therapy," Dr. Shulman said. "Based on the present data, the Bayesian predictive probability of concluding superiority of six cycles is only 0.001."

Relevant Findings

Hearing the results, Steven Vogl, MD, of Bronx, New York, commented that he viewed the findings as relevant for his clinical practice.  "I think this is an important study. It is one of the few actually looking at the duration of chemotherapy as the isolated variable." Nevertheless, he said that the study did have its limitations (see sidebar).
Dr. Vogl suggested that the investigators zero-in on distant metastases when assessing differences between the arms.

"Because this is such a good-risk population, you may not expect many of the relapse-free survival events to be affected by chemotherapy. We would hope that chemotherapy would reduce the incidence of distant metastases, and you should look at this as the study matures," he offered.

Dr. Shulman noted that at this point there are more breast cancer deaths with six cycles in the ER-positive group, although this difference is not statistically significant. This finding is consistent with results in the ER-negative subgroup. He also mentioned that six cycles should be more likely to induce menopause and thus enhance the benefit of longer therapy in the ER-positive subgroup.

"It did induce menopause, but the additional benefit was not observed," he said.  The good prognosis of the patient population, however, may have diluted an effect, he added. ■

Reference

1. Shulman LN, Cirrincione C, Berry DA, et al: Four vs 6 cycles of doxorubicin and cyclophosphamide  or paclitaxel as adjuvant therapy for breast cancer in women with 0-3 positive axillary nodes: CALGB 40101. 33rd Annual San Antonio Breast Cancer Symposium. Abstract S6-3. Presented December 11, 2010.