Dr. Mamounas presented the results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-28. This large randomized trial (n = 3,060) tested the effect of adding Paclitaxel after Doxorubicin/Cyclophosphamide (AC) chemotherapy in patients with node-positive breast cancer. Investigators enrolled patients with operable breast cancer and pathologically positive nodes. After stratification, patients were randomized to 2 groups. The first group received standard doses of AC (60/600 mg/m²) for 4 cycles, and the second group received standard AC (60/600 mg/m²) followed by 4 cycles of Paclitaxel (225mg/m² as a three hour infusion).

Estrogen or progesterone receptor positive patients less than 50 years of age and all patients over the age of 50 received tamoxifen (20 mg po qd) for five years starting with AC chemotherapy. Patients treated with lumpectomy also received breast radiation. Patients who underwent mastectomy did not receive radiation therapy to the chest wall or regional nodes.

The primary endpoint of the trial was disease free survival and overall survival. The median follow-up was 64.8 months for the AC group and 64.4 for the AC/paclitaxel group.

The distribution of patients and tumor characteristics was well balanced between the two arms. About half the patients were under age 50, and about one-third were between ages 50 and 59. About two-thirds of the patients had tumors less than 2 cm in diameter; 70% of the patients had 1 to 3 positive nodes, and only 4% had more than 10 positive nodes. Half of the patients underwent mastectomy, and half underwent lumpectomy. About two-thirds of the patients had tumors positive for estrogen receptors, and also about two-thirds had tumors positive for progesterone receptors. Eighty-four percent of the patients received tamoxifen.

Toxicity was acceptable for the adjuvant setting, according to Dr. Mamounas. About 27% of the patients had grade 3 or 4 toxicity during AC administration, and about 35% of the patients had grade 3 or 4 toxicity during Paclitaxel administration. The most common grade 3 or higher toxicities with paclitaxel were neurosensitive toxicity in about 14%, arthralgias or myalgias in about 11%, neuromotor toxicity in about 7%, day 1 granulocytopenia in about 4%, febrile neutropenia in 2% and infection in 2%. Severe hypersensitivity reactions were uncommon (1%).

There were 8 cases of acute myelogenous leukemia or myelodysplastic syndrome, 6 in the AC followed by paclitaxel group, and 2 in the AC group. Most of those patients had also received prophylactic G-CSF and 5 of the 8 had also received radiotherapy.

For the AC/paclitaxel group, there was a 17% reduction in event rate for disease free survival, which was statistically significant (p = 0.008). The actual events were 461 in the AC group and 400 in the AC/Paclitaxel group. There was no statistically significant difference in survival, with deaths being 255 in the AC group and 243 in the AC/Paclitaxel group.

Five-year disease-free survival was 72% for AC, and 76% for AC/Paclitaxel. Overall survival was the same (85%) for both groups.

Looking at the incidence of first events at specific sites, there was evidence of a reduction in all subsets, including local recurrence, regional recurrence, distant recurrence, other second primary cancers, or death with no evidence of disease.

There was also a subset analysis looking at the effect of Paclitaxel according to hormone receptors. Prior study results suggest that paclitaxel is not very effective in receptor-positive patients. The disease free survival according to hormone receptor status showed that there was a 21% reduction in events rate in hormone receptor positive patients versus a 9% reduction in hormone receptor negative patients; however, this difference did not reach statistical significance.

Dr. Mamounas said there are now 3 studies showing that taxanes are beneficial in women with node-positive breast cancer. NSABP B-28 is the second study that shows a benefit with the addition of paclitaxel to the standard regimen of AC (the first study was CALGB 9344). In addition, investigators have reported results of a similar study of docetaxel following AC chemotherapy; that study also showed a benefit in disease-free survival and a non-significant benefit in overall survival.

Taken together, these results suggest there is now another option for patients with node-positive breast cancer that can actually improve their survival above and beyond the administration of anthracyclines, which have been the gold standard for many years.