The NSABP (National Surgical Adjuvant Breast and Bowel Project) is a clinical trials cooperative group supported by the National Cancer Institute (NCI). NSABP B-36 is a prospective randomized trial that was trying to answer the question of whether women with node negative breast cancer can undergo a less onerous four cycle chemotherapy regimen of adriamycin and cyclophosphamide (AC) rather than the longer six cycles of 5-fluorouracil (5-FU), epirubicin, and cyclophosphamide (FEC).
At the beginning of the study there was also a randomization arm which included Celexocib (a COX-2 inhibitor) vs. placebo for three years. COX-2 selective inhibitor is a form of non-steroidal anti-inflammatory drug (NSAID) that directly targets COX-2, an enzyme responsible for inflammation and pain. As several studies had suggested that the enzyme cyclooxygenase-2 (COX-2) was associated with aggressive breast cancer, there was interest in studying if adding Celexocib (which inhibits the enzyme COX-2) might result in better outcomes. As it was later found that COX-2 inhibitor drugs caused a significant increase in heart attacks and strokes, in 2004 some of them were removed from the market and others received a warning label from the FDA. The trial began in May 2004, and after seven months it was suspended due to the newly discovered toxicity in COX-2 inhibitors. At that point, researchers decided to drop the randomization of the Celexocib arm and the trial became a two arm trial. Additionally, the trial later allowed for additional use of trastuzumab after chemo for HER2+ patients when new studies showed benefits of this therapy.
The trial’s endpoints measured progression free survival (PFS) as well as overall survival (OS) of women treated with six cycles of FEC-100 vs. those treated with four cycles of AC. This study also compared the number and severity of adverse events experienced by women in each arm of the trial. The mean follow-up was seven years.
The FEC-100 treatment arm did not perform better than standard chemotherapy and was highly toxic, resulting in five deaths. The results of this study showed no differences in either the eight year PFS (82%) or OS (91-92%) between the two arms. There were a total of seven treatment-related deaths in the study group of 2,722 patients – two in the AC group and five in the FEC-100 group. Non-lethal toxicity for patients in the FEC-100 group experienced included an increased amount of fatigue, low white blood cell count, infections, mouth ulcers and low platelets. Therefore, the study showed that the six cycle antracycline- based regiments should not be used for women with node negative breast cancer.
One of the ongoing challenges of breast cancer treatments is to select the most effective treatments with the least toxicity. Unfortunately, many chemotherapies bring intolerable side effects for women, some which are fatal. Breast Cancer Action will continue to push for more effective, less toxic treatments.
NSABP B-36: randomized Phase III trial comparing six cycles of 5-fluorouracil (5-FU), epirubicin, and cyclophosphamide (FEC) to four cycles of adriamycin and cyclophosphamide (AC) in patients with node-negative breast cancer. Dr. Charles Geyer –Supported by NCI