PITTSBURGH—Adjuvant therapy in patients with small, node-negative breast tumors has been controversial due to the lack of randomized studies. To explore this question, University of Pittsburgh researchers reviewed data on patients with tumors of 1 cm or less from five large clinical trials of adjuvant therapy that enrolled women with various-sized tumors.
Results show that regardless of estrogen-receptor (ER) status, patients with small tumors benefited from adjuvant treatment with chemotherapy or tamoxifen(Drug information on tamoxifen) (Nolvadex), Elizabeth Tan-Chiu, MD, of the University of Pittsburgh, said at the San Antonio Breast Cancer Symposium.
However, the reduction in relapse rates and breast cancer events has not translated into improved overall survival at a median follow-up of 8 years. “I think the reason we didn’t see a difference in terms of overall survival is that we haven’t followed the patients long enough,” she said.
The findings came from an analysis of five clinical trials organized by the National Surgical Adjuvant Breast and Bowel Project (NSABP). Collectively, the trials included more than 10,000 patients. A computer search identified 1,260 patients who had tumors of 1 cm or less at diagnosis, 236 with ER-negative tumors and 1,024 with ER-positive tumors. About 60% of patients had tumors 1 cm in size, and about 40% had smaller tumors.
Four of the five studies included in the analysis were initiated during the early or late 1980s and were completed by the early 1990s. B-06 was conducted between 1976 and 1983. “The trials were designed in a hierarchical fashion, whereby results of earlier trials formed the starting point for succeeding trials,” Dr. Tan-Chiu said.
B-13 and B-19 involved ER-negative patients. In B-13, patients were randomized to surgery or surgery plus adjuvant chemotherapy with metho-trexate and fluorouracil(Drug information on fluorouracil) (5-FU).
B-19 involved randomization to the two-drug adjuvant therapy used in B-13 (MF) or to the three-drug combination of cyclophosphamide(Drug information on cyclophosphamide), methotrexate(Drug information on methotrexate), and 5-FU (CMF).
B-14 and B-20 enrolled ER-positive patients. In B-14, patients were randomized to adjuvant tamoxifen or placebo, and in B-20, to tamoxifen alone or to tamoxifen combined with MF or CMF chemotherapy.
B-06 asked whether lumpectomy with or without radiation therapy was equivalent to mastectomy in terms of survival. Among the lumpectomy patients, only those who received radiation therapy were included in the five-trial analysis.
Relapse-free survival was defined as the time free from first recurrence, whether local, regional, or distant, but not contralateral. Event-free survival was the time free from ipsilateral or contralateral recurrence, second primary, and non-breast-cancer death. Overall survival encompassed death from all causes, including breast cancer. Median follow-up ranged between 8 and 17 years. Dr. Tan-Chiu said 8 years was chosen to permit inclusion of B-06, which had the shortest median follow-up period.
Study Results
In the ER-negative patients, surgery alone was associated with an 8-year relapse-free survival of 79%, which was improved to 94% with the addition of chemotherapy. “This corresponds to a relative risk reduction of about 40%, which is comparable to the published results from B-13,” Dr. Tan-Chiu said. Event-free survival was 70% in the surgery-alone group and 81% in patients who received adjuvant combination chemotherapy. However, overall survival, which was slightly greater than 90%, did not differ between the two groups.
In ER-positive patients, relapse-free survival was 86% in patients who had surgery alone, 92% in patients who received adjuvant tamoxifen, and 94% in those who had chemotherapy and tamoxifen. “These results are consistent with about a 30% reduction in risk of recurrence for tamoxifen over surgery and a 40% reduction for tamoxifen plus chemotherapy over surgery,” she said, and are consistent with findings from B-14 and B-20.
Event-Free Survival
Event-free survival in ER-positive patients was 74% with surgery alone, 82% with adjuvant tamoxifen, and 88% with tamoxifen and adjuvant chemotherapy. Overall survival at 8 years was 90% with surgery, 92% with adjuvant tamoxifen, and 97% with chemotherapy plus tamoxifen, which was not significantly different.
Covariance analysis identified age (49 and younger), tumor size (1 cm vs smaller tumors), and invasive ductal or lobular histology as predictors of increased risk.
If the combined results follow those from the individual studies, a benefit in overall survival eventually could emerge, Dr. Tan-Chiu said in the question-and-answer period. “In B-14, we did not see a survival difference until 10 years later,” she said. “If we were to follow and update this set of patients at 10 or 15 years, we might be able to see the same results. Also, we need to realize that these patients with small tumors have good prognosis overall. The event rate was very small. All of us know that statistical significance is dependent on two factors: follow-up time and number of events.”
