Dutch Study Confirms Importance of Tamoxifen Duration

SAN ANTONIO—A long-term Dutch study has provided additional evidence that the duration of tamoxifen (Nolvadex) therapy influences the degree of benefit for reducing breast cancer recurrence. However, the optimal duration of therapy remains an open question, Dr. Jan Vermorken, an oncologist at University Hospital, Antwerp, said at the San Antonio Breast Cancer Symposium.

Nine Years of Follow-up

“After 9 years of follow-up, we’ve found that recurrence-free and overall survival are significantly improved when a patient receives tamoxifen vs no tamoxifen,” Dr. Vermorken said. “We’ve also found during 7.2 years of follow-up that continuation of tamoxifen for 3 years leads to a better recurrence-free interval than stopping at 1 year” (see Table 1). However, he added, “we are not sure whether 5 years is better than 3 years.”

Dr. Vermorken believes that “when other trials are done in the future, 3 years of tamoxifen therapy could be a standard for the control arm.”

The study also showed that tamoxifen reduces the risk of contralateral breast cancer (see Table 2). Additionally, Dr. Vermorken reported that the benefits of tamoxifen in this study were restricted to estrogen-receptor (ER)-positive patients.

The Protocol

The findings emerged from a randomized clinical evaluation—from the Comprehensive Cancer Center Amsterdam (CCCA) Cooperative Breast Cancer Group—involving more than 1,600 postmenopausal patients with stage T1-4, N0-2, M0 breast cancer.

A total of 1,242 patients were stratified by axillary node status and, after initial curative therapy, randomized to receive tamoxifen (30 mg/d) for 1 year or no tamoxifen (first randomization). If patients receiving tamoxifen were relapse-free after 1 year, they were re-randomized to stop treatment or to continue tamoxifen for another 2 years (second randomization).

Because interim data analyses showed that tamoxifen significantly improved progression-free survival in patients with positive nodes, after 1989 all node-positive patients received tamoxifen from the start and, like other patients in the tamoxifen arm, were randomized after 1 year to stop the drug or continue therapy for 2 more years. (These patients contributed to the second randomization.)

The first randomization occurred in a 2:1 ratio of tamoxifen to placebo, and 828 patients received tamoxifen. The second randomization involved a total of 991 patients. Median follow-up from first randomization exceeds 9 years, and median follow-up from second randomization has reached 7.2 years.

Study Results

Patients receiving tamoxifen did better at all endpoints. From first randomization, tamoxifen resulted in recurrence-free survival rates of 75.5% at 5 years and 57.2% at 10 years, compared with 67.6% and 50.7%, respectively, in the control group. Overall survival was 82.2% and 64.2% at 5 and 10 years with tamoxifen vs 78.6% and 56.6%, respectively, in the control group.

Following second randomization, continuation of tamoxifen for a total of 3 years was associated with a recurrence-free survival rate of 75.4% at 5 years and 58.5% at 10 years, compared with 72.4% and 52.7%, respectively, for patients who stopped tamoxifen therapy after a year. The 5- and 10-year overall survival figures were 80.7% and 64.1%, respectively, for 3 years of tamoxifen therapy vs 77.7% and 61.8% in patients who received tamoxifen for 1 year.

The analysis showed higher than expected event rates in ER-positive patients who did not receive tamoxifen, as well as in all ER-negative patients. The event rate was lower than expected (158 vs 191.8) in ER-positive patients who received tamoxifen.

Contralateral Breast Cancer

From first randomization, 84 (10.1%) tamoxifen patients developed second primary cancers, and 28 of these (33%) were contralateral breast cancers. That compared with 48 second primaries (11.6%) in patients who received no tamoxifen, 23 (47.9%) of which were contralateral breast cancers.

Following second randomization, 21 of 52 (40.4%) second primary cancers were contralateral breast cancers in patients who stopped tamoxifen after a year. That compared with 15 of 45 (33%) in patients who continued therapy for 3 years.

“The results demonstrate significant improvement in recurrence-free and overall survival with tamoxifen vs control,” Dr. Vermorken said. “The effect is clearest in ER-positive patients. Though not statistically significant, a trend toward improved recurrence-free and overall survival is associated with longer use of tamoxifen, specifically 3 years vs 1 year. The optimal duration of tamoxifen therapy remains to be determined.”