Advantage of Chemo plus Tam
Given that yesterday was a holiday, I had a little time to spend cleaning out my electronic drawers--aka my email box. In doing so, I came across this summary of a study presented at the December San Antonio meeting that found, for many post-menopausal woman, an advantage of receiving sequential chemo and tamoxifen. Here it is:
SAN ANTONIO -- After more than two decades of follow-up, anthracycline-based chemotherapy added to tamoxifen continues to offer a survival advantage for postmenopausal breast cancer, according to a study reported here at the San Antonio Breast Cancer Symposium and online.
Women treated with chemotherapy and then tamoxifen had a 24% improvement in disease-free survival compared with women treated with tamoxifen alone (P=0.002). Chemotherapy also led to a trend toward improved overall survival.
The trial also showed a trend toward better survival when the chemotherapy and tamoxifen were given sequentially rather than concurrently.
"We believe that for postmenopausal women with few comorbidities who have a substantial risk of recurrence or death based on the prognostic profile of their tumor, the risk-benefit balance favors anthracycline-based chemotherapy followed by tamoxifen," Kathy Albain, MD, of Loyola University in Maywood, Ill., and colleagues concluded online in The Lancet. "However, characteristics of the tumor should also be factored into the risk-benefit ratio. This study shows the necessity of long-term follow-up of adjuvant therapies to determine the outcome of treatment," they wrote.
A companion study, also reported here as well as online in The Lancet Oncology, suggested that genetic profiling can identify a subset of women who may not benefit from chemotherapy -- in particular those whose tumors had low scores on an assay of gene expression.
Researchers said the risks and toxicity of chemotherapy make it critical to identify patients who are highly unlikely to respond to it.
Upon its approval for clinical use, tamoxifen became the gold standard of adjuvant therapy for estrogen receptor-positive, postmenopausal breast cancer. Adding chemotherapy to tamoxifen offered attractive theoretical benefits, but no consensus existed about chemotherapy for tamoxifen-responsive postmenopausal breast cancer patients.
Most trials of chemotherapy in postmenopausal breast cancer involved regimens containing cyclophosphamide, methotrexate, and fluorouracil (CMF), but some studies had suggested the superiority of anthracycline-containing regimens, the authors wrote.
Moreover, preclinical studies suggested possible interference with cytotoxicity when tamoxifen and CMF were given concurrently. Nonetheless, concurrent therapy had been the standard in many clinical trials, the authors continued.
To address the unresolved issues, Southwest Oncology Group investigators in 1988 launched a randomized clinical trial involving postmenopausal patients with receptor-positive, node-positive breast cancer. Patients were randomized 2:3:3 to tamoxifen alone or to tamoxifen plus chemotherapy, administered sequentially or concurrently. The chemotherapy regimen consisted of cyclophosphamide, doxorubicin, and methotrexate (CAF).
The primary outcome was disease-free survival, and investigators performed two comparisons: tamoxifen alone versus tamoxifen plus chemotherapy; and sequential versus concurrent therapy with CAF and tamoxifen.
Albain and colleagues reported findings from an analysis of 1,477 patients. After a median follow-up of 8.94 years (maximum of 13), chemotherapy plus tamoxifen (sequential or concurrent) was associated with a 10-year disease-free survival of 57%, compared with 48% for tamoxifen alone. The difference translated into a hazard ratio of 0.76 in favor of chemotherapy (95% CI 0.64 to 0.91, P=0.002).
Women who received chemotherapy had a 10-year overall survival of 65% compared with 60% for tamoxifen alone. The 5% absolute difference represented a 17% improvement compared with tamoxifen alone, but the difference did not reach statistical significance (HR 0.83, 95% CI 0.68 to 1.01, P=0.057).
The comparison of sequential versus concurrent therapy favored the former for both disease-free survival (HR 0.84, 95% CI 0.70 to 1.01, P=0.061) and overall survival (HR 0.90, 95% CI 0.73 to 1.10, P=0.30), but the differences did not achieve statistical significance.
The second study reported by Albain and colleagues involved use of a multigene tumor assay to identify women who were likely or unlikely to respond to the CAF chemotherapy regimen. They used a 21-gene recurrence score assay that previously demonstrated prognostic value for women with node-negative, estrogen-receptor positive breast cancer treated with tamoxifen.
Albain and colleagues extended the evaluation to the SWOG study, examining the assay's ability to determine which women with node-positive, receptor-positive breast cancer are unlikely to benefit from chemotherapy. The study included tumor specimens from 367 patients. The investigators assessed correlation between the recurrence score and disease-free survival by treatment group (tamoxifen versus CAF-tamoxifen). Derived from RT-PCR analysis of gene-expression, the recurrence score ranged from 0 to 100. The results confirmed the recurrence score's prognostic value for treatment with tamoxifen alone (HR 2.64, P=0.006, for a 50-point difference in the score). Additionally, the results showed that a recurrence score of less than 18 predicted no benefit from chemotherapy with respect to the trial's primary endpoint of disease-free survival (HR 1.02, P=0.97).
In contrast, women whose tumors had a score of 31 or greater had a significantly greater likelihood of improved disease-free survival with chemotherapy (HR 0.59, P=0.033). Recurrence score by treatment group remained significant throughout the first five years of follow-up (P=0.029) but not beyond that time period (P=0.58).
Analyses of overall survival and cancer-specific survival yielded similar findings.
In a commentary that accompanied the Lancet article, Michael Gnant, MD, and Guenther G. Steger, MD, of the Medical University of Vienna in Austria, said the 5% overall survival benefit is a worthwhile improvement but comes at a price of increased toxicity. "For that reason, identification of subgroups of patients who have an above-average outcome is important," Gnant and Steger wrote. "Since risk is something we cannot change, response prediction is nowadays judged more important for clinical decision-making than risk itself, but calculation of individual benefit is still poor," they added. "Avoidance of unnecessary or ineffective treatment should be one of the main goals in adjuvant breast oncology today."
Acknowledging the 21-gene assay score's correlation with recurrence, Gnant and Steger noted that the benefit of therapy was limited to the highest risk patient subgroup (score ≥31), which constituted less than a third of the trial cohort. Moreover, the finding that low-risk patients derived little or no benefit from chemotherapy could mean that overtreatment is an even greater problem for patients with node-negative breast cancer.