Many adjuvant treatment options exist, and yet there is no definitive go-to regimen to treat women with early breast cancer. At the 29th Annual Miami Breast Cancer Conference, three prominent breast cancer clinicians and researchers presented overviews of three adjuvant components: anthracyclines, fluoropyrimidines, and taxane agents.
Adjuvant chemotherapy regimens have seen an evolution of three successive generations. Insights into these treatment trends are gleaned from adjuvant early- stage breast cancer clinical trial data that are pooled together every five years in the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).
Cytotoxic therapy consisting of cyclophosphamide– methotrexate–5-fluorouracil (CMF)-based regimens showed a 24% reduction in breast cancer recurrence and 14% reduction in death, compared with placebo.1
Anthracycline therapy showed an advantage, although modest, over CMF-based chemotherapy.2
The reduction in risk of recurrence was 11%, and reduction in risk of breast-cancer mortality was 16% for anthracyclines compared with CMF. Finally, the 2006 EBCTCG overview showed that the thirdgeneration adjuvant therapy of anthracycline and taxane-based chemotherapy further reduced the risk of breast cancer recurrence by 17% compared with anthracycline-based chemotherapy.3
The breast cancer-specific, absolute improvement in survival with these generations of adjuvant chemotherapy is approximately 4% to 5%.
Julie R. Gralow, MD
Julie R. Gralow, MD, director of Breast Medical Oncology at the Fred Hutchinson Cancer Research Center in Seattle, Washington, provided an overview of the evidence for anthracycline-based adjuvant therapies. “Anthracyclines have been extensively tested in clinical trials over several decades,” said Gralow. “Currently, there are insufficient data to recommend replacing them in adjuvant treatment of breast cancer.”
She added that for a patient with a “high enough risk of recurrence to warrant chemotherapy, it is hard to confidently identify a population who will not benefit from an anthracycline-based regimen”—channeling the key message of a 2009 review on the topic.4
“We are desperately looking for anthracycline response and resistance,” she added.
In Gralow’s view, most patients are eligible for anthracyclines— except when heart toxicity may be an issue—but she generally gives maximal endocrine therapy over a chemotherapy regimen.
The current anthracycline regimens use a 60 mg/m2 dose based on the Cancer and Leukemia Group B (CALGB) 9344 trial that did not show an added benefit in increased anthracycline (doxorubicin) dosage. In contrast, epirubicin trials have not stuck to a consistent dose, according to Gralow.
Gralow highlighted major trials that led to the utilization of anthracyclines in the adjuvant setting. The EBCTCG 2006 meta-analysis of CMF versus anthracycline regimens showed a 5% absolute difference in mortality at 10 years, favoring anthracycline. The magnitude of the benefit was probably underestimated in this analysis, as many of the included studies used anthracyclines at much lower doses than those used today, Gralow said.
Two large North American trials have compared anthracycline with CMF. The NCIC-CTG MA5 trial, which compared CMF with cyclophosphamide-epirubicin-fluorouracil (CEF) in node-positive patients, showed an overall survival of 58% to 62%, respectively.5
“Clearly a positive trial,” Gralow stated. However, the conclusion of the SWOG-8897 node-negative patient trial (new analysis is expected shortly) at the 10- year mark suggested that a regimen of cyclophosphamide, doxorubicin, and fluorouracil (CAF) is not superior to the CMF regimen. Gralow stated that she did not agree with the conclusion of that study, mainly because the disease-free survival was likely confounded by events that could not have been impacted by the adjuvant regimen.6
Kathy D. Miller, MD
Kathy D. Miller, MD, of the Simon Cancer Center, Indiana University, Indianapolis, discussed the evolution of fluoropyrimidine in breast cancer treatment. “Once the mainstay of adjuvant therapy, a crucial component of CMF, the use of 5-fluorouracil plummeted through the last two decades,” according to Miller. Based on clinical trials, it is difficult to determine the actual contribution of fluoropyrimidine to multicomponent adjuvant regimens.