May 22, 2009 — Docetaxel (Taxotere, sanofi-aventis) added to standard anthracycline-based adjuvant chemotherapy had no overall effect on disease-free survival among patients with early breast cancer, according to results of a study published in the May 16 issue of the Lancet. These results contrast with those from other adjuvant trials, which showed a modest survival benefit when sequential docetaxel was added to the standard treatment regimen.
However, the data also suggest that estrogen-receptor (ER) and human epidermal growth-factor receptor-2 (HER2) status might be able to help predict response to taxane-based therapy.
At a median follow-up of 62 months, 75.6% of patients who received docetaxel plus anthracycline chemotherapy remained disease free, compared with 74.3% who did not receive docetaxel. The proportion of patients who reported any acute grade 3 or 4 adverse event was significantly greater among patients who received docetaxel.
TACT (Taxotere as Adjuvant Chemotherapy Trial) is the largest first-generation taxane study to date, and the results are "particularly surprising" because the sequential administration of full-dose docetaxel is a schedule that has consistently shown efficacy in other breast cancer adjuvant trials, writes Miguel Martin, MD, in an accompanying editorial.
Dr. Martin, from the Hospital Clinico San Carlos in Madrid, Spain, points out that the reason for the lack of significant differences between groups remains unresolved. "The only clear lesson from TACT is that the [fluorouracil, epirubicin, and cyclophosphamide plus docetaxel] is not superior to a conventional, less toxic adjuvant treatment, and should not be recommended as an adjuvant treatment for early breast cancer," he notes.
"The benefit from adjuvant taxanes is small, and there are few trials in this area that did not confirm a taxane's benefit," he writes. "Publication of the largest of these trials will refocus the debate around what the true benefit of a taxane might be and which patients might obtain that benefit."
Earlier Trials Often Show Taxane Benefit
The study authors point out that there is substantial variation in results from individual taxane trials, but many studies have shown some benefit to their use. As previously reported by Medscape Oncology, a review of 6 major randomized clinical trials evaluating the role of adjuvant taxanes for node-positive breast cancer recommended their use (Cancer Treat Rev. 2007;33:474-483).
Data from the USO-9735 trial showed the superiority of a taxane combination in women with early breast cancer (J Clin Oncol. 2009;27:1177-1183). Docetaxel plus cyclophosphamide was found to be superior to 4 cycles of anthracycline doxorubicin (Adriamycin) combined with cyclophosphamide. But as reported by Medscape Oncology, the study prompted considerable debate.
The TACT authors note that "in view of the molecular diversity of breast cancer, adjuvant taxanes might provide different benefits for particular patient subgroups. Therefore, clinicians need to identify patients who would — and, just as importantly, who would not — obtain benefit from this treatment."
Biomarkers May Target Population
Biological markers such as ER and HER2 do not appear to have much predictive value in determining response to taxanes when looked at in isolation. However, the authors note, evaluating the biomarkers in more complex biological groupings could be important. They point to the retrospective subgroup analysis of 1322 node-positive patients in the CALGB 9344 trial, in which patients with ER-negative or HER2-positive tumors derived the most benefit from taxane use. In their own subanalysis, docetaxel seemed most beneficial among patients with ER-negative and HER2-positive tumors.
"We postulate that patients with ER-positive and HER2-negative cancers might not gain a clinically worthwhile benefit from taxanes; however, long-term follow-up is needed to confirm this hypothesis," they write.
No Survival Benefit Seen
TACT, led by Paul Ellis, MD, FRACP, consultant medical oncologist at Guy's & St Thomas' NHS Trust and at Kings College Hospital in London, United Kingdom, was developed in 2000 to determine if giving docetaxel sequentially at 3-weekly intervals after anthracycline chemotherapy would improve outcomes, compared with patients who received standard treatment for a similar duration. The primary end point of TACT was disease-free survival.
The cohort consisted of 4162 women with node-positive or high-risk node-negative operable early breast cancer who were randomized to either FEC (fluorouracil 600 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 600 mg/m2 at 3-weekly intervals) for 4 cycles followed by docetaxel (100 mg/m2 at 3-weekly intervals) for 4 cycles (n = 2073) or the control group (n = 2089).
Control regimens consisted of either FEC for 8 cycles (n = 1265) or epirubicin (100 mg/m2 at 3-weekly intervals) for 4 cycles followed by CMF (cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 at 4-weekly intervals) for 4 cycles (n = 824). The choice of regimen was determined by the each participating center.
The researchers did not find any evidence of a difference in disease-free survival between the 2 groups. Overall survival also did not differ; 5-year overall survival rates were 82.5% for patients in the docetaxel group and 83.0% for those in the control group. In addition, no differences were observed in the 5-year metastasis-free survival rates (78.8% in the docetaxel group vs 77.7% in the control group).
Higher Toxicity in Docetaxel Group
As they expected, the toxicity profile differed in the 2 study groups. The proportion of patients reporting any acute grade 3 or 4 toxicity that occurred during treatment and up to 30 days afterward was significantly greater among those receiving docetaxel. The most frequently reported events were neutropenia (937 vs 797 events for the docetaxel and control groups, respectively), leucopenia (507 vs 362 events, respectively), and lethargy (456 v. 272 events, respectively).
Late adverse events, reported more than 2 months after the end of treatment, were also more common among patients who had received docetaxel, and included musculoskeletal disorders, central nervous system disorders, skin conditions, edema, and alopecia.
Among the 829 patients participating in the quality-of-life substudy, deterioration in quality of life during chemotherapy was shown to be clinically relevant, with greater impairment reported among those receiving docetaxel. Impairments were reported in physical, emotional, and social functioning, and patients also reported pain and fatigue. Significantly more nausea and vomiting were reported in the control group, however (P = .01), and differences between groups lessened over the course of 24 months.
Long-Term Data Needed
Although no survival benefit was seen in this study, the authors say that the long-term benefits of taxanes need further investigation, and point out that the risk for relapse among women with ER-positive disease continues for at least 15 years after their initial diagnosis.
"We support the view that 'one-size-fits-all' adjuvant chemotherapy trials in early breast cancer are too simple and we propose that future trials are designed around specific biological patient subgroups, with the aim of accelerating advances in tailored therapy," they conclude.
The study was funded by Cancer Research UK (CRUK 01/001), sanofi-aventis, Pfizer, and Roche. Several study authors report financial relationships with Pfizer, Roche, and sanofi-aventis. Dr. Martin has received consultancy and speakers' fees from Pfizer, sanofi-aventis, Bristol-Myers Squibb, and Roche
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