Sequential chemo regimen provides survival gains in early-stage breast cancer
Sequential administration of epirubicin and docetaxel yields a nonsignificant but possibly clinically meaningful improvement in disease-free survival (DFS) in patients with node-negative but high-risk early breast cancer as compared with concurrent use of the two drugs, according to data from the phase III Hellenic study.
In a planned interim analysis of early-stage breast cancer patients with tumours >2 cm or T1c randomly assigned to the sequential (n=329) or concurrent arm (n=329), the proportion of patients with disease relapses (8.8 vs 12.8 percent; p=0.102) and deaths (3.3 vs 5.8 percent; p=0.135) after a median follow-up of 70.5 months did not significantly differ between the treatment arms. [Br J Cancer 2017;117:164-170]
However, a trend was seen for an improvement in the primary outcome of DFS (5-year rate, 92.6 vs 88.2 percent), as well as in overall survival (OS; 5-year rate, 98.7 vs 96.3 percent), in favour of the sequential arm. The hazard ratios (HRs) were 1.591 (95 percent CI, 0.990 to 2.556; p=0.055) for DFS and 1.896 (0.902 to 3.987; p=0.091) for OS.
The investigators noted that the trend towards better OS was interestingly more pronounced for patients with triple-negative tumours (HR, 3.369; 0.940 to 12.081; p=0.062).
Toxicity included grade 2 to 4 neutropaenia in 54 percent of patients in the sequential arm vs 41 percent of patients in the concurrent arm (p=0.001), febrile neutropaenia in 2.7 vs 6.1 percent (p=0.06) and nausea/vomiting in 18.5 vs 12.4 percent (p=0.03). There were no reports of toxicity-related deaths.
The study population comprised 658 early-stage breast cancer patients (median age 53 years; 49 percent premenopausal) with two of the following characteristics: no oestrogen receptor (ER) and progesterone receptor (PR) expression, histological grade III, Ki67 >40 percent, and vascular, lymphovascular or perineural invasion. Of the tumours, 44.2 percent were ≤2 cm, 52.7 percent histological grade 3 and 35.3 percent were hormone receptor-negative.
Patients in the sequential regimen arm received four cycles of epirubicin 90 mg m−2 followed by four cycles of docetaxel 75 mg m−2, while those in the concurrent arm received six cycles of epirubicin 75 mg m−2 plus docetaxel 75 mg m−2. All chemotherapy cycles were administered every 21 days with G-CSF (granulocyte colony-stimulating factor) prophylaxis only for the concurrent arm.
“In the era of molecular selection of patients with node-negative disease for whom adjuvant chemotherapy is indicated, we believe that our study provides valuable information regarding the optimal use of the most active drugs to achieve a better clinical outcome,” the investigators said.
They, however, acknowledged that the results being based on an interim analysis is one important caveat to interpreting the present data. Other potential limitations of the study include the relatively small sample size, the borderline significance of the primary outcome, the omission of cyclophosphamide on the anthracycline arm, as well as the initial inclusion of a small number of HER2-positive patients.
In an accompanying editorial, Drs Nathalie LeVasseur and Stephen Chia from the British Columbia Cancer Agency in Vancouver, Canada, pointed out that the present data contribute further to the foundation of evidence that supports the recommendation of a sequential, appropriately dose-intensified anthracycline–taxane-based regimen in early-stage breast cancer. [Br J Cancer 2017;117:157–300]
“What perhaps is the most interesting aspect of the study results is to decipher why the sequential arm appeared to outperform the combination arm… The combination arm in fact delivered higher cumulative doses of both epirubicin (450 mg m−2) and docetaxel (450 mg m−2) compared to the sequential arm (epirubicin 360 mg m−2 and docetaxel 300 mg m−2),” they said.
“Thus, perhaps once the threshold of total dose is surpassed, higher cumulative doses do not add to efficacy but rather do add to cumulative toxicity (such as cardiac toxicity and neuropathy for anthracyclines and taxanes, respectively),” they added.
Drs LeVasseur and Chia noted that slight modifications of cytotoxic chemotherapeutic regimens or schedules will unlikely result in further dramatic gains in survival.
Future clinical trials should instead investigate the use of genomic assays to enrich patient populations enrolled into adjuvant systemic trials, and the addition of targeted agents (either in combination or in sequence) to standard-of-care therapy to further improve clinical outcomes in early-stage breast cancer, they said.