1. This randomized, open label, phase 3 trial found that dose-dense adjuvant chemotherapy did not significantly improve breast cancer recurrence-free survival compared to standard adjuvant chemotherapy in high-risk early breast cancer patients.
2. Non-hematologic toxic effects were more frequent in the dose-dense group compared to the standard adjuvant chemotherapy group.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Studies have shown that adjuvant chemotherapy reduces mortality in breast cancer patients by up to one third, with this effect being seen in all subpopulations. Furthermore, a meta-analysis has shown that higher doses of anthracyclines increases the overall effectiveness of adjuvant chemotherapy, but is limited by cardiotoxicity and secondary hematologic malignancies. An alternative evaluated in this study is dose-dense chemotherapy, which involves delivery of chemotherapy at shorter intervals without increasing the cumulative dose, with the purpose of increasing overall efficacy. This randomized, open label, multicenter, phase 3 trial found that dose-dense adjuvant chemotherapy did not significantly improve breast cancer recurrence-free survival compared to standard adjuvant chemotherapy in high-risk early breast cancer patients. In addition, non-hematologic toxic effects were more frequent in the dose-dense group compared to the standard adjuvant chemotherapy group.
There are a few limitations to this study. First of all, the null hypothesis could not be rejected in either the primary or secondary endpoints, indicating a lack of statistical power in the design of the trial. Longer follow-up could potentially resolve this issue. In addition, there is ambiguity in whether the different strategies for dose intensification (this study employed dose tailoring, dose-dense scheduling, or both) are responsible for the observed outcomes. Overall, the results from this trial suggest that dose-dense adjuvant chemotherapy does not yield significant benefits in terms of breast cancer recurrence-free survival compared to standard adjuvant chemotherapy.
In-Depth [randomized clinical trial]: This study aimed to evaluate the effectiveness of dose-dense adjuvant chemotherapy compared to standard adjuvant chemotherapy in high-risk, early breast cancer patients. This study was a multicenter, open-label, randomized, phase 3 trial, encompassing 86 study sites across Sweden, Germany, and Austria as a collaboration between various cancer study groups. A total of 2,017 patients aged 18-65 years with histology confirmed, completely resected invasive primary breast cancer were included in this study. Main exclusion criteria included previous adjuvant / neoadjuvant chemotherapy, positive margins after surgery, ongoing pregnancy or lactation, peripheral neuropathy, and previous malignant neoplasms. The primary outcome measure was breast cancer recurrence-free survival (BCRFS). Secondary outcome measures included distant disease-free survival (DDFS), event-free survival (EFS), and overall survival (OS).
The analyses showed no significant difference in BCRFS between treatment groups (HR 0.79; 95%CI 0.61 – 1.01; log-rank p = 0.06). Five-year BCRFS rates were 88.7% in the tailored dose-dense group and 85.0% in the control group. There was a significantly better EFS in the dose-dense group compared to the control group (HR 0.79; 95%CI 0.63 – 0.99; p = 0.04), but the two groups did not differ in terms of their OS. Non-hematologic grade 3 or 4 toxic effects were seen in 527 patients (52.6%) in the tailored dose-dense group and 366 (36.6%) in the control group, with the most common reported adverse events being fatigue, musculoskeletal pain, and neutropenic infection for both groups.
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