An interim analysis of the GAIN-2 study in patients with high-risk early-stage breast cancer indicated that the use of neoadjuvant/adjuvant intense, dose-dense epirubicin, nab-paclitaxel, and cyclophosphamide (iddEnPC) and dose-dense, dose-tailored epirubicin/cyclophosphamide followed by dose-dense, dose-tailored docetaxel (dtEC-dtD) were equivalent (Abstract 516).
“Dose-dense chemotherapy is recommended as a standard of care, but direct comparisons of dose-dense regimens are rare,” said Volker Möbus, MD, PhD, of the University of Frankfurt, in Germany.
GAIN-2 was a phase III study designed to compare the efficacy and safety of iddEnPC versus dtEC-dtD for patients with node-positive or high-risk, node-negative early-stage breast cancer.
Patients were randomly assigned to either iddEnPC (epirubicin 150 mg/m2, nab-paclitaxel 330 mg/m2, and cyclophosphamide 2,000 mg/m2, all every 2 weeks for three cycles) or four courses of tailored dose-dense dtEC every 2 weeks (starting dose 90/600 mg/m2) followed after 1 week rest by four courses of tailored dose-dense dtD every 2 weeks (starting dose 75 mg/ m2). Pegfilgrastim was given in both arms on day 2 after each cycle. The primary endpoint was invasive disease-free survival (iDFS), with safety and compliance as secondary objectives. Over a 5-year period (2012 to 2017), 2,887 patients were randomly selected and 2,857 started treatment. The authors reported the interim analysis after 50% of events had occurred.
Baseline characteristics were well balanced between arms. The mean age was 51; 47.2 % of patients had ≥ four positive lymph nodes, 68.4 % were positive for either one or both hormone receptors, and 27.2% had an overexpression of HER2.
The median follow-up duration was 45.8 months. Overall, 88.1% of patients completed treatment in both arms, 66.8% with iddEnPC versus 58.8% with dtEC-dtD delayed chemotherapy dose (p < 0.001). Grade 3/4 leukopenia, neutropenia, and febrile neutropenia were significantly higher in the iddEnPC arm without a significant difference of infection between the two arms. Grade 3/4 nonhematological adverse events were also more frequent with iddEnPC (50.8%) versus dtEC-dtD (45.1%; p = 0.002), especially arthralgia; peripheral sensory neuropathy was significantly higher. Despite the higher toxicity in the iddEnPC arm, two treatment-related deaths occurred only during dtEC-dtD.
At the time of interim analysis, 414 events for iDFS were reported. There was no difference in iDFS between arms, with 4-year iDFS rates of 84.3% (95% CI [82.0%, 86.4%]). Among all predefined subgroups, only luminal B/HER2-negative predicted for shorter iDFS in the iddEnPC arm.
“The GAIN-2 trial confirmed dose-dense chemotherapy as a standard of care in the neo-/adjuvant treatment [setting], which is also recommended by the National Comprehensive Cancer Network and other guidelines.” - Dr. Volker Möbus
“The GAIN-2 trial confirmed dose-dense chemotherapy as a standard of care in the neo-/adjuvant treatment [setting], which is also recommended by the National Comprehensive Cancer Network and other guidelines. The GAIN-2 trial compared two intense dose-dense regimens with fixed versus tailored dosing of the drugs. These schedules may increase efficacy both when tumor growth follows Gompertzian kinetics requiring higher density and when partially resistant clones require higher doses. This hypothesis is confirmed by the results of the recent meta-analysis of the Early Breast Cancer Trialists' Collaborative Group, which showed that the largest risk reductions were generally seen in those trials with the largest dose-intensity ratios,” Dr. Möbus said.
– Muriel Cunningham
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