Neoadjuvant Paclitaxel Before Anthracycline Improves Response in High-Risk Early Breast Cancer
In a phase III 2×2 factorial trial (Neo-tAnGo) reported in The Lancet Oncology, Earl et al compared neoadjuvant therapy with epirubicin/cyclophosphamide followed by paclitaxel with or without gemcitabine vs paclitaxel with or without gemcitabine followed by epirubicin/cyclophosphamide in newly diagnosed breast cancer. Paclitaxel-first treatment was associated with a significantly better pathologic complete response rate, and no difference in response rate was observed between treatment with vs without gemcitabine.
Study Details
In this open-label trial, 831 women aged > 18 years with newly diagnosed breast cancer (tumor size > 20 mm) were randomly assigned at 57 UK centers between January 2005 and September 2007 to receive epirubicin/cyclophosphamide followed by paclitaxel (n = 207), paclitaxel followed by epirubicin/cyclophosphamide (n = 208), epirubicin/cyclophosphamide followed by paclitaxel and gemcitabine (n = 208), or paclitaxel and gemcitabine followed by epirubicin/cyclophosphamide (n = 208).
For component analysis, 413 patients were in the group receiving epirubicin/cyclophosphamide plus paclitaxel and 415 were in the group receiving epirubicin/cyclophosphamide plus paclitaxel and gemcitabine; for sequencing analysis, 414 were in the group given epirubicin/cyclophosphamide followed by paclitaxel with or without gemcitabine, and 414 were in the group given paclitaxel with or without gemcitabine followed by epirubicin/cyclophosphamide.
Regimens were epirubicin at 90 mg/m² and cyclophosphamide at 600 mg/m² once every 21 days, and paclitaxel at 175 mg/m² with or without gemcitabine at 2,000 mg/m² once every 14 days. Each component was given for four cycles. The primary endpoint was pathologic complete response, defined as absence of invasive cancer in the breast and axillary lymph nodes.
Patient groups according to component and sequence were well balanced for baseline patient and disease characteristics. Overall, 37% of patients were aged > 50 years, 67% were estrogen receptor–positive, 51% were progesterone receptor–positive, 27% were HER2 positive, 20% had tumor size > 50 mm, 50% had clinical axillary node involvement, 49% had inflammatory disease, 70% had advanced disease, 57% were premenopausal, 57% had one invasive tumor, 79% had ductal or no special tumor type, 30% had moderately differentiated and 40% had poorly differentiated tumor grade, and 25% had ductal carcinoma in situ associated with tumor.
Better Response With Paclitaxel First
Median follow-up was 47 months. In component analysis, pathologic complete response was achieved in 17% of the epirubicin/cyclophosphamide plus paclitaxel group vs 17% of the epirubicin/cyclophosphamide plus paclitaxel and gemcitabine group (P = .98) in analysis adjusted for age, estrogen receptor status, clinical axillary lymph node involvement, and inflammatory or locally advanced disease. There were no significant differences between groups in analyses according to estrogen receptor status, HER2 receptor status, and grade.
In the sequence analysis, pathologic complete response was achieved in 15% of the epirubicin/cyclophosphamide followed by paclitaxel group vs 20% of the paclitaxel followed by epirubicin/cyclophosphamide group (P = .03) on adjusted analysis. Significant benefit with paclitaxel-first treatment was observed among HER2-negative (13% vs 18%, P = .03), estrogen receptor–negative (30% vs 33%, P = .02), and estrogen receptor–positive and HER2-negative subgroups (5% vs 10%, P = .02), whereas response rate was better with epirubicin/cyclophosphamide–first treatment in the estrogen receptor–positive, HER2-negative, grade 1 or 2 subgroup (4% vs 3%, P = .03).
Toxicities were as expected with these neoadjuvant regimens. Overall, grade 3 toxicities included neutropenia in 21% of patients, infection in 8%, fatigue in 5%, muscle and joint pain in 5%, nausea in 5%, vomiting in 4%, neuropathy in 4%, transaminitis in 3%, acute hypersensitivity in 2%, and rash in 2%. Grade 4 adverse events consisted of neutropenia in 11% and infection in < 1%.
The investigators concluded, “Although addition of gemcitabine to paclitaxel and epirubicin and cyclophosphamide chemotherapy does not improve [pathologic complete response], sequencing chemotherapy so that taxanes are received before anthracyclines could improve [pathologic complete response] in standard neoadjuvant chemotherapy for breast cancer.”
Helena Earl, MBBS, of the University of Cambridge, and Louise Hiller, PhD, of theUniversity of Warwick, are the corresponding authors for The Lancet Oncology article.
The study was funded by Cancer Research UK, Eli Lilly, and Bristol-Myers Squibb. For full disclosures of the study authors, visit www.thelancet.com.
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