Department of Oncology/Pathology, Karolinska Institutet, Stockholm; Breast Center, Karolinska University Hospital, Stockholm, Sweden.
Department of Oncology/Pathology, Karolinska Institutet, Stockholm; Breast Center, Karolinska University Hospital, Stockholm, Sweden.
Ann Oncol. 2019 Jan 1;30(1):109-114. doi: 10.1093/annonc/mdy475.
Adjuvant chemotherapy (ACT) for breast cancer improves relapse-free survival (BCRFS) and overall survival. Differences in terms of efficacy and toxicity could partly be explained by the significant interpatient variability in pharmacokinetics which cannot be captured by dosing according to body surface area. Consequently, tailored dosing was prospectively evaluated in the PANTHER trial.
PANTHER is a multicenter, open-label, randomized phase III trial which compared tailored, dose-dense (DD) epirubicin/cyclophosphamide (E/C) and tailored docetaxel (D) (tDD) with standard interval 5-fluorouracil/E/C and D. The primary end point was BCRFS and the primary efficacy analysis has been previously published. In this secondary analysis, we aimed to retrospectively explore the concept of dose tailoring. Our two hypotheses were that BCRFS would not vary depending on the cumulative administered epirubicin dose; and that dose tailoring would lead to appropriate dosing and improved outcomes for obese patients, who are known to have worse prognosis and increased toxicity after DD ACT.
Patients treated with tDD had similar BCRFS regardless of the cumulative epirubicin dose (P = 0.495), while obese patients in this group [body mass index (BMI) ≥30] had improved BCRFS compared with nonobese ones (BMI <30) [hazard ratio (HR) = 0.51, 95% confidence interval (CI) 0.30-0.89, P = 0.02]. Moreover, tDD was associated with improved BCRFS compared with standard treatment only in obese patients (HR = 0.49, 95% CI 0.26-0.90, P = 0.022) but not in nonobese ones (HR = 0.79, 95% CI 0.60-1.04, P = 0.089). The differences were not formally statistically significant (P for interaction 0.175). There were no differences in terms of toxicity across the epirubicin dose levels or the BMI groups.
Dose tailoring is a feasible strategy that can potentially improve outcomes in obese patients without increasing toxicity and should be pursued in further clinical studies.
CLINICALTRIALS.GOV IDENTIFIER: NCT00798070.
乳腺癌辅助化疗（ACT）可改善无病生存期（BCRFS）和总生存期。由于药代动力学的显著个体间差异，疗效和毒性的差异部分可以解释，而根据体表面积进行剂量给药无法捕捉到这些差异。因此，在 PANTHER 试验中前瞻性地评估了个体化剂量。
PANTHER 是一项多中心、开放标签、随机 III 期试验，比较了密集型（DD）表柔比星/环磷酰胺（E/C）和个体化多西他赛（D）（tDD）与标准间隔 5-氟尿嘧啶/E/C 和 D 的疗效。主要终点是 BCRFS，主要疗效分析已在之前发表。在这项二次分析中，我们旨在回顾性探索剂量个体化的概念。我们的两个假设是：BCRFS 不会随累积给予的表柔比星剂量而变化；并且剂量个体化将为肥胖患者提供适当的剂量，并改善他们的预后，已知肥胖患者在接受 DD ACT 后预后较差且毒性增加。
接受 tDD 治疗的患者无论累积表柔比星剂量如何，其 BCRFS 相似（P=0.495），而该组中的肥胖患者（BMI≥30）的 BCRFS 优于非肥胖患者（BMI<30）（风险比 [HR] = 0.51，95%置信区间 [CI] 0.30-0.89，P=0.02）。此外，与标准治疗相比，tDD 仅在肥胖患者中与改善的 BCRFS 相关（HR=0.49，95%CI 0.26-0.90，P=0.022），而非肥胖患者中则无相关性（HR=0.79，95%CI 0.60-1.04，P=0.089）。差异没有统计学意义（P 交互作用=0.175）。在表柔比星剂量水平或 BMI 组之间，毒性没有差异。
剂量个体化是一种可行的策略，可在不增加毒性的情况下提高肥胖患者的治疗效果，应在进一步的临床研究中进行探索。
临床试验.gov 标识符：NCT00798070。
