Reiss Kim A, Yu Shun, Mamtani Ronac, Mehta Rajni, D'Addeo Kathryn, Wileyto E Paul, Taddei Tamar H, Kaplan David E
Kim A. Reiss, Shun Yu, Ronac Mamtani, E. Paul Wileyto, and David E. Kaplan, University of Pennsylvania Perelman School of Medicine; David E. Kaplan, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA; Rajni Mehta, Kathryn D'Addeo, and Tamar H. Taddei, Yale University School of Medicine, New Haven; and Tamar H. Taddei, VA Connecticut Healthcare System, West Haven, CT.
J Clin Oncol. 2017 Nov 1;35(31):3575-3581. doi: 10.1200/JCO.2017.73.8245. Epub 2017 Sep 5.
Purpose Sorafenib is currently the only Food and Drug Administration-approved first-line therapy for patients with advanced hepatocellular carcinoma. There are few data examining how sorafenib starting dose may influence patient outcomes and costs. Patients and Methods We retrospectively evaluated 4,903 patients from 128 Veterans Health Administration hospitals who were prescribed sorafenib for hepatocellular carcinoma between January 2006 and April 2015. After 1:1 propensity score matching to account for potential treatment bias, hazard ratios (HRs) were calculated using Cox regression and were tested against a noninferiority margin of HR = 1.1. A matched multivariate logistic regression was performed to adjust for potential confounders. The primary end point was overall survival (OS) of patients who were prescribed standard starting dosage sorafenib (800 mg/d per os) versus that of patients who were prescribed reduced starting dose sorafenib (< 800 mg/d per os). Results There were 3,094 standard dose sorafenib patients (63%) and 1,809 reduced starting dose sorafenib patients (37%). Reduced starting dose sorafenib patients had more Barcelona Clinic Liver Cancer stage D ( P < .001), higher Model for End-Stage Liver Disease Sodium scores ( P < .001), higher Child-Turcotte-Pugh scores ( P < .001), and higher Cirrhosis Comorbidity Index scores ( P = .01). Consequently, reduced starting dose sorafenib patients had lower OS (median, 200 v 233 days, HR = 1.10). After propensity score matching and adjusting for potential confounders, there was no longer a significant OS difference (adjusted hazard ratio [HR], 0.92; 95% CI, 0.83 to 1.01), and this fell significantly below the noninferiority margin ( P < .001). Reduced starting dose sorafenib patients experienced significantly lower total cumulative sorafenib cost and were less likely to discontinue sorafenib because of gastrointestinal adverse effects (8.7% v 10.8%; P = .047). Conclusion The initiation of sorafenib therapy at reduced dosages was associated with reduced pill burden, reduced treatment costs, and a trend toward a decreased rate of discontinuing sorafenib because of adverse events. Reduced dosing was not associated with inferior OS relative to standard dosing.
目的 索拉非尼是目前美国食品药品监督管理局批准的唯一用于晚期肝细胞癌患者的一线治疗药物。关于索拉非尼起始剂量如何影响患者预后和成本的数据较少。
患者与方法 我们回顾性评估了2006年1月至2015年4月期间在128家退伍军人健康管理局医院接受索拉非尼治疗肝细胞癌的4903例患者。在进行1:1倾向评分匹配以消除潜在的治疗偏倚后，使用Cox回归计算风险比（HR），并与HR = 1.1的非劣效性界值进行比较。进行匹配的多变量逻辑回归以调整潜在的混杂因素。主要终点是接受标准起始剂量索拉非尼（口服800 mg/d）的患者与接受降低起始剂量索拉非尼（口服<800 mg/d）的患者的总生存期（OS）。
结果 有3094例接受标准剂量索拉非尼治疗的患者（63%）和1809例接受降低起始剂量索拉非尼治疗的患者（37%）。降低起始剂量索拉非尼治疗的患者巴塞罗那临床肝癌分期D期更多（P <.001），终末期肝病钠评分更高（P <.001），Child-Turcotte-Pugh评分更高（P <.001），肝硬化合并症指数评分更高（P =.01）。因此，降低起始剂量索拉非尼治疗的患者总生存期较低（中位数分别为200天和233天，HR = 1.10）。在进行倾向评分匹配并调整潜在的混杂因素后，总生存期不再有显著差异（调整后的风险比[HR]为0.92；95%置信区间为0.83至1.01），且显著低于非劣效性界值（P <.001）。降低起始剂量索拉非尼治疗的患者索拉非尼总累积成本显著较低，且因胃肠道不良反应而停用索拉非尼的可能性较小（8.7%对10.8%；P =.047）。
结论 以降低剂量开始索拉非尼治疗与减少药丸负担、降低治疗成本以及因不良事件导致停用索拉非尼的发生率降低的趋势相关。与标准剂量相比，降低剂量与总生存期不劣相关。
