Center for Personalized Cancer Therapy, University of California San Diego, Moores Cancer Center, San Diego, USA.
National Comprehensive Cancer Network, Plymouth Meeting, Pennsylvania, USA.
Ann Oncol. 2019 Oct 1;30(10):1647-1652. doi: 10.1093/annonc/mdz232.
A previous analysis of 113 National Comprehensive Cancer Network® (NCCN®) recommendations reported that NCCN frequently recommends beyond Food and Drug Administration (FDA)-approved indications (44 off-label recommendations) and claimed that the evidence for these recommendations was weak.
In order to determine the strength of the evidence, we carried out an in-depth re-analysis of the 44 off-label recommendations listed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).
Of the 44 off-label recommendations, 14 were later approved by the FDA and/or are supported by randomized controlled trial (RCT) data. In addition, 13 recommendations were either very minor extrapolations from the FDA label (n = 8) or were actually on-label (n = 5). Of the 17 remaining extrapolations, 8 were for mechanism-based agents applied in rare cancers or subsets with few available treatment options (median response rate = 43%), 7 were based on non-RCT data showing significant efficacy (>50% response rates), and 2 were later removed from the NCCN Guidelines because newer therapies with better activity and/or safety became available.
Off-label drug use is a frequent component of care for patients with cancer in the United States. Our findings indicate that when the NCCN recommends beyond the FDA-approved indications, the strength of the evidence supporting such recommendations is robust, with a significant subset of these drugs later becoming FDA approved or supported by RCT. Recommendations without RCT data are often for mechanism-based drugs with high response rates in rare cancers or subsets without effective therapies.
之前对美国国家综合癌症网络（NCCN®）113 项建议的分析报告称，NCCN 经常推荐超出食品和药物管理局（FDA）批准适应证的治疗方案（44 项超适应证推荐），并声称这些推荐的证据薄弱。
为了确定证据的强度，我们对 NCCN 肿瘤临床实践指南（NCCN 指南®）中列出的 44 项超适应证推荐进行了深入的重新分析。
在这 44 项超适应证推荐中，有 14 项后来获得了 FDA 的批准，或者有随机对照试验（RCT）数据支持。此外，有 13 项推荐要么是对 FDA 标签的非常微小的推断（n=8），要么实际上是适应证内的推荐（n=5）。在其余的 17 项推断中，有 8 项是针对机制性药物在罕见癌症或治疗选择有限的亚组中的应用（中位缓解率=43%），有 7 项是基于非 RCT 数据，显示出显著的疗效（>50%的缓解率），有 2 项后来从 NCCN 指南中删除，因为有了活性和/或安全性更好的更新疗法。
美国癌症患者的治疗方案中经常出现超适应证用药。我们的研究结果表明，当 NCCN 推荐超出 FDA 批准的适应证时，支持这些推荐的证据强度是可靠的，其中相当一部分药物后来获得了 FDA 的批准，或者得到了 RCT 的支持。没有 RCT 数据的推荐通常是针对在罕见癌症或没有有效治疗方法的亚组中具有高缓解率的机制性药物。
