SCI
20 June 2020
Clarification of Definitions of Hyperprogressive Disease During Immunotherapy for Non–Small Cell Lung Cancer
Baptiste Kas, BSc; Hugues Talbot, PhD; Roberto Ferrara, MD, PhD,et al.Clarification of Definitions of Hyperprogressive Disease During Immunotherapy for Non–Small Cell Lung Cancer.JAMA Oncology；JAMA Oncol. doi:10.1001/jamaoncol.2020.1634
Published online June 11, 2020.
Corresponding Author: Caroline Caramella, MD, Radiology Department, Gustave Roussy, Université Paris-Saclay, Villejuif, France, 114 Rue Édouard-Vaillant, 94805 Villejuif Cedex, France (caroline.caramella@gustaveroussy.fr).
IMPORTANCE 重要性
Hyperprogressive disease (HPD) is an aggressive pattern of progression reported for patients treated with programmed cell death 1 (PD-1)/programmed cell death 1 ligand (PD-L1) inhibitors as a single agent in several studies. However, the use of different definitions of HPD introduces the risk of describing different tumoral behaviors.
高进展性疾病（HPD）是一种进展性的侵犯模式，在一些以程序性细胞死亡受体1及其配体抑制剂（PD-1/PD-L1抑制剂）作为患者治疗的单一药剂的研究中被报道。然而，HPD的不同定义的使用引起了描述不同肿瘤性行为的风险。
OBJECTIVE 目标
To assess the accuracy of each HPD definition to identify the frequency of HPD and the association with poorer outcomes of immune-checkpoint inhibitor (ICI) treatment in patients with advanced non–small cell lung cancer (NSCLC) and to provide an optimized and homogenized definition based on all previous criteria for identifying HPD.
为了评估每个HPD定义的精确性，以确定HPD的频率以及使用免疫检查点抑制剂治疗的晚期非小细胞肺癌患者较差预后的相关性；为了提供一个优化的，均质性的定义，且基于之前定义HPD的所有标准。
DESIGN, SETTING, AND PARTICIPANTS 设计，设定和参与者
This retrospective cohort study included 406 patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors from November 1, 2012, to April 5, 2017, in 8 French institutions. Measurable lesions were defined using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria on at least 2 computed tomographic scans before the initiation of ICI therapy and 1 computed tomographic scan during treatment. Data were analyzed from November 1, 2012, to August 1, 2019.
这个回顾性队列研究包括406位接受PD-1/PD-L1抑制剂治疗的晚期非小细胞肺癌患者，数据来自8个法国机构，从2012年11月1日到2017年4月5日。可测病灶是根据实体肿瘤的反应评估标准（RECIST）1.1确定的，在进行免疫检查点抑制剂治疗前，至少进行两次CT扫描以及在治疗过程中进行一次CT扫描。数据分析从2012年11月1日持续至2019年8月1日。
EXPOSURES 暴露
Advanced NSCLC and tretment with PD-1/PD-L1 inhibitors.
晚期非小细胞肺癌患者，以PD-1/PD-L1抑制剂治疗
MAIN OUTCOMES AND MEASURES 主要结果及措施
Association of the definition with the related incidence and the HPD subset constitution and the association between each HPD definition and overall survival. All dynamic indexes used in the previous proposed definitions, such as the tumor growth rate (TGR) or tumor growth kinetics (TGK), were calculated before and during treatment.
相关发病率的定义和HPD分组组成的联系；每种HPD定义和总生存率之间的联系。用于之前提出的定义的所有动力指标比如肿瘤生长率或者肿瘤生长动力学，在治疗前均被计算。
RESULTS 结果
Among the 406 patients with NSCLC included in the analysis (259 male [63.8%]; median age at start of ICI treatment, 64 [range, 30-91] years), the different definitions resulted in incidences of the HPD phenomenon varying from 5.4% (n = 22; definition based on a progression pace >2-fold and a time to treatment failure of <2 months) to 18.5% (n = 75; definition based on the TGR ratio). The concordance between these different definitions(using the Jaccard similarity index) varied from 33.3% to 69.3%. For every definition, HPD was associated with poorer survival (range of median overall survival, 3.4 [95% CI, 1.9-8.4] to 6.0 [95% CI, 3.7-9.4] months). The difference between TGR before and during therapy (ΔTGR) was the most correlated with poor overall survival with an initial plateau for a larger number of patients and a slower increase, and it had the highest ability to distinguish patients with HPD from those with progressive disease not classified as HPD. In addition, an optimal threshold of ΔTGR of greater than 100 was identified for this distinction.
我们分析了406位非小细胞肺癌的患者，（男性259位，占63.8%；在ICI治疗前中位年龄为64，范围在30-91之间）；不同的定义导致HPD现象的发生率为5.4%（n=22；定义基于进展速度>2倍和治疗失败时间<2个月）到18.5%（n=75；定义基于肿瘤生长率）。这些不同定义之间的一致性是在33.3%到69.3%（使用Jaccard相似度）。对于每一个定义，HPD与较差存活率相关（中位总生存率的范围，3.4（95%CI为1.9-8.4）到6.0月（95%CI为3.7-9.4））。治疗前和治疗期间的肿瘤生长率的差异反映了较差的总体存活率。最初的稳定阶段有较多的患者，并且增长缓慢，这能够轻易地在患有进展性疾病的未被定义为HPD的患者中分辨出HPD患者。此外，一个肿瘤生长率差异最优阈值--超过100，有助于此种分辨。
CONCLUSIONS AND RELEVANCE 结论与关联
The findings of this retrospective cohort study of patients with NSCLC suggest that the previous 5 definitions of HPD were not associated with the same tumor behavior. A new definition, based on ΔTGR of greater than 100, appeared to be associated with the characteristics expected with HPD (increase of the tumor kinetics and poor survival). Additional studies on larger groups of patients are necessary to confirm the accuracy and validate this proposed definition.
这个非小细胞肺癌患者的回顾性队列研究的结果表明，之前的五种HPD定义并非与同一肿瘤行为相关。一个新的定义，基于 ΔTGR超过100，似乎与HPD的预期的特征相关（肿瘤生长动力学的增加和差的预后）。有必要对大量患者进行额外的研究以证实这个提出的定义的准确性和有效性。
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