Incidence and risk factors of hyperprogressive disease caused by PD-1 inhibitors for treatment of digestive system malignancies
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摘要:
背景 免疫检查点抑制剂(immunocheckpoint inhibitors，ICIs)已经被批准用于多种类型的肿瘤治疗，并显示出了良好的抗肿瘤活性。但在临床实践中，一些患者似乎并没有从ICI中受益，而是出现了疾病的加速进展，称为超进展(hyper progressive disease，HPD)。 目的 分析消化系统恶性肿瘤患者应用PD-1抑制剂时超进展的发生率并探究其相关因素。 方法 收集解放军总医院第一医学中心2015年4月- 2019年4月行PD-1抑制剂(纳武利尤单抗/帕博利珠单抗)治疗的消化系统恶性肿瘤患者病历，计算治疗前和治疗过程中的肿瘤生长速率(tumor growth rate，TGR)。超进展定义为在应用免疫治疗后6 ~ 8周内首次评估时的TGR与先前治疗时的TGR增加值超过50%。计算超进展发生率并分析其影响因素。 结果 从135例可评估的消化系统恶性肿瘤患者中鉴定出22例超进展患者(16.3%)，其中胰腺癌7例、食管癌2例、结直肠癌5例、胆管癌3例、肝癌2例、壶腹癌1例、胃癌2例。超进展组行免疫治疗前转移器官数目超过2个的患者比例更高(54.5% vs 18.6%，P＜0.01)，肝转移(77.3% vs 52.2%，P＜0.01)及乳酸脱氢酶超出正常上限者(45.5% vs 18.6%，P＜0.01)比例更高。与未发生HPD的进展(progressive disease，PD)患者相比，HPD组患者的总生存期(overall survival，OS)较低(中位OS：3.6个月vs 6.2个月，P＜0.01)。ROC分析显示，胰腺癌患者使用PD-1单抗治疗后1个月内特征性肿瘤标志物CA199较影像学检查前升高166.84%，对HPD的发生有预示作用(敏感度85.70%，特异性94.10%)。 结论 接受PD-1抑制剂治疗的消化系统恶性肿瘤患者中，超进展可能与转移器官数目、肝转移、乳酸脱氢酶水平升高相关，其中胰腺癌患者在接受免疫治疗后CA199在1个月内上升幅度达到166.84%或以上提示可能发生HPD。 Abstract:Background Immunocheckpoint inhibitors (ICIs) have been approved for treatment of many types of tumors and have shown promising antitumor activity. In clinical practice, some patients show an accelerated progression of the disease instead of benefiting from ICIs, which is called hyperprogressive disease (HPD). Objective To describe the incidence of HPD in patients with various digestive system malignancies treated with PD-1 inhibitors and explore its related factors. Methods The medical records of patients with digestive system malignancies treated with PD-1 inhibitors (Nivolumab or Pembrolizumab) in the First Medical Center of Chinese PLA General Hospital from April 2015 to April 2019 were retrospectively reviewed. Tumor growth rate (TGR) were calculated before and during treatment. HPD was defined as the increase between TGR at the first evaluation within 6-8 weeks after immunotherapy and TGR in previous treatment was more than 50%. The incidence and risk factors of HPD were analyzed. Results Twenty-two patients (16.3%) were identified with HPD from 135 patients with evaluable digestive system malignancies, including 7 cases with pancreatic cancer, 2 cases with esophageal cancer, 5 cases with colorectal cancer, 3 cases with cholangiocarcinoma, 2 cases with liver cancer, 1 case with ampullary carcinoma, and 2 cases with gastric cancer. Univariate analysis showed that the proportion of patients associated with more than two metastatic sites was significantly higher in the HPD group before immunotherapy (54.5% vs 18.6% , P＜0.01), so did patients with liver metastasis (77.3% vs 52.2%, P＜0.01) and higher level of lactate dehydrogenase (LDH) (45.5% vs 18.6%, P＜0.01). Compared with the patients without HPD, those with HPD had a lower overall survival (OS) (3.6 months vs 6.2 months, P＜0.01). ROC curve analysis showed that in patients with pancreatic cancer, the amplitude of CA199>166.84% within 1 month after PD-1 treatment predicted the occurrence of HPD (specificity, 85.70%; sensitivity, 94.10%). Conclusion Among patients with digestive system malignancies treated with ICIs, it is observed that HPD occurs in some patients, which may be related to some clinicopathological characteristics, including the number of metastatic sites, liver metastasis, and elevated LDH level, causing poor prognosis. The amplitude of CA199>166.84% within one month after immunotherapy may indicate the occurrence of HPD. -
图 1 135例消化系统恶性肿瘤患者TGRPOST与TGRPRE的成对比较散点图。红点为HPD，蓝点为非HPD
Figure 1. Pairwise comparison of TGRPOST and TGR PRE in 135 patients with malignant tumors of digestive system. Blue spots indicate patients with non-HPD, and red spots indicate patients with HPD
图 2 CA199预测HPD的ROC曲线(最佳阈值为166.84%)
Figure 2. ROC curve of change in serum levels of CA199 to predictHPD (the optimal cut-off value is 166.84%)
图 3 HPD组与非HPD的PD组OS曲线比较
Figure 3. Overall survival for hyperprogressive disease (HPD) compared with progressive disease without hyperprogression
表 1 PD-1抑制剂治疗的消化系统恶性肿瘤患者HPD与非HPD相关指标比较(n, %)
Table 1. Comparisons of demographic and clinical characteristics between the HPD and the non-HPD patients with digestive system malignant tumors treated with PD-1 inhibitors (n, %)
Characteristic Non-HPD (n=113) HPD (n=22) χ2 P Characteristic Non-HPD (n=113) HPD
(n=22)χ2 P Age/yrs 1.332 0.248 Surgical history 0.547 0.460 ≥ 60 51(45.1) 7(31.8) Yes 76(67.3) 13(59.1) < 60 62(54.9) 15(68.2) No 37(32.7) 9(40.9) Gender 0.133 0.715 PD-L1 positivity 1.897 0.168 Male 62(54.9) 13(59.1) Positive 63(66.3) 10(50.0) Female 51(45.1) 9(40.9) Negative 32(33.7) 10(50.0) Smoking history 0.786 0.375 Missing 18 2 Ever-smoker 45(39.8) 11(50.0) Response to line before
immunotherapy2.265 0.322 Never-smoker 68(60.2) 11(50.0) PR 3(2.7) 0(0.0) Smoking exposure 0.959 0.407 SD 35(31.0) 4(18.2) > 30 packs per year 26(23.0) 3(13.6) PD 75(66.4) 18(81.8) ≤ 30 packs per year 87(77.0) 19(86.4) Number of metastatic sites 12.894 0.000 Tumor type 6.183 0.403 0-1 92(81.4) 10(45.5) Pancreatic cancer 18(15.9) 7(31.8) ≥ 2 21(18.6) 12(54.5) Esophageal cancer 8(7.1) 2(9.1) ECOG performance status 3.818 0.085 Colorectal cancer 17(15.0) 5(22.7) ≥ 2 4(3.5) 3(13.6) Cholangiocarcinoma 19(16.8) 3(13.6) 0-1 109(96.5) 19(86.4) Liver cancer 15(13.3) 2(9.1) Neutrophil-to-lymphocyte ratio 0.733 0.392 Ampullary carcinoma 5(4.4) 1(4.5) > 3 47(41.6) 7(31.8) Gastric carcinoma 31(27.4) 2(9.1) ≤ 3 66(58.4) 15(68.2) Pathology 8.479 0.132 Lactate dehydrogenase level 7.516 0.006 Adenocarcinoma 91(80.5) 16(72.7) ≤ Upper limit of normal 92(81.4) 12(54.5) Squamous carcinoma 5(4.4) 4(18.2) > Upper limit of normal 21(18.6) 10(45.5) Hepatocellular carcinoma 5(4.4) 2(9.1) Liver metastasis 4.700 0.030 Cholangiocarcinoma 9(8.0) 0(0.0) Present 59(52.2) 17(77.3) Neuroendocrine carcinoma 2(1.8) 0(0.0) Absent 54(47.8) 5(22.7) Small cell carcinoma 1(0.9) 0(0.0) 
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表 2 接受PD-1抑制剂治疗的胰腺癌及结直肠癌患者基因状态与超进展的关系(n, %)
Table 2. Association between genetic status and HPD for immunotherapy-treated patients with pancreatic cancer and colorectal cancer (n, %)
Characteristic Non-HPD (n=35) HPD (n=12) χ2 P KRAS mutation 1.154 0.283 Mutated type 14(48.3) 8(66.7) Wild type 15(51.7) 4(33.3) Missing 6 0 No. of molecular alterations 0.256 0.613 0-1 12(41.4) 6(50.0) ≥ 2 17(58.6) 6(50.0) Missing 6 0
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表 3 胰腺癌患者免疫抑制剂治疗前后两组肿瘤标志物CA199水平比较(Md , IQR)
Table 3. Comparison of levels of CA199 before and after immunotherapy in patients with pancreatic cancer (Md , IQR)
CA199 HPD Non-HPD Z P Baseline/(U·ml-1) 163.00
(156.50, 3524.00)181.20
(21.03, 1 185.75)−0.848 0.397 Increase/% 214.50
(194.64,425.18)30.37
(−7.48,93.42)−2.724 0.006
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表 4 CA199对接受免疫疗法的胰腺癌患者HPD发生的预测价值(%)
Table 4. Value of CA199 in predicting HPD in patients with pancreatic cancer undergoing immunotherapy (%)
Diagnosis performance parameter Data Sensitivity 85.70 Specificity 94.10 Positive predictive value 85.71(6/7) Negative predictive value 94.44(17/18)
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