Abstract
目的
评估非甾体抗炎药（NSAIDs）对接受免疫治疗的肝癌患者临床结局的影响。
方法
回顾性分析2018年6月~ 2020年10月期间接受过免疫治疗的215例原发性肝癌患者。通过倾向性匹配评分，筛选出基线特征基本平衡的病例，根据1∶3的比例将33例使用NSAIDs的患者与78例未使用NSAIDs的患者匹配成功。统计比较使用NSAIDs组与未使用NSAIDs组的总生存率（OS）、无进展生存率（PFS）、疾病控制率（DCR）的差异。
结果
使用NSAIDs的患者（29.7%）与未使用NSAIDs的患者（70.2%）OS没有显着差异。单因素与多因素分析未显示NSAIDs使用与DCR（单因素分析：优势比（OR），0.602；95%置信区间（CI），0.299~1.213；P=0.156；多因素分析：OR，0.693；95% CI，0.330~1.458；P=0.334）、PFS（单因素分析：风险比（HR），1.230；95% CI，0.789~1.916；P=0.361；多因素分析：HR，1.151；95% CI，0.732~1.810；P=9.544）或OS（单因素分析：HR，0.552；95% CI，0.208~1.463；P=0.232；多因素分析：HR，1.085；95% CI，0.685~1.717；P=0.729）之间的关联。
结论
NSAIDs药物对晚期原发性肝癌患者免疫治疗的效果无有利影响。
Keywords: 免疫治疗, 原发性肝癌, 非甾体抗炎药
Abstract
Objective
To assess the impact of nonsteroidal anti-inflammatory drugs (NSAIDs) on clinical outcomes of patients receiving anti-PD-1 immunotherapy for hepatocellular carcinoma.
Methods
We conducted a retrospective study among 215 patients with primary liver cancer receiving immunotherapy between June, 2018 and October, 2020. The patients with balanced baseline characteristics were selected based on propensity matching scores, and among them 33 patients who used NSAIDs were matched at the ratio of 1∶3 with 78 patients who did not use NSAIDs. We compared the overall survival (OS), progression-free survival (PFS), and disease control rate (DCR) between the two groups.
Results
There was no significant difference in OS between the patients using NSAIDs (29.7%) and those who did not use NSAIDs (70.2%). Univariate and multivariate analyses did not show an a correlation of NSAIDs use with DCR (univariate analysis: OR=0.602, 95% CI: 0.299-1.213, P=0.156; multivariate analysis: OR=0.693, 95% CI: 0.330-1.458, P=0.334), PFS (univariate analysis: HR=1.230, 95% CI: 0.789-1.916, P=0.361; multivariate analysis: HR=1.151, 95% CI: 0.732-1.810, P=9.544), or OS (univariate analysis: HR=0.552, 95% CI: 0.208-1.463, P=0.232; multivariate analysis: HR=1.085, 95% CI: 0.685-1.717, P=0.729).
Conclusion
Our results show no favorable effect of NSAIDs on the efficacy of immunotherapy in patients with advanced primary liver cancer, but this finding still needs to be verified by future prospective studies of large cohorts.
Keywords: immunotherapy, primary liver cancer, nonsteroidal anti-inflammatory drugs
原发性肝癌（PLC）是世界上第五大常见的癌症，也是癌症死亡的第2大原因[1]。肝细胞癌（HCC）是最常见的原发性肝癌类型，占原发性肝脏恶性肿瘤的95% 以上，其次是肝内胆管癌（ICC）[2, 3]。全球原发性肝癌新发病例从1990年的471 000例增加到2020年的905 677例，发病率持续上升[4]。据报道，2015年中国原发性肝癌新发患者46.6万例，超过世界原发性肝癌发病总例数的一半[5]。因此，对原发性肝癌的治疗尤为重要。
免疫检查点抑制剂（ICI）是针对免疫检查点分子的单克隆抗体，已在多种恶性肿瘤中显示出临床活性，并改变了医学肿瘤学实践[6-8]。ICI疗法的出现是肿瘤治疗领域的一个重大突破，获得了2018年诺贝尔生理学或医学奖的认可。美国食品和药物管理局于2011年批准推出了第1个ICI，ipilimumab，用于治疗转移性黑色素瘤[9]。ICI越来越多地应用于肝胆肿瘤领域。有临床前研究和临床研究表明，免疫检查点疗法能够为包括肝细胞癌和胆管癌在内的许多肝癌患者提供生存益处[10-13]。
然而，免疫治疗过程中的合并用药可能会影响免疫疗法的效果。因为药物间的相互作用会对免疫治疗产生影响，通过影响身体对抗癌药物的利用和代谢来改变全身免疫治疗的疗效或加重毒性[14]。
非甾体抗炎药（NSAIDs）是世界上使用最广泛的药物之一，具有强大的抗炎、镇痛和解热活性，其主要作用机制之一是抑制环氧化酶（COX）[15]。目前已有临床前研究表明，COX抑制剂与程序性细胞死亡受体-1（PD-1）受体阻滞剂可以协同诱导根除肿瘤，这意味着NSAIDs可能是癌症患者免疫疗法的有效合并用药，并且可以提高免疫治疗的疗效[16, 17]。NASIDs能否提高肿瘤患者免疫治疗的疗效，现已备受研究者关注。在一项多中心回顾性研究中，研究者发现NSAIDs对非小细胞肺癌、黑色素瘤、肾细胞癌患者的总生存期（OS）、无进展生存期（PFS）和客观缓解率（ORR）无显著影响[18]。一项临床试验对接受特瑞普利单抗联合或不联合塞来昔布治疗的晚期结直肠癌患者进行了研究，发现接受塞来昔布的患者完全缓解率更高[19]。研究表明在转移性黑色素瘤和非小细胞肺癌患者中，接受NSAIDs联合用药的患者的疾病进展时间（TTP）和ORR明显长于单独使用ICI的患者[20]。尽管已有研究报道了联合使用NASIDs对免疫治疗疗效影响，但并未有研究报道NSAIDs对接受免疫治疗的原发性肝癌患者生存率和免疫治疗效果的影响。在这项回顾性研究中，我们评估了NSAIDs对原发性肝癌抗PD-1疗效的影响。
1. 资料和方法
1.1. 研究对象
我们回顾性地收集了从2018年6月~2020年10月在南方医科大学南方医院接受免疫治疗的原发性肝癌患者322例，排除了合并其他癌症以及没有影像学资料不能评估其疗效的患者，最终将215例患者纳入进行分析（图 1）。本研究在研究开始前获得伦理委员会的批准（NFEC-2021-048），所有参与者均可豁免知情同意书。
1.
研究流程图
Flowchart of patient enrollment.
1.2. 终点指标
疗效评估标准为实体瘤反应评估标准（RECIST 1.1）横断面成像标准。研究终点包括无进展生存期（PFS），疾病控制率（DCR），次要终点为总生存期（OS）。DCR是指肿瘤在一定时间内缩小或保持稳定的患者比例，包括完全缓解（CR）、部分缓解（PR）或稳定（SD）至少4周的患者比例。PFS定义为从治疗开始到肿瘤进展的时间。OS定义为从治疗开始到死亡或最后一次随访的时间。
1.3. 合并用药
从患者的电子病历中收集合并药物的处方信息，并获得基线统计数据、临床特征与用药数据。在抗PD-1治疗之前或之后42 d内使用NSAIDs的患者被纳入研究中（NSAIDs包括塞来昔布，布洛芬，吲哚美辛，帕瑞昔布，氟比洛芬，丙帕他莫，阿司匹林）。
1.4. 倾向性评分匹配（PSM）
为了排除混杂因素影响，我们采用PSM方法来控制使用NSAID与未使用NSAID两组之间患者特征的平衡。倾向性评分匹配作为一种可以有效降低混杂偏倚的方法，能够提高对比组间的均衡性，减少混杂因素对研究结果的影响[21]。通过χ2检验与秩和检验，我们发现基线时队列中几个亚组在免疫治疗后使用靶向药物（P=0.001），免疫治疗后进行经动脉化疗栓塞（TACE）（P=0.000），免疫治疗前进行消融（P=0.004），和免疫治疗前进行肝切（P=0.045）方面存在组间差异。为平衡组间差异，在基线时根据上述因素进行匹配。卡钳值设置为0.02，根据1∶3的比例将33例使用NSAID的患者与78例未使用NSAID的患者匹配成功。
1.5. 统计学分析
使用描述性统计报告基线患者特征，并使用χ2检验与秩和检验进行组间比较。用Kaplan-Meier方法描述PFS和OS，Cox比例风险回归用于PFS和OS的单变量分析和多变量分析，并以95% 的置信区间（CI）计算疾病进展和死亡的风险比（HR），用单变量和多变量逻辑回归模型来测试影响因素与DCR的关联。所有分析的显著性水平设置为α=0.05。所有统计分析使用SPSS统计软件V.22.0进行。
2. 结果
2.1. 患者基线情况
对于PSM前和PSM后队列中使用与未使用NSAIDs的患者，其基线特征如表 1所示。匹配后共纳入符合条件的患者111例，其中使用NSAID 33例，未使用NSAIDs 78例，仅有3例使用了NSAIDs的患者在匹配后被排除。PSM前队列中几个亚组在[免疫治疗后使用靶向药物（P=0.001）、TACE（P=0.000）、免疫治疗前进行消融（P=0.004）、免疫治疗前进行肝切（P=0.045）]存在组间差异。
1.
使用NSAIDs组与未使用NSAIDs组的基线特征和后续治疗
Baseline characteristics and Subsequent therapy of patients in both groups with and without NASIDS
| Characteristics | Before matching | After matching | |||||
| NASIDS(+) (n=36) | NASIDS(-) (n=179) | P | NASIDS(+)(n=33) | NASIDS(-)(n=78) | P | ||
| Values are expressed as n(%); (+): The drug has been used; (-): The drugs have not been used; ECOG PS: Eastern cooperative oncology group performance status; BCLC: Barcelona clinic liver cancer; TACE: Transcatheter arterial chemoembolization; HAIC: Hepatic arterial infusion chemotherapy; AFP: α-fetoprotein. | |||||||
| Age(≥65 years) | 2(5.6) | 30(16.8) | 0.085 | 2(6.1) | 12(15.4) | 0.224 | |
| Male | 32(88.9) | 157(87.7) | 1.000 | 67(85.9) | 30(90.9) | 0.549 | |
| History | |||||||
| Hepatitis B | 32(88.9) | 151(84.4) | 0.486 | 29(87.9) | 60(76.9) | 0.186 | |
| Cirrhosis | 17(47.2) | 109(60.9) | 0.129 | 16(48.5) | 48(61.5) | 0.203 | |
| Drink | 12(33.3) | 37(20.7) | 0.098 | 11(33.3) | 21(26.9) | 0.496 | |
| Lymph node metastasis | 11(30.6) | 75(41.9) | 0.205 | 10(30.3) | 30(38.5) | 0.413 | |
| Extrahepatic metastasis | 10(27.8) | 73(40.8) | 0.144 | 8 (24.2) | 30(38.5) | 0.149 | |
| Tumor thrombus | 16(44.4) | 80(44.7) | 0.978 | 13(39.4) | 30(38.5) | 0.927 | |
| BCLC stage | |||||||
| A | 3(8.3) | 6(3.4) | 0.894 | 3(9.1) | 2(2.6) | 0.239 | |
| B | 5 (13.9) | 38(21.2) | 5 (15.2) | 20(25.6) | |||
| C | 28(77.8) | 135(75.4) | 25(75.8) | 56(71.8) | |||
| ECOG PS | 0.721 | 1.000 | |||||
| 0-1 | 33(91.7) | 167(93.3) | 30(90.9) | 72(92.3) | |||
| ≥2 | 3(8.3) | 12(6.7) | 3(9.1) | 6(7.7) | |||
| Child-Pugh | 0.622 | 0.476 | |||||
| A | 30(83.3) | 142(79.3) | 27(81.8) | 59(75.6) | |||
| B | 6 (16.7) | 37(20.6) | 6 (18.2) | 19(24.4) | |||
| Prior therapy | |||||||
| Targeted Therapy | 9 (25.0) | 64(35.8) | 0.214 | 8 (24.2) | 22(28.2) | 0.667 | |
| TACE | 25(69.4) | 104(58.1) | 0.205 | 23(69.7) | 38(48.7) | 0.042 | |
| Ablation | 2(5.6) | 50(27.9) | 0.004 | 2(6.1) | 5(6.4) | 1.000 | |
| Surgical resection | 41(22.9) | 14(38.9) | 0.045 | 14(42.4) | 28(35.9) | 0.517 | |
| HAIC | 9 (25.0) | 36(20.1) | 0.511 | 8 (24.2) | 16(20.5) | 0.663 | |
| Subsequent therapy | |||||||
| Targeted Therapy | 18(50.0) | 137(76.5) | 0.001 | 18(54.5) | 47(60.3) | 0.577 | |
| TACE | 15(41.7) | 28(15.6) | 0.000 | 12(36.4) | 18(23.1) | 0.150 | |
| Ablation | 2(5.6) | 9(5.0) | 1.000 | 2(6.1) | 1(1.3) | 0.210 | |
| HAIC | 5 (13.9) | 30(16.8) | 0.670 | 4 (12.1) | 6(7.7) | 0.480 | |
| AFP (≥400 ug/L) | 16(44.4) | 97(54.2) | 0.285 | 18(54.5) | 35(44.9) | 0.351 | |
2.2. NSAIDs的使用和疗效
在生存分析中，使用NSAIDs的患者与未使用NSAIDs的患者相比，其PFS无明显改善（PFS中位数：4.00 vs 6.00个月；P=0.338）（图 2A）。在我们的队列中，使用NSAIDs组与未使用NSAIDs组的OS无差异（P=0.221，图 2B）。在单变量分析中，基线NSAIDs暴露与PFS无关（P=0.361，表 2），与PFS相关的因素是东部肿瘤协作组活动状态评分（ECOG PS）≥2和Child-Pugh评分B级。在多变量分析中，基线NSAIDs暴露与PFS无关（P=0.544）。ECOG PS是该模型中一个重要的独立预测因子（P=0.025，表 2）。在单变量分析中，基线NSAIDs暴露与DCR无关（P=0.156）；多变量分析中，基线NSAIDs暴露也与DCR无关（P=0.334，表 3）。单变量和多变量分析中，基线NSAIDs暴露均与OS无关（单变量分析，P=0.232；多变量分析，P=0.729，表 4）。
2.
Kaplan-Meier生存分析
Kaplan-Meier survival estimates. A: Survival analysis comparing the PFS between patients with and without NASIDs use. B: Survival analysis comparing the OS between patients with and without NASIDs use.
2.
匹配后111例患者PFS的单变量和多变量分析
Univariate and multivariate analyses of PFS in 111 patients with and without NASIDs use
| Characteristics | Univariate | Analysis | Multivariate | Analysis | ||||
| HR | 95% CI | P | HR | 95% CI | P | |||
| ECOG PS: Eastern cooperative oncology group performance status; BCLC: Barcelona clinic liver cancer; TACE: Transcatheter arterial chemoembolization; HAIC: Hepatic arterial infusion chemotherapy; AFP: α-fetoprotein. | ||||||||
| Age | < 65 vs ≥65 | 0.862 | 0.467-1.590 | 0.634 | ||||
| Gender | Male vs Female | 0.928 | 0.505-1.707 | 0.811 | ||||
| Hepatitis B | Yes vs No | 1.095 | 0.664-1.807 | 0.723 | ||||
| Cirrhosis | Yes vs No | 1.156 | 0.764-1.748 | 0.493 | ||||
| Drinking | Yes vs No | 0.858 | 0.541-1.360 | 0.514 | ||||
| Lymph node metastasis | Yes vs No | 1.427 | 0.940-2.167 | 0.095 | ||||
| Extrahepatic metastasis | Yes vs No | 1.282 | 0.839-1.960 | 0.250 | ||||
| Tumor thrombus | Yes vs No | 1.259 | 0.816-1.940 | 0.298 | ||||
| BCLC stage | 0.375 | 0.463 | ||||||
| B vs A | 1.006 | 0.344-2.944 | 0.991 | 0.947 | 0.319-2.809 | 0.922 | ||
| C vs A | 1.397 | 0.508-3.845 | 0.518 | 1.281 | 0.461-3.558 | 0.634 | ||
| ECOG PS | 0-1 vs ≥2 | 2.733 | 1.339-5.576 | 0.006 | 0.426 | 0.203-0.897 | 0.025 | |
| Child-Pugh | Yes vs No | 1.745 | 1.050-2.901 | 0.032 | 1.545 | 0.910-2.625 | 0.107 | |
| Prior therapy | ||||||||
| Targeted therapy | Yes vs No | 1.105 | 0.699-1.745 | 0.669 | ||||
| TACE | Yes vs No | 1.170 | 0.777-1.761 | 0.453 | ||||
| Ablation | Yes vs No | 0.949 | 0.413-2.182 | 0.903 | ||||
| Surgical resection | Yes vs No | 0.683 | 0.602-1.395 | 0.683 | ||||
| HAIC | Yes vs No | 1.677 | 0.862-3.262 | 0.128 | ||||
| Subsequent therapy | ||||||||
| Targeted therapy | Yes vs No | 0.918 | 0.609-1.384 | 0.684 | ||||
| TACE | Yes vs No | 1.168 | 0.735-1.858 | 0.511 | ||||
| Ablation | Yes vs No | 1.096 | 0.344-3.497 | 0.876 | ||||
| HAIC | Yes vs No | 1.181 | 0.718-1.942 | 0.513 | ||||
| AFP | < 400 vs ≥400 | 1.141 | 0.931-1.398 | 0.204 | ||||
| NASIDS | Yes vs No | 1.230 | 0.789-1.916 | 0.361 | 1.151 | 0.732-1.810 | 0.544 | |
3.
匹配后111例患者DCR的单变量和多变量分析
Univariate and multivariate analysis of DCR in 111 patients with and without NASIDs use
| Characteristics | Univariate | Analysis | Multivariate multivariate | Analysis | ||||
| OR | 95% CI | P | OR | 95% CI | P | |||
| ECOG PS: Eastern cooperative oncology group performance status; BCLC: Barcelona clinic liver cancer; TACE: Transcatheter arterial chemoembolization; HAIC: Hepatic arterial infusion chemotherapy; AFP: α-fetoprotein. | ||||||||
| Age | < 65 vs ≥65 | 1.161 | 0.521-2.584 | 0.715 | ||||
| Gender | Male vs Female | 1.377 | 0.590-3.215 | 0.459 | ||||
| Hepatitis B | Yes vs No | 0.955 | 0.425-2.146 | 0.912 | ||||
| Cirrhosis | Yes vs No | 1.350 | 0.757-2.408 | 0.309 | ||||
| Drink | Yes vs No | 0.930 | 0.470-1.841 | 0.835 | ||||
| Lymph node metastasis | Yes vs No | 0.965 | 0.538-1.730 | 0.905 | ||||
| Extrahepatic metastasis | Yes vs No | 0.520 | 0.290-0.932 | 0.028 | 0.570 | 0.313-1.039 | 0.066 | |
| Tumor thrombus | Yes vs No | 1.394 | 0.779-2.496 | 0.264 | ||||
| BCLC stage | 0.185 | |||||||
| B vs A | 3.022 | 0.670-13.628 | 0.15 | |||||
| C vs A | 1.529 | 0.395-5.920 | 0.539 | |||||
| ECOG PS | 0-1 vs ≥2 | 1.324 | 0.406-4.318 | 0.642 | ||||
| Child-Pugh | Yes vs No | 1.114 | 0.540-2.300 | 0.770 | ||||
| Prior therapy | ||||||||
| Targeted Therapy | Yes vs No | 1.147 | 0.623-2.111 | 0.660 | ||||
| TACE | Yes vs No | 0.659 | 0.362-1.198 | 0.171 | ||||
| Ablation | Yes vs No | 1.084 | 0.553-2.127 | 0.814 | ||||
| Surgical resection | Yes vs No | 0.561 | 0.297-1.060 | 0.075 | ||||
| HAIC | Yes vs No | 1.219 | 0.550-2.704 | 0.626 | ||||
| Subsequent therapy | ||||||||
| Targeted Therapy | Yes vs No | 1.992 | 1.072-3.703 | 0.029 | 1.918 | 1.014-3.629 | 0.045 | |
| TACE | Yes vs No | 0.974 | 0.477-1.988 | 0.942 | ||||
| Ablation | Yes vs No | 0.818 | 0.231-2.894 | 0.756 | ||||
| HAIC | Yes vs No | 1.209 | 0.589-2.483 | 0.605 | ||||
| AFP | < 400 vs ≥400 | 0.732 | 0.547-0.978 | 0.035 | 0.755 | 0.560-1.018 | 0.065 | |
| NASIDS | Yes vs No | 0.602 | 0.299-1.213 | 0.156 | 0.693 | 0.330-1.458 | 0.334 | |
4.
匹配后111例患者OS的单变量和多变量分析
Univariate and multivariate analyses of OS in 111 patients with and without NASIDs use
| Characteristics | Univariate | Analysis | Multivariate | Analysis | ||||
| HR | 95% CI | P | HR | 95% CI | P | |||
| ECOG PS: Eastern cooperative oncology group performance status; BCLC: Barcelona clinic liver cancer; TACE: Transcatheter arterial chemoembolization; HAIC: Hepatic arterial infusion chemotherapy; AFP: α-fetoprotein. | ||||||||
| Age | < 65 vs ≥65 | 0.914 | 0.275-3.042 | 0.883 | ||||
| Gender | Male vs Female | 0.494 | 0.198-1.229 | 0.129 | ||||
| Hepatitis B | Yes vs No | 1.358 | 0.514-3.588 | 0.538 | ||||
| Cirrhosis | Yes vs No | 1.038 | 0.481-2.240 | 0.924 | ||||
| Drink | Yes vs No | 0.601 | 0.227-1.588 | 0.304 | ||||
| Lymph node metastasis | Yes vs No | 0.625 | 0.264-1.482 | 0.286 | ||||
| Extrahepatic metastasis | Yes vs No | 0.873 | 0.381-1.999 | 0.748 | ||||
| Tumor thrombus | Yes vs No | 1.675 | 0.784-3.575 | 0.183 | ||||
| BCLC stage | 0.950 | 0.308 | ||||||
| B vs A | 1.089 | 0.134-8.870 | 0.936 | 0.793 | 0.261-2.407 | 0.683 | ||
| C vs A | 0.945 | 0.126-7.062 | 0.956 | 1.196 | 0.429-3.340 | 0.732 | ||
| ECOG PS | 0-1 vs ≥2 | 0.547 | 1.836 | 0.832-4.051 | 0.133 | |||
| Child-Pugh | Yes vs No | 2.398 | 1.042-5.517 | 0.040 | 1.730 | 1.010-2.964 | 0.046 | |
| Prior therapy | ||||||||
| Targeted Therapy | Yes vs No | 1.443 | 0.648-3.215 | 0.369 | ||||
| TACE | Yes vs No | 0.825 | 0.388-1.757 | 0.619 | ||||
| Ablation | Yes vs No | 1.022 | 0.242 -4.327 | 0.976 | ||||
| Surgical resection | Yes vs No | 0.456 | 0.184-1.130 | 0.090 | ||||
| HAIC | Yes vs No | 2.706 | 1.010-7.250 | 0.048 | 1.674 | 0.774-3.617 | 0.190 | |
| Subsequent therapy | ||||||||
| Targeted Therapy | Yes vs No | 0.765 | 0.358-1.636 | 0.490 | ||||
| TACE | Yes vs No | 0.502 | 0.190-1.327 | 0.165 | ||||
| Ablation | Yes vs No | 0.047 | 0-994.653 | 0.548 | ||||
| HAIC | Yes vs No | 1.169 | 0.493-2.769 | 0.723 | ||||
| AFP | < 400 vs ≥400 | 1.620 | 1.085-2.418 | 0.018 | 1.281 | 0.832-1.972 | 0.261 | |
| NASIDS | Yes vs No | 0.552 | 0.208-1.463 | 0.232 | 1.085 | 0.685-1.717 | 0.729 | |
3. 讨论
在这项针对接受ICI治疗的原发性肝癌患者的回顾性队列研究中，联合使用NSAIDs后，没有发现肿瘤缓解或生存率的显著改善。
本研究表明，NSAIDs的使用不会影响OS、PFS，也不会影响免疫治疗的疗效。尽管有体外研究和动物实验表明NSAIDs对肝癌具有预防和治疗作用[22-24]，但我们在原发性肝癌患者队列中未发现NSAIDs与免疫治疗临床结果之间存在任何关联。目前在其他类型的肿瘤的临床研究中，也报道没有发现NSAIDs会影响患者的临床结果。在一项黑色素瘤的回顾性研究中，使用NSAIDs的患者的PFS和OS没有显著改善[25]。一项纳入1012名患者的多肿瘤研究报道，除阿司匹林外的其他NSAIDs与免疫治疗的疗效没有任何相关性[18]。本研究未见NSAIDs与免疫治疗的临床结果之间存在关联，可能的原因是：以往的研究中显示阿司匹林更能改善患者的预后[26, 27]，但是我们队列中长期使用阿司匹林的患者仅一例。有研究表明NSAIDs的保护作用与频繁用药有关，使用越频繁，保护作用越大[28]，而我们的研究中NSAIDs使用的中位持续时间为4.5 d，大多数患者只是短期内使用NSAIDs，无法增强免疫治疗抗肿瘤效果。
这项研究首次揭示了NSAIDs对接受免疫治疗的原发性肝癌患者的疗效。所有患者均来自中国，更能代表中国患者的特点。本研究的优势在于平衡了可能影响患者生存结果和预后的混杂因素。PSM是用过观察数据比较两种治疗效果的常用方法[29, 30]，可以减少观察研究中混杂因素的影响。为了使研究结果更加可靠，我们使用PSM来平衡使用NSAIDs组与未使用NSAIDs组之间的混杂因素。而以往的研究却没有展示不同组间的基线特征，基线时的混杂因素可能会影响到最后的结果。另外，我们研究之外的药物也可能影响免疫系统，如糖皮质激素与接受ICI治疗的患者的不良临床结果有关[31, 32]，但是本研究中215名的患者中使用类固醇药物的患者不超过10人，因此我们的队列不会受到影响。
本研究的局限性包括回顾性研究的固有局限性，还可能存在药物使用与否和使用频率被漏报的情况。NSAIDs药物对晚期原发性肝癌患者免疫治疗的效果无有利影响，这些结果需要在前瞻性队列中得到验证，结论还需要通过更大规模、更系统的分析来证实。
Biographies
李芮宁，在读博士研究生，E-mail: lrn13562727102@gmail.com
黄超艺，在读硕士研究生，E-mail: 13922134826hcy@gmail.com
洪畅，在读博士研究生，E-mail: hongchang15@i.smu.edu.cn
Funding Statement
国家自然科学基金（81773008，81972879）；由中国教育部广东省教育厅高水平大学建设基金（LC2019ZD003）；中国博士后科学基金（2021M701629）
Supported by National Natural Science Foundation of China (81773008, 81972879)
Contributor Information
李 芮宁 (Ruining LI), Email: lrn13562727102@gmail.com.
黄 超艺 (Chaoyi HUANG), Email: 13922134826hcy@gmail.com.
洪 畅 (Chang HONG), Email: hongchang15@i.smu.edu.cn.
刘 莉 (Li LIU), Email: liuli@i.smu.edu.cn.
肖 芦山 (Lushan XIAO), Email: 15622178423@163.com.
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