Abstract
目的
探讨安罗替尼联合替吉奥二线治疗复发转移性食管鳞癌的临床疗效。
方法
选取2018年7月~2020年2月我院收治的一线紫杉醇联合铂类化疗失败的26例复发转移性食管鳞癌患者，给予患者12 mg安罗替尼口服，1次/d，联合50 mg替吉奥口服2次/d，连服2周，停药1周，共3周为1周期，分析其近期临床疗效、不良反应及中位无进展生存期。
结果
26例患者行安罗替尼联合替吉奥二线治疗后，其中无完全缓解者，部分缓解者（PR）6例，疾病稳定者12例，疾病进展者8例，客观缓解率为23.1%，疾病控制率（DCR）为69.2%，中位PFS为4.5月（95%CI：2.7-6.4）。单因素分析发现中高分化食管鳞癌患者较低分化者有更长的PFS（6.1月vs 1.9月，P < 0.05）。Cox比例风险回归模型分析显示病理分化程度（HR=6.778，95%CI：1.997-23.012）是安罗替尼联合替吉奥治疗复发转移性食管鳞癌患者PFS延长的独立影响因素。安罗替尼联合替吉奥治疗的主要不良反应为乏力、高血压、手足综合症、蛋白尿、肝功能异常和腹泻等，多为Ⅰ~Ⅱ度。
结论
复发转移性食管鳞癌患者可从安罗替尼联合替吉奥二线治疗中获益，主要不良反应较轻，安全性高。
Keywords: 食管鳞癌, 安罗替尼, 替吉奥, 临床疗效, 不良反应
Abstract
Objective
To investigate the efficacy of anlotinib plus S-1 for treatment of patients with recurrent or metastatic esophageal squamous cell carcinoma with failed first-line chemotherapy.
Methods
Twenty-six patients with recurrent or metastatic esophageal squamous cell carcinoma patients who experienced progression after first-line paclitaxel plus platinum chemotherapy in our hospital between July, 2018 and February, 2020 were enrolled in this study. The patients received oral anlotinib along with S-1 treatment (anlotinib at 12 mg once daily and S-1 at 50 mg twice daily for two weeks; 3 weeks per cycle). The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and adverse effects were evaluated for all the patients.
Results
No complete remission (CR) was observed in the 26 patients. Partial remission (PR) was achieved in 6 cases, stable disease (SD) in 12 cases, and progressive disease (PD) occurred in 8 cases, with an ORR of 23.1% and a DCR of 69.2% in these patients. The median PFS was 4.5 months (95%CI: 2.7-6.4 months). Univariate analysis showed that the patients with moderate or high tumor differentiation had significantly longer PFS than those with low tumor differentiation (6.1 months vs 1.9 months, P < 0.05). Multivariate analysis suggested that pathological differentiation grade (HR=6.778, 95%CI: 1.997-23.012) was an independent factor for a prolonged PFS. The adverse effects in the patients included mainly fatigue, hypertension and hand-foot syndrome, mostly of grade 1 to 2.
Conclusion
Patients with recurrent or metastatic esophageal squamous cell carcinoma can benefit from a second-line anlotinib plus S-1 treatment, which has relatively mild adverse effects with a good safety profile.
Keywords: esophageal squamous cell carcinoma, Anlotinib, S-1, clinical efficacy, adverse effects
食管癌是中国常见的消化道恶性肿瘤，其中90%以上为鳞癌[1]。全球每年新发食管癌约57.2万例，死亡约50.8万例，我国新发和死亡数分别占全部恶性肿瘤第6位、第4位[2-3]。大多数患者确诊时已属晚期，晚期预后差，总体5年生存率低于20%[4]。晚期食管癌一线化疗失败后中位生存时间仅有5~10月，因此，寻找新的有效药物和治疗方案成为治疗的关键。
我国自主研发的小分子靶向药物安罗替尼被纳入2019年中国CSCO食管癌诊治指南，推荐用于复发转移性食管癌的二线及以后治疗。安罗替尼是一种小分子多靶点酪氨酸激酶抑制剂，具有抗肿瘤血管生成和抑制肿瘤生长的双重作用[5]。安罗替尼在肺癌、软组织肉瘤、甲状腺髓样癌、肾癌、肝癌等实体瘤中疗效确切[6-10]，在我国分别于2018年获批用于非小细胞肺癌的三线治疗、2019年获批软组织肉瘤二线治疗及小细胞肺癌的三线治疗[11-13]。已有少数文献报道了安罗替尼单药以及安罗替尼联合替吉奥用于二线及以上治疗复发转移性食管鳞癌的临床研究[14-16]，未见安罗替尼联合化疗仅限于二线治疗复发转移性食管鳞癌的临床报道。本研究回顾性分析了安罗替尼联合替吉奥二线治疗复发转移性食管鳞癌的临床资料，探讨了治疗的近期临床疗效及安全性，为临床治疗提供借鉴，现将结果报告如下。
1. 资料和方法
1.1. 纳入和排除标准
（1）纳入标准：①经组织病理学确诊的食管鳞癌患者，所有患者根据AJCC第八版TNM分期为临床IIIB期或Ⅳ期；②根据实体瘤的疗效评定标准（RECIST 1.1），所有患者均有可测量的靶病灶；③PS评分≤2分；④接受一线紫杉醇联合铂类化疗方案失败者；（2）排除标准：①合并其他恶性肿瘤者；②存在心、肝、肾等主要脏器严重疾病者；③既往使用过抗肿瘤血管生成的单克隆抗体或小分子酪氨酸激酶抑制剂治疗者；④预计生存期 < 3月。
1.2. 研究对象
选取2018年7月~2020年2月在江苏省中医院明确诊断且符合本研究纳入和排除标准的26例复发转移性食管鳞癌患者作为本研究对象。治疗药物：盐酸安罗替尼胶囊（福可维），江苏正大天晴药业股份有限公司，共3种规格：国药准字H20180004，12 mg×7粒，1板/盒；国药准字H20180003，10 mg×7粒，1板/盒；国药准字H20180002，8mg×7粒，1板/盒。替吉奥胶囊（维康达），山东新时代药业有限公司，国药准字H20080803，25 mg× 36粒/盒。本研究经江苏省中医院伦理委员会批准，所有患者均已签署试验知情同意书。
1.3. 治疗方法
所有纳入研究的患者初始均接受安罗替尼12 mg/d，早餐前口服，替吉奥50 mg 2次/d，早晚餐后30 min口服，两药连续口服2周，停药1周，3周为1个周期，直至疾病进展（PD）或出现不可耐受的不良反应或患者撤销知情同意书。患者在治疗过程中发生药物相关的Ⅲ级或以上不良反应时或患者难以耐受时，经药物对症治疗后控制不佳时，安罗替尼可减量至10 mg/d；如仍有Ⅲ级或以上不良反应或患者难以耐受时，可继续减量至8 mg/d；如患者口服8 mg/d剂量时仍有Ⅲ级或以上不良反应或患者难以耐受时，则永久停用安罗替尼，患者可继续口服替吉奥化疗，此病例即为删失数据。
1.4. 观察指标
治疗前所有患者均接受基线检验检查，包括一般体格检查、血尿粪常规、肝肾功能、凝血功能、肿瘤指标、心电图及可测量靶病灶CT等。用药3周（即1周期）后进行首次疗效评价，以后每2周期进行疗效评价。疗效评价包括症状、肿瘤指标、可测量靶病灶CT等。依据RECIST 1.1进行疗效评价，包括完全缓解（CR）、部分缓解（PR）、疾病稳定（SD）、疾病进展（PD），客观缓解率（ORR）=（CR+PR）/总例数×100%，疾病控制率（DCR）=（CR+PR+SD）/总例数×100%。无进展生存期（PFS）：口服安罗替尼联合替吉奥开始直至患者疾病进展、死亡或失访的时间。采用门诊随访或电话随访方式，所有随访截止日期为2020年7月31日。
1.5. 不良反应
不良反应评价按照世界卫生组织（WHO）抗肿瘤药物不良反应评分标准进行评价，共分为0~Ⅳ度。
1.6. 统计分析
使用SPSS 26.0统计软件进行数据分析。计数资料用率表示，采用χ2检验作组间比较，计数资料采用t检验。生存分析采用Kaplan-Meier法并行log-rank检验，Cox比例风险回归模型行多因素分析。P < 0.05为差异有统计学意义。
2. 结果
2.1. 临床特征分析
回顾性分析2018年7月~2020年2月在我院治疗的26例复发转移性食管鳞癌患者临床资料。其中男性23例，女性3例；年龄分布于55~86（68.3±8.1）岁，≤65岁10例，>65岁16例；13例行食管癌根治术，13例未行手术；4例行放疗，22例未放疗；17例ECOG PS评分为0~1分，9例ECOGPS评分为2分；14例为低分化，12例为中高分化；24例有远处转移，其中9例有肝转移，17例为除肝以外的其他部位转移，包括肺、骨、脑等，2例为局部复发（表 1）。
1.
不同临床特征患者近期疗效比较
Comparison of efficacy between patients with different clinical characteristics
| Characteristics | No. of patients | ORR | P value | DCR | P |
| Gender | |||||
| Male | 23 | 5(21.7%) | 0.654 | 16(69.6%) | 0.919 |
| Female | 3 | 1 (33.3%) | 2(66.7%) | ||
| Age | |||||
| ≤65 years | 10 | 4 (40.0%) | 0.105 | 8(80.0%) | 0.347 |
| > 65 years | 16 | 2(12.5%) | 10(62.5%) | ||
| Radical surgery | |||||
| Yes | 13 | 2 (15.4%) | 0.352 | 8(61.5%) | 0.395 |
| No | 13 | 4(30.8%) | 10(76.9%) | ||
| Radiotherapy | |||||
| Yes | 4 | 0(0.0%) | 0.234 | 3(75.0%) | 0.786 |
| No | 22 | 6(27.3%) | 15(68.2%) | ||
| ECOG PS score | |||||
| 0-1 | 17 | 5(29.4%) | 0.292 | 13(76.5%) | 0.272 |
| 2 | 9 | 1(11.1%) | 5(55.6%) | ||
| Differentiation grade | |||||
| Low | 14 | 0 (0.0%) | 0.003 | 8(57.1%) | 0.149 |
| Medium-high | 12 | 6(50.0%) | 10(83.3%) | ||
| Distal metastasis | |||||
| Yes | 24 | 6(25.0%) | 0.420 | 18(75.0%) | 0.027 |
| No | 2 | 0 (0.0%) | 0 (0.0%) | ||
| Liver metastasis | |||||
| Yes | 9 | 2(22.2%) | 0.940 | 6(66.7%) | 0.837 |
| No | 17 | 4(23.5%) | 12(70.6%) |
2.2. 不同临床特征患者的近期疗效分析
所有26例患者均可评价疗效，无获CR者，PR 6例、SD12例和PD 8例，ORR和DCR分别为23.1%、69.2%。比较不同性别、年龄、手术、放疗、PS评分、病例分化程度、远处转移、肝转移的患者ORR，中高分化的患者明显高于低分化患者，具有显著统计学差异（P < 0.05）；其他临床特征患者ORR比较均未见显著统计学差异（P>0.05）。比较DCR，有远处转移患者明显高于无远处转移患者，差异有统计学差异（P < 0.05）；其他临床特征患者均未见未见显著统计学差异（P>0.05，表 1）。
2.3. 生存分析
26例复发转移性食管鳞癌患者的中位PFS为4.5个月（95%CI：2.7~6.4），如图 1所示。单因素分析发现中高分化的食管鳞癌患者较低分化患者有更长的PFS（6.1月vs 1.9月，P=0.007），生存率比较差异有统计学差异。Cox比例风险回归模型分析显示，病理分化程度（HR=6.778，95%CI: 1.997-23.012）是安罗替尼联合替吉奥治疗复发转移性食管鳞癌患者PFS的独立影响因素（表 2、3）。
1.
安罗替尼联合替吉奥治疗26例复发转移性食管鳞癌患者的PFS曲线
Kaplan-Meier estimate of the progression-free survival in the 26 patients with recurrent or metastatic esophageal squamous cell carcinoma after treatment with anlotinib plus S-1.
2.
影响安罗替尼联合替吉奥治疗复发转移性食管鳞癌PFS的单因素分析
Univariate analysis of progression-free survival in the 26 patients after treatment with anlotinib plus S-1
| Characteristics | No. of patients | Median PFS (95%CI) | P |
| Gender | 0.621 | ||
| Male | 23 | 4.5 (2.4-6.7) | |
| Female | 3 | 7.6(0.0-16.6) | |
| Age | 0.296 | ||
| ≤65 years | 10 | 4.6 (4.2-5.0) | |
| > 65 years | 16 | 3.2(1.1-5.4) | |
| Radical Surgery | 0.834 | ||
| Yes | 13 | 3.8(0.7-6.8) | |
| No | 13 | 4.8(2.8-6.7) | |
| Radiotherapy | 0.226 | ||
| Yes | 4 | 3.1 (1.2-4.9) | |
| No | 22 | 4.6 (2.7-6.5) | |
| ECOG PS score | 0.330 | ||
| 0-1 | 17 | 4.6 (2.5-6.7) | |
| 2 | 9 | 3.8(0.0-9.4) | |
| Differentiation grade | 0.007 | ||
| Low | 14 | 1.9 (0.5-3.4) | |
| Medium-high | 12 | 6.1 (4.4-7.8) | |
| Distal metastasis | 0.087 | ||
| Yes | 24 | 4.6 (3.4-5.8) | |
| No | 2 | 1.9(-) | |
| Liver metastasis | 0.318 | ||
| Yes | 9 | 4.5 (2.3-6.8) | |
| No | 17 | 4.7 (2.4-7.0) |
3.
影响安罗替尼联合替吉奥治疗复发转移性食管鳞癌患者PFS的Cox比例风险回归模型分析
Multivariate analysis of the progression-free survival in the 26 patients after treatment with anlotinib plus S-1
| Factors | HR (95%CI) | P |
| Radical surgery | 4.887 (0.676-35.358) | 0.116 |
| Radiotherapy | 2.329 (0.588-9.228) | 0.229 |
| ECOG PS score | 0.348 (0.096-1.255) | 0.107 |
| Differentiation grade | 6.778 (1.997-23.012) | 0.002 |
| Distal metastasis | 3.628 (0.222-59.398) | 0.366 |
| Liver metastasis | 0.190 (0.026-1.392) | 0.102 |
2.4. 不良反应
26例复发转移性食管鳞癌患者经安罗替尼联合替吉奥治疗后主要不良反应有乏力、高血压、手足综合症、蛋白尿、肝功能异常和腹泻等，除1例患者出现Ⅲ级高血压外，余均为Ⅰ~Ⅱ级不良反应，经对症治疗后好转（表 4）。1例患者因Ⅲ级高血压不良反应而减少安罗替尼剂量至10 mg继续治疗，直至治疗完成。所有26例患者未见Ⅳ级严重不良反应或治疗相关性死亡。
4.
安罗替尼联合替吉奥治疗26例复发转移性食管鳞癌患者的主要不良反应
Treatment-related adverse effects of anlotinib plus S-1 treatment in the 26 patients (number of cases)
| Adverse effects | Ⅰ | Ⅱ | Ⅲ | Ⅳ | In total |
| Fatigue | 7 | 3 | 0 | 0 | 10 |
| Hypertension | 6 | 1 | 1 | 0 | 8 |
| Hand-foot syndrome | 6 | 2 | 0 | 0 | 8 |
| Proteinuria | 3 | 1 | 0 | 0 | 4 |
| Abnormal liver function | 3 | 0 | 0 | 0 | 3 |
| Diarrhea | 2 | 0 | 0 | 0 | 2 |
3. 讨论
复发转移性食管鳞癌患者一线化疗后进展的二线治疗，目前尚无统一的标准治疗方案[17-19]。在本研究中，复发转移性食管鳞癌患者一线化疗进展后使用安罗替尼联合替吉奥作为二线治疗方案，获得了69.2%的疾病控制率，中位PFS达到了4.5月，相比单纯化疗作为二线治疗的PFS有了明显延长，可见安罗替尼联合化疗方案具有良好的疗效[20-21]。因此相对高效低毒的靶向治疗及其与化疗的联合治疗成为晚期食管癌的一个研究热点[22-23]。
安罗替尼用于二线及以上治疗复发转移性食管鳞癌在ALTER 1102研究中进行了探讨。该研究是一项双盲多中心随机对照的Ⅱ期临床试验，研究结果显示110例安罗替尼组患者较55例安慰剂组患者中位PFS延长了1.6月（3.0月vs 1.4月），达到了主要研究终点[13]。国内邵岚等报道的一项回顾性研究揭示安罗替尼用于二线及以上治疗复发转移性食管鳞癌的中位PFS达到了4.4月[12]，较ALTER 1101研究中的3.0个月的PFS明显延长，此差异可能由其病例数少造成（22例患者）。安罗替尼联合化疗用于复发转移性食管的治疗未见相关报道，本研究中安罗替尼联合替吉奥治疗的中位PFS为4.5月，与安罗替尼单药治疗相比，有一定的延长，提示安罗替尼联合化疗可作为临床的一个治疗选择。黄镜教授的一项前瞻性、随机、多中心Ⅲ期临床研究ESWN 01评估了伊立替康联合替吉奥在二线及以上复发转移性食管鳞癌患者中的疗效和安全性。该研究共入组123例患者，其中伊立替康联合替吉奥组61例，替吉奥单药组62例。结果显示伊立替康联合替吉奥组的中位PFS较替吉奥组明显延长（3.8月vs 1.7月）[24]。本研究中安罗替尼联合替吉奥组较ESWN 01研究中的伊立替康联合替吉奥组的中位PFS延长了0.7月，具有一定的优势，可作为难以耐受联合化疗的患者尤其老年患者的治疗方案。本研究亚组分析发现，中高病理分化的食管鳞癌患者在安罗替尼联合替吉奥治疗后PFS有延长，由于入组的病例数不多，需要进一步扩大样本量的临床研究来证实。有文献报道有放疗史的非小细胞肺癌患者的PFS相比无放疗史患者更有机会在安罗替尼治疗中延长[25]，本研究中有放疗史患者的PFS在安罗替尼联合替吉奥治疗中未见优势，可能是放疗史患者例数偏少有关（仅有4例患者）。本研究中排除了既往使用过抗肿瘤血管生成的单克隆抗体或小分子酪氨酸激酶抑制剂治疗者，有研究提示既往安维汀、恩度等抗肿瘤血管生成不影响安罗替尼在非小细胞肺癌中的疗效[25]，此情况是否同样在食管鳞癌中存在，需要进一步纳入更多的临床病例包括既往使用过抗肿瘤血管生成治疗药物的患者来证实。
复发转移性食管鳞癌二线以后靶向治疗研究不多，除了本研究中的安罗替尼，还有阿帕替尼、索拉非尼、西妥昔单抗等。在食管鳞癌中靶向VEGF的索拉非尼的COG研究以及西妥昔单抗的SCOPE1、RTOG 0436研究均未取得阳性结果[26-28]。研究显示阿帕替尼治疗62例食管鳞癌患者有3.8月的中位PFS，显示了一定的疗效[29]。目前复发转移性食管鳞癌的二线及以后的靶向联合治疗研究鲜有报道。一项病例报告揭示安罗替尼联合PD1抑制剂纳武利尤单抗二线治疗一例食管鳞癌术后复发患者，取得了CR的疗效，提示联合免疫治疗可能在食管鳞癌治疗具有潜在疗效[30]。鉴于其只是个案报道，尚需进一步大样本的临床研究来证实。
综上所述，我们的研究表明安罗替尼联合替吉奥二线治疗复发转移性食管鳞癌具有较好的近期临床疗效，且其主要毒副作用基本可耐受，治疗过程较为顺利，可作为目前临床治疗复发转移性食管鳞癌的一个治疗选择。进一步大样本的多中心随机对照临床试验能够提供更有说服力的循证证据。
Funding Statement
国家自然科学基金(81673918);北京医卫健康公益基金会科研基金(YWJKJJHKYJJ-F2012E)
Supported by National Natural Science Foundation of China (81673918)
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