Anti-PD-1 Inhibitor for the Treatment of Esophageal Cancer Refractory or Intolerant to Previous Chemotherapy: A Meta-Analysis of Randomized Controlled Trials

have suggested that PD-1 inhibitor is useful in the management of advanced Esophageal However, the ecacy and safety of Anti-PD-1 inhibitor for the treatment of advanced Esophageal Cancer is Thus, we conducted a meta-analysis aiming to comprehensively explore the effectiveness and safety of the therapeutic effects of PD-1 inhibitors on patients with advanced esophageal cancer.


Introduction
Esophageal cancer (EC) is one of the common cancer and with poor prognosis. It is reported that 572,034 new cases and 508,585 deaths were reported globally [1]. Despited the advanced of treatment technology and surgery, the overall survival of EC is still poor [2].
Immune checkpoint inhibitors (ICI) is widely used for various types of cancer [2]. Pd-1 inhibitors now are gain worldwide attention. Moreover, ICIs are considered as an option for salvage-line chemotherapy for metastatic or recurrent EC patients. Here, we performed a meta-analysis of randomized controlled trials (RCTs) assessing the e cacy and safety of anti-PD-1 inhibitors in the treatment of EC refractory or intolerant to previous chemotherapy. Page  This meta-analysis only included fully published RCTs. Other types of studies (such as animal studies, case reports, retrospective studies, comments) were excluded.

Types of patients
Cancer patients aged ≥18 years old, with histological con rmed of EC refractory or intolerant to previous chemotherapy.

Types of interventions
Treatment intervention: PD-1 inhibitor was given for the management of EC.

Outcomes of interest
The primary outcomes included overall survival(OS),progression-free survival(PFS) ,objective response rate and completed response rate. The secondary outcomes included grade 3 or more adverse events rate.

Searching methods for Eligibility studies
The following databases were included for searching: PubMed (since its inception), Cochrane library (since its inception), EMBASE (since its inception), and ClinicalTrials.gov (since its inception). The lasted search was December 1 st ,2020. The language was restricted to English only. The main search terms included "PD-1"," Immune checkpoint inhibitors",and "esphagus cancer" . Furthermore, references of all relevant identi ed studies were examined for yielding more RCTs.

Selection of study
The studies from initial search were import into the Note express software. By using this software, duplicated references were excluded. The remaining studies were required a title and abstracts screen by two independent researches (G.L and Z.Z) in accordance to the inclusion criteria. The potential meet inclusion criteria studies retrieved as a full text form will be screen and evaluated by two independent reviewers for the nal inclusion. Any disagreement was discussed and resolved by the author group. References of the studies identi ed for including analysis was evaluated for the potential missing studies.

Data extraction
Data from the inclusion studies were extracted using a pre-piloted and standardized form. The extracted information included the following: rst author of the study , country location, years of publication, samples sizes of each interventions, details of intervention methods, details of patients in each intervention (including ages, sex, body mass index, cancer types, dose and duration of radiation), and outcomes of interest Adverse events were de ned as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. Data extraction was carried out by two independent reviewers. Any disputes were resolved by discussion by the reviewer group.

Assessment risk of bias for the inclusion RCTs
Risk of bias were appraised using the Cochrane tools [7] by pair reviewers.

Measurement of treatment effect
For dichotomous parameters (e.g. response rate and adverse events), the events in each arm was recorded. The analysis was using odds ratio (OR) and its 95% con dence interval (CI). Hazard ratio(HR) and its 95% CI were applied for measuring survival outcomes.

Publication bias assessment
Publication bias was evaluated using funnel plot of the outcomes of interest. In addition, the Egger's test and Begg's test [8]were also used for detection of publication bias.
2.9 Data synthesis STATA 12.0 and RevMan 5.3 software will be utilized for the data analysis. As we list above, Chi 2 test will be adopt for measuring the heterogeneity. The I 2 values [7] of 25%, 50%, and 75% were considered low, moderate, and high, respectively. Continuous variables were measured using weighted mean difference (MD) with a 95% con dence interval (CI). Dichotomous variables, like the incidence of complications, were analyzed using odds ratios (ORs) with a 95% CI. If I 2 <25%, a xed-effects models will be adopted for evaluation. Otherwise, a randomeffects model was utilized. Subgroup analysis was performed to validate the reliable of the results and to nd out the potential source of heterogeneity. Sensitivity analysis was carried out without trials of great risk of bias.

Results
In total, there were 973 studies identi ed from the initial search. After carefully title and abstract screening, 29 studies were left for full text screening. In accordance to the inclusion criteria, only three studies [9][10][11] were included for this analysis. The study selection chart is presented in Fig. 1. The general information regarding studies were listed in Table 1. Risk of bias assessment is presented in Fig. 2.

The grade 3 or more adverse events
All of the three studies [9][10][11] reported of adverse events(AE). In terms of more than grade 3 events ,Pd-1 groups had a lower rate of adverse events compared to that of chemotherapy group(OR:0.25,95%:0.13,0.46,P < 0.0001),the analysis was used a random-effected model due to high heterogeneity(I 2 = 85%, P = 0.001) (Fig. 7) .

Subgroup analysis
In terms of OS ,we performed a subgroup analysis and meta-regeression based on the ECOG status, sex, age, and TPS score, and the results were not affected as outlined in Table 2.

Publication bias
Publication bias was evaluated using funnel plot of adverse events. The studies were outlined in the 95% CI and indicated no obvious publication bias (Fig. 8).Because the limited studies, Egger's test and Begg's test were not performed.

Discussion
EC is a lethal disease, it is the 7th in incidence and 6th in mortality worldwide [12]. Treatment guidelines for the second-line or later-line of the treatment of EC is not well established. Recently, three randomized controlled trials have published their e cacy results regarding the use of PD-1 inhibitor in the management of EC. Therefore, we undertook a systemic review and meta-analyze the results of these studies. Our studies indicated that compared to chemotherapy, the application of PD-1 inhibitor had a better OS (HR:0.80,95% CI:0.70,0.91,P = 0.0007) and lower grade 3 or more adverse events(OR:0.25,95% CI:0.13,0.46,P < 0.0001)in the second-line treatment of EC. The two groups had no signi cant difference in PFS, objective response rate, and completed response rate.
The application of PD-1/PD-L1 inhibitors in the treatment of a variety cancers had been widely reported [12]. The level of PD-L1 expression, and/or tumor mutation burden (TMB) in tumor cells can be a prognostic factor for determining the e ciency of PD-1/PD-L1 inhibitors. According to published reports, the proportion PD-L1 expression in EC was ranged from (14.5 to 82.8% ) [2]. The application of PD-1/PD-L1 inhibitors in EC patients were reported in several trials [9-11, 13, 14].
Our analysis indicated the application of PD-1 inhibitors can prolong the OS as compared to chemotherapy in EC patients. As reported in KEYNOTE-181 trial [9], In the intentions treatment (ITT) population, the application of Pembrolizumab in the treatment of EC did not gain survival bene t in terms of median OS .However, in patients with PD-L1 CPS score more than 10, the used of Pembrolizumab had survival bene t compared with chemotherapy ( median OS :9.3 and 6.7 months) .Moreover, in the ESCORT trial [10],the application of camrelizumab resulted in better overall survival in the second-line treatment of EC. Our analysis also indicated in subgroup analysis the results were not affected, as according to ECOG status, sex, age, and TPS score.And the meta-regerssion analysis indicated the results was stable. In the attraction-3 trial [11], The median OS was 10·9 months and 8.4mionth in the Nivomab group and chemotherapy group, respectively. In the Keynote-028 trial [14] ,the application of Pembrolizumab as a late-line treatment for EC achieved a median OS of 7 month. In the atraction-1 trial, sixty-ve patients with metastatic oesophageal squamous cell carcinoma (ESCC) received of Nivolumab and the meidian OS was 1.51 month [13].
In terms of PFS, as reported in Keynote-181 trial [9],In patients with PD-L1 CPS more than 10, median PFS was longer in the Pembrolizumab group compared with that of in the chemotherapy group. In the ESCORT trial, median PFS was both 1·9 months in Camrelizumab group or in chemotherapy group.
In the attraction-3 trial,The PFS was not signi cant difference between Nivolumab group and chemotherapy group.
In terms of ORR, as mentioned in attraction-3 trial, The ORR rate was 19% in the Nivolumab group and 22% in the chemotherapy group .as reported in the ESCORT trial, the ORR was 20.2 % in the Camrelizumab group and 6.4% in the chemotherapy group. In the Keynote-181 trial [9], the ORR was 13.1% in the in the Pembrolizumab group and 6.7% in the chemotherapy group.
In terms of treatment AE,as reported in the attraction-3 trial, serious treatment-related adverse events (Grade 3 or higher) rate was 16% in the Nivolumab group and 23% in the chemotherapy group.
Grade 3 or higher treatment-related AEs was 18% in the Pembrolizumab group and 40.9% in the chemotherapy group as reported in the Keynote-181 trial [9]. And in the ESCORT trial, the serious treatment-related adverse events was 19% in the Camrelizumab group and 39% in the chemotherapy group. In published studies, the grade 3 or higher AE was ranged from 10.3% t0 14.3% [9].The most common any-grade treatment related adverse events were fatigue.
Limitations in this meta-analysis should be taken into account. First, the numbers of study included is limited and only three trials were included. Second, the included patients were from different parts of the world ,including Japan ,China and USA, some heterogeneity may exist.
In conclusion, our study indicated treatment EC refractory or intolerant to previous chemotherapywith PD-1 inhibitors resulted a better OS. The grade 3 or more adverse events rate were lower in the PD-1 group. Due to the limited studies, More well designed RCTs are required to explore the treatment effect of PD-1inhibitor for secondline treatment of EC refractory or intolerant to previous chemotherapy.
Abbreviations RCT

Declarations
Disclosure Availability of data All data generated or analysed during this study are included in this published article.

Ethics approval
The study did not need ethics approval.