Hesong Wang,Chunyang Song,Xiaohan Zhao,Wenzhao Deng,Jing Dong,Wenbin Shen
Evaluation of neoadjuvant immunotherapy and traditional neoadjuvant therapy for resectable esophageal cancer: a systematic review and single-arm and network meta-analysis
neoadjuvant therapy,immunotherapy,neoadjuvant immunotherapy,curative resection,esophageal carcinoma,meta-analysis
Objective This systematic review and meta-analysis aimed to investigate the role of neoadjuvant immunochemotherapy with or without radiotherapy [NIC(R)T] compared to traditional neoadjuvant therapies, without immunotherapy [NC(R)T]. Summary background data NCRT followed by surgical resection is recommended for patients with early-stage esophageal cancer. However, it is uncertain whether adding immunotherapy to preoperative neoadjuvant therapy would improve patient outcomes when radical surgery is performed following neoadjuvant therapy. Methods We searched PubMed, Web of Science, Embase, and Cochrane Central databases, as well as international conference abstracts. Outcomes included R0, pathological complete response (pCR), major pathological response (mPR), overall survival (OS) and disease-free survival (DFS) rates. Results We included data from 5,034 patients from 86 studies published between 2019 and 2022. We found no significant differences between NICRT and NCRT in pCR or mPR rates. Both were better than NICT, with NCT showing the lowest response rate. Neoadjuvant immunotherapy has a significant advantage over traditional neoadjuvant therapy in terms of 1-year OS and DFS, with NICT having better outcomes than any of the other three treatments. There were no significant differences among the four neoadjuvant treatments in terms of R0 rates. Conclusions Among the four neoadjuvant treatment modalities, NICRT and NCRT had the highest pCR and mPR rates. There were no significant differences in the R0 rates among the four treatments. Adding immunotherapy to neoadjuvant therapy improved 1-year OS and DFS, with NICT having the highest rates compared to the other three modalities. Systematic Review Registration https://inplasy.com/inplasy-2022-12-0060/ , identifier INPLASY2022120060.
Evaluation of neoadjuvant immunotherapy and traditional neoadjuvant therapy for resectable esophageal cancer: a systematic review and single-arm and network meta-analysis

This systematic review and meta-analysis aimed to investigate the role of neoadjuvant immunochemotherapy with or without radiotherapy [NIC(R)T] compared to traditional neoadjuvant therapies, without immunotherapy [NC(R)T].

NCRT followed by surgical resection is recommended for patients with early-stage esophageal cancer. However, it is uncertain whether adding immunotherapy to preoperative neoadjuvant therapy would improve patient outcomes when radical surgery is performed following neoadjuvant therapy.

We searched PubMed, Web of Science, Embase, and Cochrane Central databases, as well as international conference abstracts. Outcomes included R0, pathological complete response (pCR), major pathological response (mPR), overall survival (OS) and disease-free survival (DFS) rates.

We included data from 5,034 patients from 86 studies published between 2019 and 2022. We found no significant differences between NICRT and NCRT in pCR or mPR rates. Both were better than NICT, with NCT showing the lowest response rate. Neoadjuvant immunotherapy has a significant advantage over traditional neoadjuvant therapy in terms of 1-year OS and DFS, with NICT having better outcomes than any of the other three treatments. There were no significant differences among the four neoadjuvant treatments in terms of R0 rates.

Among the four neoadjuvant treatment modalities, NICRT and NCRT had the highest pCR and mPR rates. There were no significant differences in the R0 rates among the four treatments. Adding immunotherapy to neoadjuvant therapy improved 1-year OS and DFS, with NICT having the highest rates compared to the other three modalities.

https://inplasy.com/inplasy-2022-12-0060/, identifier INPLASY2022120060.

Esophageal cancer is the seventh most common malignant tumor and the sixth leading cause of cancer-related mortality worldwide (1). Surgical resection has advocated for the treatment of early-stage esophageal cancer (2). The CROSS trial showed that neoadjuvant chemoradiation followed by surgical resection was more beneficial for esophageal cancer (3). Accordingly, the National Comprehensive Cancer Network guidelines recommend it as the standard therapy (4). Nevertheless, the treatment efficacy for esophageal cancer remains poor, with a 5-year survival rate of approximately 20% (5, 6). Immunotherapy has become an effective treatment for many malignancies including esophageal cancer (7–9). By rescuing the immune checkpoint pathway to resist carcinoma, the anti-tumor action of T cells is blocked by immune checkpoint blockade. Immunotherapy has proven beneficial as a third-, second-, and even first-line treatment for patients with esophageal cancer. However, it remains unclear whether adding immunotherapy therapy to preoperative neoadjuvant confers an overall benefit to patient outcomes when radical surgery is performed after neoadjuvant therapy. Several studies have documented benefits when immunotherapy is added to neoadjuvant therapy (10, 11); on the other hand, adding immunotherapy to neoadjuvant therapy increases the severity of toxic side effects (12, 13). Therefore, this systematic review and meta-analysis was conducted to evaluate the outcomes of patients treated with either of two neoadjuvant immunotherapies – neoadjuvant immunotherapy combined with chemoradiotherapy (NICRT) and neoadjuvant immunochemotherapy (NICT) – compared with two traditional neoadjuvant therapies – neoadjuvant chemoradiotherapy (NCRT) and neoadjuvant chemotherapy (NCT).

This study was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 (14). The present study was registered in the INPLASY (identifier: INPLASY2022120060).

We searched PubMed, Web of Science, Embase, and Cochrane Central databases, as well as international conference abstracts from American Society of Clinical Oncology, European Society for Medical Oncology and American Association for Cancer Research, along with various other resources, until December 16, 2022. The detailed search strategies are summarized in Supplementary Table 1 . We searched for studies that explored patients with histologically confirmed-, resectable-, esophageal carcinoma who received either NICRT or NICT followed by surgery. Meanwhile, the patients treated with traditional neoadjuvant therapy (NCRT or NCT) were all derived from control patients in these studies, rather than from other studies that did not involve NICRT or NICT. We followed the Population, Intervention, Comparison, Outcome, and Study Design (PICOS) principles ( Supplementary Table 2 ). The detailed inclusion and exclusion criteria are shown in Supplementary Table 3 .

Two authors (CS and XZ) independently assessed each study and extracted the pertinent information therefrom. Another author (WD) resolved any differences that might have arisen in the process. Relevant parameters were extracted from each included study: author, year, country, study type, registration number, intervention model, type of article, treatment modalities and side effects, sample size, age, sex, histologic subtype, relevant clinical characteristics, and outcome data of interest.

The outcome indicators in this study included direct measures of treatment efficacy – R0, pathological complete response (pCR), and major pathological response (mPR) rates – as well as survival-related indicators, including overall survival (OS), disease-free survival (DFS), and death within 30 days after surgery. We did not include treatment-related adverse events during neoadjuvant therapy or post-operative complications, as the evaluation criteria used to evaluate these indicators were not uniform across different studies. The primary goal of our study was to explore immediate post-treatment efficacy and subsequent survival outcomes, to investigate the effectiveness of neoadjuvant immunotherapy.

Two authors (CS and XZ) independently evaluated the quality of each study. If there were any disagreements in the process, another author (JD) settled it. The Methodological Index for Non-randomized Studies (MINORS) was used to assess single-arm and retrospective dual-arm studies (15, 16). Each item was scored from 0 to 2. There were 8 items for non-comparative studies and 12 items for comparative studies. For non-comparative studies, an overall score > 12 was considered high, between 8 and 12 was considered intermediate, and < 8 was considered low. The Cochrane Risk of Bias tool was used to assess randomized controlled trials (RCT) (17, 18). The tool scores RCT studies according to five items. The overall bias included low risk of bias, some concerns, and high risk of bias. The quality of this systematic review and meta-analysis was evaluated according to the PRISMA 2020 Checklist (14) and the AMSTAR-2 Checklist (19).

All analyses were performed by STATA (STATA, version 14.0, College, TX),. Survival curve data from included studies which were not reported were extracted by Engauge Digitizer, version 12.1 (http://markummitchell.github.io/engauge-digitizer/). We performed a single-group meta-analysis of all included studies. In order to compare the four different neoadjuvant treatment modalities with each other and to rank their respective efficacies, we performed a network meta-analysis of the comparative studies among them. The significance level of the results was set at P <0.05, as per the convention. The combined risk ratio (RR) and 95% confidence interval (CI) were used as the outcome indicators. For OS and DFS rates, the number of events used to calculate the RR value was the number of survivors rather than the number of deaths. Therefore, in the present study, RR and 95% CI > 1 indicated that treatment was more conducive to survival, whereas RR and 95% CI < 1 indicated that treatment was more detrimental to survival (Detailed data synthesis are shown in Supplementary Table 4 ). Subsequently, we merged NICRT and NICT into the neoadjuvant immunotherapy group and NCRT and NCT into the traditional neoadjuvant therapy group. We performed a traditional pairwise meta-analysis of these two groups, with head-to-head studies to explore the comparative advantages of neoadjuvant immunotherapy vs. traditional neoadjuvant therapy. Exploratory subgroup analyses were performed based on the study type (prospective or retrospective), intervention model (single-arm or dual-arm), immunotherapy drugs (PD-1 or PD-L1 inhibitors), and cancer type (squamous cell carcinoma [SCC] or adenocarcinoma [AC]). Additionally, sensitivity analyses were performed by omitting each study to evaluate the stability of the results. Publication bias was assessed using the Begg’s funnel plot (20).

From the 1,755 considered studies, we eventually selected 86 studies (10–13, 21–102) describing a total of 5,034 patients ( Figure 1 ). This number consisted of 16 dual-arm studies and 70 single-arm studies, five RCTs and 81 non-RCTs. All studies were published between 2019 and 2022, most of which were conducted in China. Among these studies, the number of patients who received NICRT, NICT, NCRT, and NCT were 427, 3508, 701, and 398, respectively. The median age of all patients ranged from 42.7 to 68.8. For cancer type, the studies included SCC only (n=73), AC only (n=6), mixed SCC and AC (n=5), and undetailed pathology (n=2). For neoadjuvant immunotherapy, PD-1 inhibitors were the most common, with only 6 studies using PD-L1 inhibitors. The radiation doses ranged from 30 Gy to 56 Gy. All neoadjuvant chemotherapy regimens were conventional treatment regimens. Detailed characteristics of each study are shown in Table 1 and Supplementary Tablea 5 - 8 .

A total of 56 trials reported R0 rates (pooled R0 rate and 95% CI: NICRT - 95.6% [91.8%-99.3%]; NICT - 97.5% [96.9%-98.2%]; NCRT - 94.9% [90.3%-99.5%]; NCT - 96.6% [93.5%-99.6%]) ( Figure 2 ). Overall, 80 trials provided pCR rates (pooled pCR rate and 95% CI: NICRT - 38.9% [32.1%-45.6%]; NICT -27.2% [24.8%-29.6%]; NCRT - 35.5% [21.3%-49.7%]; NCT - 8.6% [2.9%-14.3%]) ( Figure 2 ). Totally, 51 trials analyzed mPR rates (pooled mPR rate and 95% CI: NICRT - 64.2% [53.8%-74.7%]; NICT - 51.8% [46.7%-56.8%]; NCRT - 47.8% [10.5%-85.1%]; NCT - 43.6% [9.5%-77.7%]) ( Figure 3 ). In terms of survival outcomes, 28 trials reported death within 30 days after surgery (pooled rate and 95% CI: NICRT - 2.0% [0.0%-4.2%]; NICT - 0.3% [0.0%-0.6%]; NCRT - 1.7% [0.6%-2.8%]; NCT - 1.3% [0.0%-2.7%]) ( Figure 3 ). Thirteen trials provided 1-year OS rates (pooled 1-year OS rate and 95% CI: NICRT - 87.3% [80.9%-93.6%]; NICT - 96.2% [94.2%-98.1%]; NCRT - 86.2% [79.2%-93.1%]; NCT - 85.1% [74.9%-95.3%]) ( Figure 4 ). And a total of 16 trials analyzed 1-year DFS rates (pooled 1-year DFS rate and 95% CI: NICRT - 77.7% [70.9%-84.6%]; NICT - 90.0% [86.2%-93.7%]; NCRT - 73.2% [64.4%-82.0%]; NCT - 76.6% [64.5%-88.7%]) ( Figure 4 ). To compare different neoadjuvant treatment modalities with each other, we included 16 dual-arm trials in the network meta-analysis. Network evidence plots and contribution plots are shown in Supplementary Figures 1 , 2 . The network estimates are shown in Figure 5 and Supplementary Figures 3 , 4 . There were no significant differences in pCR and mPR rates between NICRT and NCRT (pooled RR and 95% CI of pCR rate: NICRT vs. NCRT - 1.39 [0.82,2.37]; pooled RR and 95% of mPR rate: NICRT vs. NCRT - 1.02[0.87,1.19]). Both were superior to NICT (pooled RR and 95% CI of pCR rate: NICRT vs. NICT - 1.83 [1.10,3.05], NCRT vs. NICT - 1.32 [1.00,1.74]; pooled RR and 95% CI of mPR rate: NICRT vs. NICT - 1.17[1.05,1.31], NCRT vs. NICT - 1.15[1.01,1.31]), and NCT had the poorest results (pooled RR and 95% CI of pCR rate: NICRT vs. NCT - 5.43 [2.80,10.51], NCRT vs. NCT - 3.90 [2.36,6.47], NICT vs. NCT - 2.96 [1.93,4.54]; pooled RR and 95% CI of mPR rate: NICRT vs. NCT - 1.93 [1.56,2.39], NCRT vs. NCT - 1.90 [1.52,2.37], NICT vs. NCT - 1.65[1.35,2.00]). For 1-year OS and DFS rates, NICT showed the best rates compared to other three treatments (pooled RR and 95% CI of 1-year OS rate: NICT vs. NICRT - 1.10 [1.01,1.19], NICT vs. NCRT - 1.10 [1.01,1.20], NICT vs. NCT - 1.11[1.00,1.26]; pooled RR and 95% CI of 1-year DFS rate: NICT vs. NICRT - 1.16 [1.05,1.27], NICT vs. NCRT - 1.22 [1.08,1.38], NICT vs. NCT - 1.16 [1.00,1.37]), with the other three treatments not having any statistically significant difference in these parameters amongst each other. None of the treatment modalities stood out from the others in terms of R0 rates or death within 30 days after surgery.

Next, we pooled the data for the NICRT and NICT cases into the neoadjuvant immunotherapy group and the NCRT and NCT cases into the traditional neoadjuvant therapy group. A total of 16 trials were included in this head-to-head pairwise meta-analysis. Patients in the neoadjuvant immunotherapy group exhibited significantly higher 1-year OS and DFS rates than those in the traditional neoadjuvant therapy group (pooled RR and 95% CI of the traditional group vs. immunotherapy group: 1-year OS rate - 0.90 [0.83-0.98]; 1-year DFS rate - 0.83 [0.74-0.93]) ( Figure 6 ). However, there were no significant differences between the two groups in terms of R0, pCR, mPR, or death within 30 days after surgery ( Figure 6 ).

To explore the potential association of immunotherapy between NICRT and NICT, we conducted exploratory subgroup analysis based on study type (prospective or retrospective), intervention model (single-arm or dual-arm), immunotherapy drugs (PD-1 or PD-L1 inhibitors), and cancer type (SCC or AC), respectively. The results of the subgroup NICRT and NICT analyses were generally consistent with the above results in terms of R0, pCR, mPR, death within 30 days after surgery, 1-year OS, and 1-year DFS ( Supplementary Figures 5 – 10 ).

The details of the risk of bias are provided in Supplementary Tables 9 , 10 . The MINORS was used to evaluate the 81 non-randomized studies. All the 81 studies were of high or intermediate quality. The Cochrane Risk of Bias tool was used to evaluate the five randomized studies, and it indicated that there was no high risk of bias in any of the evaluated categories among the five RCTs in our data set. Supplementary Tables 11 , 12 show the quality evaluation of the present study using the PRISMA 2020 Checklist and AMSTAR-2 Checklist. Sensitivity analysis, conducted by omitting each study, indicated that all results were stable except for death within 30 days after surgery ( Supplementary Figure 11 ). Similarly, there was no significant publication bias except for death within 30 days after surgery ( Supplementary Figure 12 ).

To the best of our knowledge, the present study is the first systematic review and meta-analysis to explore the effectiveness of four different neoadjuvant therapies (NICRT, NICT, NCRT, and NCT) followed by curative surgery for esophageal cancer, and then compare them with each other by not only postoperative outcome results but also survival-related efficacy outcomes. Drawing from data taken from 86 different studies, collectively describing 5,034 patients, we explored the comparison of R0, pCR, mPR, OS, DFS, and death within 30 days after surgery outcomes across treatment modalities. There were no significant differences in pCR and mPR rates between NICRT and NCRT; both were superior to NICT, and NCT had the poorest results. For 1-year OS and DFS rates, NICT showed the best rates compared to the other three treatments, with the other three treatments not having any statistically significant difference in these parameters amongst each other. No significant differences were observed among any of the four examined treatment modalities in terms of R0 rates or death within 30 days after surgery. As for the subgroup analyses based on the study type, intervention model, immunotherapy drugs, and cancer type, there were no significant differences between the subgroups, which is consistent with the above findings. Although this is, to date, the largest meta-analysis to examine the role of four different neoadjuvant therapies after curative resection for esophageal cancer, previous studies on this subject have been conducted. A meta-analysis conducted by Wang et al. (103), which included 20 studies with 621 patients, explored the clinical outcomes of NICRT vs. NICT. Consistent with our findings, they reported that NICRT had an advantage over NICT in terms of mPR rates, but found no significant differences in R0 rates. However, they reported no significant differences in pCR rates between NICRT and NICT, whereas we found that NICRT had superior pCR rates to NICT (pooled RR and 95% CI: 1.83 [1.10, 3.05]). This discrepancy may be explained by Wang et al.’s smaller sample size, which included only two studies that involved NICRT. In contrast, our study included 14 studies of NICRT, including the two used by Wang et al. Additionally, the patients in the NCRT and NCT groups in their study were obtained from a meta-analysis by Li et al. (104), whereas the patients in our NCRT and NCT groups were extracted from dual-arm studies with direct head-to-head comparisons with NICRT or NICT. This significantly reduced error, increased comparability, and provided assurance of the quality of the results and conclusions. In addition, with the addition of follow-up parameters (OS and DFS), our study included more survival-related outcomes than previous studies. Our study showed greater 1-year OS and 1-year DFS rates in the NICT group, while the NICRT group showed no such results. This difference might be explained by the fact that concurrent administration of all three treatment modalities in the NICRT group significantly increased treatment-related adverse effects, resulting in patients showing no advantage in terms of survival. Wang et al. (103) reported that the incidence of preoperative grade 3-4 treatment-related adverse events was 51.2% in NICRT, which was much higher than the 19.4% in NICT. A multicenter dual-arm study conducted by Yang et al. (29) directly compared the safety of NICRT and NICT, noting that treatment-related adverse events, immune-related adverse events, and post-operative complications all had higher incidences in the NICRT group than in the NICT group. The toxicity of this treatment may ultimately result in a failure of NICRT to provide long-term survival benefits. Although this review concluded that there were no significant differences among the four different neoadjuvant treatments in terms of death within 30 days after surgery, this could be attributed to three reasons. First, the incidence of mortality within 30 days after surgery was low – close to zero, in fact – regardless of the treatment type, the differences they exhibited may not be statistically evident; second, the toxic effects of the treatment did not appear in such a short period of time and needed some time to manifest; And third, this outcome showed unstable results in both sensitivity analysis and publication bias analysis. A meta-analysis by Ge et al. (105) included 27 single-arm studies with 815 patients to explore the clinical outcomes of NICT. They reported pooled rates of R0, pCR and mPR were 98.6%, 31.4% and 48.9%, respectively, largely similar to the results obtained in our study (97.5%, 27.2%, and 51.8%, respectively). Compared to CROSS (3), which received NCRT, their R0 rate was 92.0%, which was not significantly different from the results obtained in our study and those of Ge et al. (105); however, their pCR rate was 49.0%, which was significantly higher than our results or those of Ge et al. That being said, this result is consistent with our conclusion that the pCR rate in the NCRT group was higher than that in the NICT group, while there were no significant differences in terms of R0 rate. A randomized controlled multicenter study conducted by Liu et al. (106) in 2022 reported that patients receiving NCT experienced a pCR rate of 20.8% and an mPR rate of 33.3%, consistent with our findings that the NCT group had the lowest pCR and mPR rates among the all four neoadjuvant treatments. When we combined treatment modalities based on the inclusion or absence of immunotherapy (regardless of the presence of radiation therapy), we found that the neoadjuvant immunotherapy group had a significant advantage over the traditional neoadjuvant therapy group in terms of 1-year OS and DFS rates, while there were no significant differences between the two groups in other outcomes. It can be seen that the addition of immunotherapy can significantly prolong the survival of patients. This adds further evidence to the growing pile attesting to the benefit of immunotherapy in neoadjuvant therapy. As for the other results of the same, because the results obtained in this study were that there were no significant differences among the four different neoadjuvant treatments in R0 rates and death within 30 days after surgery, there were also no differences in the comparison between the combined groups. Regarding pCR and mPR rates, since the incidences were highest in the NCRT cohort and lowest in the NCT cohort, when these two were combined together in the traditional group, it canceled out the difference that had been seen when the four cohorts were being compared individually. This systematic review and meta-analysis also had limitations. First, as most of the studies included in this review were single-armed, potential bias may arise; second, since immunotherapy is still in the process of exploration, some studies have not yet released their final results. Moreover, survival endings could only be extracted for 1 year, as for the follow-up of long-term survival, follow-up studies are needed to report; third, there were only five RCTs in this review, and the lack of RCTs may potentially lead to bias; fourth, as previously noted, both sensitivity and publication bias analysis indicated instability in the data used for death within 30 days after surgery in this review, which prohibits rigorous conclusions from being drawn therefrom; more studies and data will be needed to verify the relevant findings of this study; fifth, due to the lack of available data, the role of effective biomarkers, for instance, combined positive score (CPS) and tumor proportion score (TPS), in neoadjuvant immunotherapy could not be investigated; Sixth, due to the inconsistent guidelines for and definitions of treatment-related adverse events in the different studies used in this meta-analysis, we were unable to properly compare them, instead focusing on the endpoints of efficacy and survival.

In conclusion, among the four neoadjuvant treatment modalities NICRT, NICT, NCRT, and NCT, NICRT and NCRT had the highest pCR and mPR rates. There were no significant differences in R0 rates among the four neoadjuvant treatment modalities. Adding immunotherapy to neoadjuvant therapy improved 1-year OS and DFS, with the NICT group having significantly higher longer survival according to both these metrics than any of the other three modalities. The results of this review provide a basis for future studies. Further, large multicenter RCTs and longer-term follow-ups are needed to refine these findings.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

All authors read and approved the final manuscript prior to submission. WS are responsible for the conception and design of the study. HW are responsible for analysis and interpretation of data, and drafting the article and revising it. CS and XZ are responsible for acquisition of data. WD and JD is responsible for data check. All authors contributed to the article and approved the submitted version.