Efficacy and Safety Profile of PD-1 Inhibitors Versus Chemotherapy in the Second-line Treatment of Advanced Esophageal Squamous Cell Carcinoma: Systematic Review and Meta-Analysis of Randomized Controlled Trials

doi:10.21203/rs.3.rs-2213352/v1

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Efficacy and Safety Profile of PD-1 Inhibitors Versus Chemotherapy in the Second-line Treatment of Advanced Esophageal Squamous Cell Carcinoma: Systematic Review and Meta-Analysis of Randomized Controlled Trials

https://doi.org/10.21203/rs.3.rs-2213352/v1

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Purpose: PD-1 inhibitors have emerged as the new standard of care for second-line treatment of advanced esophageal squamous cell carcinoma. There have been lots of research lately concerning the topic. A comprehensive assessment of the efficacy and safety profile between PD-1 inhibitors and chemotherapy is warranted.

Methods: PubMed, Embase, Cochrane Library, and Embase were searched systematically until May 1^st, 2022. We extracted data on efficacy and safety and calculated the pooled HRs and RRs with 95%CI using randomized-effect or fixed-effect models. A subgroup analysis was applied to explore the factors modifying the response to PD-1 inhibitors. All data were statistically analyzed by R 4.1.2.

Results: A total of 5 studies involving 1,970 patients were included in our meta-analysis. PD-1 inhibitors group could attain greater overall survival benefit (HR = 0.73, 95%CI 0.66-0.81, P < 0.001) and nearly favorable progression-free survival (HR = 0.89, 0.76-1.04, P = 0.13). TRAEs (RR = 0.76, 95%CI 0.64-0.91, P = 0.004) and level 3-5 TRAEs (RR = 0.40, 95%CI 0.32-0.49, P < 0.001) were significantly diminished in PD-1 inhibitors groups. Among all modifying factors, PD-L1 combined positive score was positively associated with the patient’s overall survival.

Conclusions: This analysis suggests that PD-1 inhibitors exhibited better survival outcomes and safety profiles than standard-of-care chemotherapy. High levels of PD-L1 combined positive scores was associated with an enhanced response to PD-1 immunotherapies with regard to overall survival.

esophagus cancer

PD-1 inhibitors

squamous

chemotherapy

second-line

Esophageal cancer is one of the most prevalent digestive system cancers with high rates of morbidity and mortality. In 2020, esophageal cancer has accounted for around 0.6 million new cases and 0.5 million deaths, making it the eighth most often diagnosed and sixth deadliest cancer worldwide[1]. Based on histological type, esophageal cancer can be further subdivided into two subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma, with the former accounting for more than 85 percent of all new cases[2–4]. However, Esophageal cancer has a distinctive spatial distribution around the globe, notably in cases of esophageal squamous cell carcinoma, with variances between nations that exceed 10-fold[4]. Approximately half of the patients with esophageal cancer are from East Asia, and 90% of them have ESCC[5]. In Western nations, esophageal adenocarcinoma accounts for roughly two-thirds of esophageal cancer cases[6]. Although the incidence of ESCC has decreased in recent decades as a result of higher socioeconomic standards and lifestyle changes, it remains an urgent public health concern in China and other developing nations[5,7].

At the time of diagnosis, 60 to 70 percent of ESCC patients have already reached the locally advanced or metastatic stage due to the disease's insidious signs and rapid progression[5]. They are confronted with a terrible prognosis, with an observed 5-year survival rate of less than 5% and 22% in regional and distant stages, respectively[8,9]. In systemic therapy, chemotherapy in combination with fluorouracil and platinum-based agents continues to be the first-line drug treatment choice for patients with advanced ESCC, with an efficacy of 40%-60%[10]. However, effective treatment options for metastatic recurrent ESCC are limited after the failure of first-line therapy or chemotherapeutic agent resistance. The previous conventional second-line therapy, i.e., single-agent chemotherapy with docetaxel or paclitaxel, was unsatisfactory in terms of therapeutic effect and was associated with substantial neurotoxicity, gastrointestinal damage, and hepatotoxicity. The development of programmed death 1 (PD-1) inhibitors has ushered in a new era in the treatment of patients with advanced ESCC who were refractory to conventional chemotherapies[11,12].

More recently, a number of randomized control trials (RCTs) concerning the second-line therapy of ESCC patients with immune checkpoint inhibitors have been released[13–17]. Pembrolizumab, Nivolumab, Camrelizumab, and other emerging PD-1 inhibitors have considerable clinical efficacy and safety advantages over traditional chemotherapy regimens, according to published results. In 2021, a meta-analysis examining the therapeutic efficacy and safety of PD-1 inhibitors revealed that second-line PD-1 inhibitor drugs significantly increased the OS of patients with advanced ESCC[18]. However, not all of the included research was published in extenso, and some valuable information was unavailable. Now that these clinical trials have been published as a whole, we have the opportunity to re-evaluate the clinical efficacy and safety with greater precision. Additionally, it is vital to investigate the demographic that benefits more from PD-1 inhibitors. To address these issues, we conducted a systematic review and meta-analysis of RCTs concerning second-line therapies (PD-1 inhibitors versus. standard chemotherapy) for patients with advanced ESCC.

The study’s report followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines[19]. We prospectively registered the protocol in PROSPERO (www.crd.york.ac.uk/prospero/), the international prospective register of systematic reviews, with a registration number (CRD42022326180). As a meta-analysis, the study does not require the approval of an ethics committee or institutional review board.

2.1 Search strategy and study selection

To identify relevant articles, we performed an information search on the following three databases, Cochrane Library, PubMed, and EMBASE dating from the inception of the databases to May, 1st, 2022 with no language restrictions. The keywords utilized in our search strategy were “(esophageal OR esophagus OR oesophageal) AND (carcinoma OR cancer) AND (squamous) AND (metastatic OR advanced) AND (second-line) AND (programmed cell death protein 1 OR PD-1 OR immune checkpoint inhibitors) AND (overall survival OR progression-free survival OR objective response rate OR disease control rate OR treatment-related adverse events)”. Details search strategy in Pubmed is presented in supplement material 1.

Publications retrieved through the database search were collected and screened to exclude duplicate publications with considerable care. Two investigators (Zhao Jin and Minghe Zhao) independently performed the initial review based on the titles and abstracts of the article to identify potential eligible reports. To evaluate the quality of the research and reliability of the results, we excluded conference abstracts or meeting reports because they contain only the abstract and cannot provide sufficient data. Potentially relevant reports were subjected to a full-text review, and the relevance of the reports was confirmed during the data extraction process.

2.2 Inclusion and exclusion criteria

Studies were included in the meta-analysis if they met the following criteria: (1) patients with advanced, metastatic, or recurrent ESCC who progressed on or were intolerant to previous first-line chemotherapy; (2) Single PD-1 inhibitors were administered to the experimental group and standard chemotherapy regimens were delivered to the control group; (3) The study reported reliable clinical efficacy and safety indicators, such as overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs); (4) randomized control studies;

The exclusion criteria were as follows: (1) unpublished papers, such as conferences or meeting reports; (2) the outcome index was ambiguous or could not be merged; (3) non-RCTs.

2.3 Data extraction

The two aforementioned investigators independently extracted the data on characteristics and results including the year of publication, trial ID, study design and phase, period of enrollment, treatment arms, sample size, study quality, and the quality of evidence. Any discrepancies between reviewers were resolved by consensus.

2.4 Quality assessment

The risk of bias assessment for the RCTs would be conducted by one researcher and verified by the second using the Cochrane Risk of Bias tool (https://methods.cochrane.org/bias/resources/cochrane-risk-bias-tool). Trials were assessed based on the following domains: (i) bias arising from the randomization process and the timing of identification and recruitment of participants in relation to the timing of the randomization; (ii) bias due to deviations from the intended intervention; (iii) bias due to missing outcome data; (iv) bias due to the measurement of the outcome; and (v) bias due to the selection of the reported result.

2.5 Statistical analysis

All data were gathered and preserved in Microsoft Excel spreadsheets (Microsoft Excel® software, Microsoft, Spokane, WA). Then we performed the meta-analyses using R software, version 4.1.2 (R Foundation for Statistical Computing), and the meta package in R[20]. A two-side, p-value < 0.05 was considered statistically significant.

We initially analyzed the clinical efficacy and safety of PD-1 inhibitors versus. Chemotherapies in the second-line therapy of ESCC patients. HRs (hazard ratio) for OS and PFS with the relative 95% CI (confidence intervals) and incidence of ORR, DCR, and TRAEs (any grade TRAEs and grade 3–5 TRAEs) were respectively extracted from each study. To assess the heterogeneity of the results from individual studies, the Higgins I² statistic was calculated, and I² > 50% was regarded as a threshold indicating significant heterogeneity between studies. Summary HRs and RRs (relative ratios) were calculated with random- or fixed-effect models depending on the heterogeneity of included studies. To confirm the robustness of the results, sensitivity analysis was conducted by omitting one study by turn. The publication bias could be evaluated via a funnel plot, Harbord’s rank test, and Egger’s linear regression test. In our study, however, publication bias has not been quantitatively assessed through insufficient RCTs.

Then as for the main clinical efficacy endpoint OS, a subgroup analysis was applied to explore the factors modifying the response to PD-1 inhibitors. Nine subgroups were available for the analyses, including sex, combined positive score (CPS) of PD-L1 expression, tumor proportion score (TPS) of PD-L1 expression, Eastern Cooperative Oncology Group performance score (ECOG PS), region, race, smoking status, age, organ metastasis, and lymph node metastassi. Because the subgroups within each trial were independent, We could conduct the interaction effect utilizing the forming formulas: log HRAB = log HRAC-log HRBC, and SE²(log HRAB) = SE²(log HRAC) + SE²(log HRBC)[21]. Then we summarized the HRs in different studies and analyzed the differences in subgroups.

Considering the differences in the participants included in each study and our inability to obtain individual patient data, we did not perform an indirect comparison of the differences in efficacy and safety among PD-1 inhibitors.

3.1 Search results and study characteristics

The literature search originally yielded 96 identified articles from three following electronic databases (PubMed, EMBASE, and Cochrane central). There were 60 records left after the duplicate was discarded. After the screening of titles and abstracts, 18 articles were further scrutinized by a full-text screen. We ultimately conceal 13 articles for different reasons (i.e. Conferences or meeting posters, reviews, letters, comments, and subgroups of included RCTs) based on the inclusion and exclusion criteria. 5 trials were finally included in the quantitative meta-analysis. The flow diagram of the search and selection process is shown in Fig. 1.

The 5 included articles (1 phase II and 4 phase III) were all designed as RCTs with low bias. The sample size varied from 190 to 512, with a total of 1,970 subjects. Among them, 987 received PD-1 inhibitors including Pembrolizumab, Nivolumab, Camrelizumab, Tirelizumab, and Sintilimab, and the other 983 received standard chemotherapy including paclitaxel, irinotecan, and docetaxel. The total number of males in the study subjects was 1,705 (86.5%). Table 1 presents the study characteristics of these five studies.

Table 1

characteristics of the studies included in the meta-analysis
Trial ID	Design(phase), histology	Period of enrollment	Treatment arms	No. of patients for analysis (male%)	OS	PFS	ORR	DCR	Incidence of TRAEs
Trial ID	Design(phase), histology	Period of enrollment	Treatment arms	No. of patients for analysis (male%)	OS	PFS	ORR	DCR	Any Grade	3–5 Grade
ATTRACTION-3 (NCT02569242), 2019	RCT(III), Squamous	Jan 7, 2016-May 25, 2017	Nivolumab	210(85.2%)	10.9 (9.2–13.3)	1.7 (1.5–2.7)	19.2%	37.4%	65.6%	18.2%
ATTRACTION-3 (NCT02569242), 2019	RCT(III), Squamous	Jan 7, 2016-May 25, 2017	(1) Paclitaxel (2) Docetaxel	209 (88.5%)	8.4 (7.2–9.9)	3.4 (3.0-4.2)	21.5%	62.7%	95.2%	63.9%
ESCORT (NCT03099382), 2020	RCT(III), Squamous	May 10, 2017-July 24, 2018	Camrelizumab	228 (91.2%)	8.3 (6.8–9.7)	1.9 (1.9–2.4)	20.2%	44.7%	94.3%	19.3%
ESCORT (NCT03099382), 2020	RCT(III), Squamous	May 10, 2017-July 24, 2018	(1) Docetaxel (2) Irinotecan	220 (87.2%)	6.2 (5.7–6.9)	1.9 (1.9–2.1)	6.4%	34.5%	88.5%	39.5%
KEYNOTE-181 (NCT02564263), 2020	RCT(III), Squamous and adenomatous	Dec 8, 2015-June 16, 2017	Pembrolizumab	198 (337, 84.0%)	8.2 (6.7–10.3)	2.2 (2.1–3.2)	16.7%	46.0%	64.3%	18.2%
KEYNOTE-181 (NCT02564263), 2020	RCT(III), Squamous and adenomatous	Dec 8, 2015-June 16, 2017	(1) Paclitaxel (2) Docetaxel (3) Irinotecan	203	7.1 (6.1–8.2)	3.1 (2.2–3.9)	7.4%	49.8%	88.5%	40.9%
RATIONALE 302 (NCT03430843), 2021	RCT(III), Squamous	January 2018-March 2020	Tirelizumab	256 (84.8%)	8.6 (7.5–10.4)	1.6 (1.4–2.7)	20.3%	46.9%	73.3%	18.8%
RATIONALE 302 (NCT03430843), 2021	RCT(III), Squamous	January 2018-March 2020	(1) Paclitaxel (2) Docetaxel (3) Irinotecan	256 (84.0%)	6.3 (5.3-7.0)	2.1 (1.5–2.7)	9.8%	41.8%	93.8%	55.8%
ORIENT-2 (NCT03116152), 2022	RCT(II), squamous	May 16, 2017-August 30, 2018	Sintilimab	95 (92.6%)	7.2 (5.8–9.7)	1.6 (1.5–2.8)	12.8%	44.7%	54.3%	20.2%
ORIENT-2 (NCT03116152), 2022	RCT(II), squamous	May 16, 2017-August 30, 2018	(1) Paclitaxel (2) irinotecan	95 (88.4%)	6.2 (5.4–7.9)	2.9 (2.6–3.6)	6.3%	43.2%	90.8%	39.1%

3.2 Clinical efficacy and Safety

As depicted in Fig. 2 and Table 2, we conducted a meta-analysis and created a forest plot to uncover the association between the clinical efficacy and safety and PD-1 inhibitors. OS, PFS, ORR, and DCR were employed as indicators to assess clinical efficacy. Results revealed that the PD-1 inhibitors group obtained greater OS benefit compared with the standard chemotherapy group (HR = 0.73, 95%CI 0.66–0.81, P < 0.001; I² = 0%, P = 0.94). PFS was nearly favorable in the PD-1 inhibitor group (HR = 0.89, 0.76–1.04, P = 0.13; I² = 58%, P = 0.05). We also observed a significant increase in ORR among patients with PD-1 inhibitors (RR = 1.88, 95%CI 1.19–2.98, P < 0.001; I² = 73%, P < 0.01). However, DCR was not significantly higher in the group treated with PD-1 inhibitors than in the standard chemotherapy group (RR = 0.96, 95%CI 0.74–1.25, P = 0.77; I² = 84%, P < 0.01).

Table 2

pooled hazard ratio for clinical efficacy and safety.
	Heterogeneity		Effect size	P-value	model
	I²	P	Effect size	P-value	model
Efficacy
OS	0%	0.94	HR: 0.73 (0.66–0.81)	< 0.001	common effect
PFS	58%	0.05	HR: 0.89 (0.76–1.04)	0.129	random effect
ORR	73%	< 0.01	RR: 1.88 (1.19–2.98)	< 0.001	random effect
DCR	84%	< 0.01	RR: 0.96 (0.74–1.25)	0.773	random effect
Safety
TRAEs	96%	< 0.01	RR: 0.76 (0.64–0.91)	< 0.001	random effect
TRAEs Grade3-5	57%	0.05	RR: 0.40 (0.32–0.49)	< 0.001	random effect

As for safety, TRAEs and the Grade 3–5 TRAEs were selected as indicators to evaluate safety. Of note, Data on TRAEs for separate subgroups of esophageal squamous carcinoma were not available in the KEYNOTE 181 study. Here, we pooled TRAEs data for esophageal squamous and adrenal carcinoma in KEYNOTE 181. Analyses of TRAEs suggested that the PD-1 inhibitors might decrease the rates of overall TRAEs (RR = 0.76, 95%CI 0.64–0.91, P = 0.004; I² = 96%, P < 0.01) and especially the Grade 3–5 TRAEs (RR = 0.40, 95%CI 0.32–0.49, P < 0.001; I² = 57.3%, P = 0.05).

Afterward, we performed a sensitivity analysis to ascertain whether the individual studies significantly affect the overall results. The results indicated that individual studies had little influence on the final results and demonstrated that the analysis was relatively robust and reliable (Supplement Fig. 1). Due to the comparatively small number of the included studies, we did not draw a funnel plot to demonstrate publication bias.

3.3 Subgroup analysis to explore factors modifying the clinical efficacy

In the subgroup analysis, no significant difference was observed in subgroups including age, sex, smoking status, race, region,ECOG status, organ metastasis, and lymph node metastasis. However, the results demonstrated the lower level of PD-L1 expression was associated with a more diminished response to PD-1 inhibitors.

The results showed that the overall HR for PD-1 inhibitors versus. Chemotherapy was 0.61 (95%CI 0.48–0.76, P < 0.001; I² = 0%, P = 0.61) for CPS of PD-L1 ≥ 10 subgroups, and 0.84 (95%CI 0.70-1.00, P < 0.001; I² = 0%, P = 0.77) for CPS of PD-L1 < 10 subgroups. The HR for interaction effect between CPS of PD-L1 ≥ 10 and PD-L1 < 10 subgroups was 0.72 (95%CI 0.53–0.96, P = 0.02; I² = 0%, P = 0.56). As regards to the TPS of PD-L1 status, we separately compared the three groups (HR interaction: ≥10% vs. <10%, 0.91; ≥5% vs. <5%, 0.83; ≥1% vs. <1%, 0.80) and ultimately identified no statistically significant differences. Regardless of the degree of PD-L1 expression, as evaluated by CPS or TPS, the PD-1 inhibitor groups all obtained a greater survival advantage compared with chemotherapy groups.

Table 3 preserved the subgroup analysis of overall survival according to different modifying factors. Apart from the PD-L1 status, sex was probably an underlying significant factor modifying the PD-1 inhibitors clinical efficiency. The overall HR for PD-1 inhibitors versus. Chemotherapy was 0.76 (95%CI 0.68–0.84, P < 0.001; I² = 0%, P = 0.97) for males and 0.62 (95%CI 0.46–0.82, P < 0.001; I² = 0%, P = 0.57) for females. There was a nearly significant interaction effect between sexes on the relationship between OS and PD-1 inhibitors (Male versus. Female, HR = 1.26, 95%CI 0.92–1.71, P = 0.14; I2 = 0%, P = 0.66).

Table 3

Subgroup analysis of meta-analysis concerning overall survival.
Subgroup	Included studies	No. of patients	HR (95% CI)	HR (interaction action, 95% CI)	P (subgroups)
Sex^13–17
Male	5	1705	0.76 (0.68–0.84)	1.26 (0.92–1.71)	0.14
Female	5	265	0.62 (0.46–0.82)	1.26 (0.92–1.71)	0.14
Age^13–17
<65 years	5	1215	0.73 (0.64–0.82)	1.00 (0.81–1.24)	0.97
≥65 years	5	755	0.73 (0.62–0.87)	1.00 (0.81–1.24)	0.97
Race rationale^16–17
Asian	2		0.75 (0.64–0.87)	1.38 (0.84–2.25)	0.20
Non-Asian	2		0.53 (0.34–0.84)	1.38 (0.84–2.25)	0.20
Region^15,17
Asia	2	635	0.70 (0.59–0.83)	0.94 (0.48–1.81)	0.99
Ex-Asia	2	278	0.74 (0.43–1.28)	0.94 (0.48–1.81)	0.99
ECOG^13–17
0	5	624	0.79 (0.66–0.95)	1.12 (0.89–1.40)	0.84
1	5	1346	0.70 (0.62–0.79)	1.12 (0.89–1.40)	0.84
Smoking status^13,16,17
Former/Current	3	863	0.75(0.64–0.88)	1.03 (0.74–1.44)	0.85
Never	3	257	0.72(0.54–0.96)	1.03 (0.74–1.44)	0.85
Number of organs with metastases^14,16
1	2	359	0.81 (0.63–1.03)	1.19 (0.87–1.63)	0.24
>=2	2	508	0.68 (0.56–0.82)	1.19 (0.87–1.63)	0.24
Lymph node metastasis^14,16
No	2	405	0.68 (0.55–0.86)	0.85 (0.63–1.15)	0.36
Yes	2	462	0.80 (0.65–0.98)	0.85 (0.63–1.15)	0.36
PD-L1 status (CPS)^{13, 15,17}
≥ 10	3	384	0.61(0.48–0.76)	0.72(0.53–0.96)	0.02
< 10	3	565	0.84(0.70-1.00)	0.72(0.53–0.96)	0.02
PD-L1 status (TPS)^13,14,16
≥ 10%	3	339	0.70 (0.51–0.96)	0.91 (0.63–1.31)	0.61
< 10%	3	931	0.75 (0.64–0.88)	0.91 (0.63–1.31)	0.61
≥ 5%	2	229	0.65 (0.48–0.87)	0.83 (0.59–1.18)	0.30
< 5%	2	628	0.76 (0.63–0.91)	0.83 (0.59–1.18)	0.30
≥ 1%	3	448	0.66 (0.53–0.81)	0.80 (0.56–1.15)	0.24
< 1%	3	550	0.82(0.68-1.00)	0.80 (0.56–1.15)	0.24

In this meta-analysis consisting of 5 RCTs involving 1910 participants, we compared the clinical efficacy and safety profile of PD-1 inhibitors versus chemotherapy for ESCC patients in the second-line settings. Furthermore, the subsequent subgroup analysis and interaction effect analysis explored the factors modifying the response to PD-1 inhibitors. The results of our study showed that PD-1 inhibitors could provide superior overall survival benefits, improved remission rates and safety profile. This means that PD-1 inhibitors has an advantage over chemotherapy in both short and long-term outcomes in patients to some content. We also discovered that patients with higher levels of PD-L1 expression responded better to treatment with PD-1 inhibitors with regard to OS.

In terms of clinical efficacy, our meta-analysis provided reliable evidence that PD-1 inhibitors could provide superior beneficial effects in OS and ORR in contrast to traditional chemotherapy in ESCC. The result was in concordance with the previous meta-analysis conducted in 2021[18,22]. Previous research has proved that tumor cells could upregulate PD-L1 expression to inhibit the function of T lymphocytes, thus evading persistent inflammatory or autoimmune reactions. PD-1 inhibitors can block the binding of PD-L1 to PD-1, suppress the proliferation of PD-1 positive cancer cells, interrupt the immune escape, and enable the T lymphocytes to eliminate cancer cells[23]. PD-1 inhibitor therapies have shown promising therapeutic effects in patients with metastatic esophageal cancer in many clinical trials in first-line or second-line settings[24,25].

However, while significant overall survival gains were observed in the immune checkpoint-suppressed group, progression-free survival was not significantly improved.The phenomoenonwere attempted to be explained in terms of lagged effects of immunotherapy and pseudo-progression[26]. Compared with traditional cytotoxic chemotherapies, immunotherapy may require additional time to attain measurable or sustained clinical effects[27]. In the initial phase of immune therapies, the pre-existing tumor may not have reduced directly in size but has further expanded into new lesions. The radiographic enlargement of the tumor following the treatment caused a misimpression of disease progression according to the RECIST criteria and was regarded as indicative of ineffective therapy[28]. However, the subsequently decreased tumor burden demonstrated the effectiveness of immunotherapeutic agents. Actually, an immune checkpoint inhibitor might enhance the accumulation and infiltration of inflammatory cells, thus inducing the expansion of tumor lesions, and result in misclassification of treated patients as disease progression and reduction in PFS. The phenomenon also called “pseudo-progression”, has been described in the previous case report of immune checkpoint inhibitor treatment in digestive system tumors and has been estimated to have an incidence of 6.0% in solid tumors[28–30]. The included 5 RCTs all employed the traditional efficacy evaluation criteria for solid tumors (RECIST v1.1) and probably underestimated the PFS in PD-1 inhibitor groups.

According to the TRAEs and Grade 3–5 TRAEs results, PD-1 inhibitors might have better drug safety and tolerability compared to standard chemotherapy. In the second-line treatment of ESCC, the past single-agent chemotherapy includes paclitaxel, docetaxel, and irinotecan. Paclitaxel and docetaxel both belong to cytotoxic antitumor drugs and exert their anticancer effects by stabilizing microtubules, blocking the cell cycle, causing abnormal mitosis or termination, and thus restricting the process of tumor cell division[31]. Irinotecan can bind to the topoisomerase I-DNA complex and prevent relegation of the DNA strand and eventually leads to double-strand DNA breakage and cell death[32]. The past single-agent chemotherapy also similarly acts on normal cells, especially in blood cells, stomach and bowel, and the hair follicles, resulting in low blood counts, nausea, diarrhea, and hair loss. Immunotherapy for the treatment of cancers can significantly lower the incidence of the aforementioned adverse effects, as has been also established with other tumors[33].Comparatively speaking, PD-1 inhibitors might have the potential to induce an excessively upregulated immune system and disrupts the “immune balance”, thus resulting in a unique set of side effects through unbridled inflammation termed immune-related adverse events, resulting in cardiovascular, endocrine, dermal, hematological, neurological, pulmonary, gastrointestinal, musculoskeletal, and ocular damage[34,35] These special complications present a challenge to oncologists to evaluate the appropriateness of referrals and management regimens for patients.

In the subgroup analysis, we concluded that PD-L1 CPS was positively associated with the patient’s OS. The expression status of PD-L1 in tumors has been utilized as a biomarker to predict the clinical efficacy in several malignancies[36,37]. Nevertheless, there are two major established methods to evaluate positive PD-L1 cells.[38] TPS is defined as the number of positive tumor cells divided by the total number of viable tumor cells multiplied by 100%. CPS is described as the ratio of positive tumor cells, lymphocytes, and macrophages to the total number of viable tumor cells.[39] Theoretically, CPS might provide a more precise depiction of the tumor microenvironment and describes the extent of PD-L1 status more accurately. Our analysis results appeared to also confirm that CPS was more predictive of the additional benefit of PD-1 inhibitors compared to traditional chemotherapy in the second-line treatment of ESCC patients. Further studies are still needed to explore the role of PD-L1 expression in immunotherapy.

In addition, we discovered that, although not statistically significant, women with advanced ESCC probably acquired a greater survival benefit with PD-1 inhibitors. The conclusion contradicted the findings of previous investigations on solid tumors. A meta-analysis included more than 11,000 patients with different kinds of solid tumors (mostly lung carcinoma and melanoma) and ultimately concluded that the immune checkpoint inhibitors might decrease the risk of death more in males compared with females[40]. However, another two studies concerning the immunotherapy of advanced cancers reported no statistically significant association between OS and participants’ sexes[41,42]. Regarding the sex factor, it cannot be ignored that the imbalance in the sex ratio of participants contributed to the challenge of determining the interaction between sex and efficacy. In the five included RCTs concerning esophagus carcinoma, the ratio of male to female was approximately eight to one, a disparate ratio. Future clinical designs should ensure sufficient female subjects to more comprehensively assess sex differences in clinical efficacy.

There are also some limitations that should be noted. Firstly, the standard chemotherapy regimen for the control group in the different studies varied slightly; for instance, Paclitaxel was used for Keynote 181, whereas Docetaxel was used for Attraction-3. This possibly affected our results to a certain extent. Secondly, the expression status of PD-L1 was determined using several antibodies, 28 − 8 assay in ATTRACTION-3, SP263 assay in RATIONALE-302, 22C3 assay in KEYNOTE- 181 and ORIENT-2, and 6E8 assay in ESCORT, which might have an influence on the evaluation of PD-L1expression. Thirdly, this study was conducted at the trial level, and the individual patient data are unavailable, which may diminish the accuracy of the result. Fourth, Due to the insufficient number of randomized controlled trials included, we did not apply meta-regression to explore the sources of heterogeneity, but applied subgroup analysis directly. Despite these limitations, the meta-analysis provided a thorough summary of the known RCTs on the second-line treatment of ESCC.

Our analysis suggested that PD-1 inhibitors exhibited better survival outcomes and safety profile than standard-of-care chemotherapy in the second-line settings of patients with ESCC. The subsequent subgroup analysis revealed that the PD-L1 CPS was positively associated with OS. More studies with larger sample sizes and long-term follow-ups are needed to evaluate the safety and efficacy of PD-1 inhibitors in ESCC.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Competing Interests

We declared that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Author Contributions

Data extraction: Zhao Jin and Minghe Zhao. Manuscript writing: Zhao Jin and Minghe Zhao. Project design: Zhao Jin.

Ethics approval

No ethical approval was required, since this is a systematic review

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209–49.
Rustgi AK, El-Serag HB. Esophageal carcinoma. N Engl J Med. United States; 2014;371:2499–509.
Arnold M, Soerjomataram I, Ferlay J, Forman D. Global incidence of oesophageal cancer by histological subtype in 2012. Gut. England; 2015;64:381–7.
Abnet CC, Arnold M, Wei W-Q. Epidemiology of Esophageal Squamous Cell Carcinoma. Gastroenterology. 2018;154:360–73.
Thrift AP. Global burden and epidemiology of Barrett oesophagus and oesophageal cancer. Nat Rev Gastroenterol Hepatol. England; 2021;18:432–43.
Thun M, Linet MS, Cerhan JR, Haiman CA, Schottenfeld D. Cancer epidemiology and prevention. Oxford University Press; 2017.
Niu C, Liu Y, Wang J, Liu Y, Zhang S, Zhang Y, et al. Risk factors for esophageal squamous cell carcinoma and its histological precursor lesions in China: a multicenter cross-sectional study. BMC Cancer. BMC Cancer; 2021;21:1–11.
Njei B, McCarty TR, Birk JW. Trends in esophageal cancer survival in United States adults from 1973 to 2009: A SEER database analysis. J Gastroenterol Hepatol. 2016;31:1141–6.
Cancer Statistics Review, 1975-2017 - SEER Statistics [Internet]. [cited 2022 Jun 5]. Available from: https://seer.cancer.gov/archive/csr/1975_2017/
Kies MS, Rosen ST, Tsang TK, Shetty R, Schneider PA, Wallemark CB, et al. Cisplatin and 5-fluorouracil in the primary management of squamous esophageal cancer. Cancer. United States; 1987;60:2156–60.
van Laarhoven HW. Is chemotherapy for advanced or metastatic oesophageal squamous cell carcinoma no longer needed? Lancet Oncol [Internet]. Elsevier Ltd; 2020;21:743–5. Available from: http://dx.doi.org/10.1016/S1470-2045(20)30182-0
Zhang W, Wang P, Pang Q. Immune checkpoint inhibitors for esophageal squamous cell carcinoma: a narrative review. Ann Transl Med. 2020;8:1193–1193.
Xu J, Li Y, Fan Q, Shu Y, Yang L, Cui T, et al. Clinical and biomarker analyses of sintilimab versus chemotherapy as second-line therapy for advanced or metastatic esophageal squamous cell carcinoma: a randomized, open-label phase 2 study (ORIENT-2). Nat Commun. 2022;13:1–12.
line therapy for advanced or metastatic oesophageal squamous cell carcinomaHuang J, Xu J, Chen Y, Zhuang W, Zhang Y, Chen Z, et al. Camrelizumab versus investigator’s choice of chemotherapy as second- (ESCORT): a multicentre, randomised, open-label, phase 3 study. Lancet Oncol. 2020;21:832–42.
Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, et al. Randomized phase III KEYNOTE-181 study of pembrolizumab versus chemotherapy in advanced esophageal cancer. J Clin Oncol. 2020;38:4138–48.
Kato K, Cho BC, Takahashi M, Okada M, Lin CY, Chin K, et al. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol [Internet]. Elsevier Ltd; 2019;20:1506–17. Available from: http://dx.doi.org/10.1016/S1470-2045(19)30626-6
Shen L, Kato K, Kim S-B, Ajani JA, Zhao K, He Z, et al. Tislelizumab Versus Chemotherapy as Second-Line Treatment for Advanced or Metastatic Esophageal Squamous Cell Carcinoma (RATIONALE-302): A Randomized Phase III Study. J Clin Oncol. 2022;1.
Zhu X, Shanzhou Q, Li D, Pang X, Ma D. PD-1 inhibitors versus chemotherapy as second-line treatment for advanced esophageal squamous cell carcinoma: a meta-analysis. BMC Cancer. BMC Cancer; 2021;21:1–10.
Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4:1.
Schwarzer G. meta: An R package for meta-analysis. R news. 2007;7:40–5.
Higgins JPT, Li T, Deeks JJ. Choosing effect measures and computing estimates of effect. Cochrane Handb Syst Rev Interv. Wiley Online Library; 2019;143–76.
Maoxi Z, Jinmin X, Xiaozhu Z, Yubing Y, Yuxi Z. PD-1/PD-L1 Inhibitors versus Chemotherapy for Previously Treated Advanced Gastroesophageal Cancer: A Meta-Analysis of Randomized Controlled Trials. J Oncol [Internet]. 2021;2021. Available from: https://www.embase.com/search/results?subaction=viewrecord&id=L2014887206&from=export
Bagchi S, Yuan R, Engleman EG. Annual Review of Pathology: Mechanisms of Disease: Preface. Annu Rev Pathol. 2007;2:1–27.
Luo H, Lu J, Bai Y, Mao T, Wang J, Fan Q, et al. Effect of Camrelizumab vs Placebo Added to Chemotherapy on Survival and Progression-Free Survival in Patients With Advanced or Metastatic Esophageal Squamous Cell Carcinoma: The ESCORT-1st Randomized Clinical Trial. JAMA. 2021;326:916–25.
Wang Z-X, Cui C, Yao J, Zhang Y, Li M, Feng J, et al. Toripalimab plus chemotherapy in treatment-naïve, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial. Cancer Cell. United States; 2022;40:277-288.e3.
Somarouthu B, Lee SI, Urban T, Sadow CA, Harris GJ, Kambadakone A. Immune-related tumour response assessment criteria: A comprehensive review. Br J Radiol. 2018;91.
Chiou VL, Burotto M. Pseudoprogression and immune-related response in solid tumors. J Clin Oncol. 2015;33:3541–3.
Taghizadeh H, Lampichler K, Beer A, Preusser M, Ilhan-Mutlu A. A case report of pseudo-progression after pembrolizumab in metastatic gastric cancer and a review of immunotherapy in gastroesophageal tumors. Memo - Mag Eur Med Oncol. 2019;12:51–9.
Michalarea V, Fontana E, Garces AI, Williams A, Smyth EC, Picchia S, et al. Pseudoprogression on treatment with immune-checkpoint inhibitors in patients with gastrointestinal malignancies: Case series and short literature review. Curr Probl Cancer. Elsevier Inc.; 2019;43:487–94.
Park HJ, Kim KW, Pyo J, Suh CH, Yoon S, Hatabu H, et al. Incidence of pseudoprogression during immune checkpoint inhibitor therapy for solid tumors: A systematic review and meta-Analysis. Radiology. 2020;297:87–96.
Ikeda G, Yamamoto S, Kato K. The safety of current treatment options for advanced esophageal cancer after first-line chemotherapy. Expert Opin Drug Saf [Internet]. Taylor & Francis; 2022;21:55–65. Available from: https://doi.org/10.1080/14740338.2021.1955100
Hsiang YH, Liu LF. Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res. United States; 1988;48:1722–6.
Nishijima TF, Shachar SS, Nyrop KA, Muss HB. Safety and Tolerability of PD-1/PD-L1 Inhibitors Compared with Chemotherapy in Patients with Advanced Cancer: A Meta-Analysis. Oncologist. 2017;22:470–9.
Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol [Internet]. Springer US; 2019;16:563–80. Available from: http://dx.doi.org/10.1038/s41571-019-0218-0
Reid PD, Cifu AS, Bass AR. Management of Immunotherapy-Related Toxicities in Patients Treated With Immune Checkpoint Inhibitor Therapy. JAMA. United States; 2021;325:482–3.
Abdel-Rahman O. Correlation between PD-L1 expression and outcome of NSCLC patients treated with anti-PD-1/PD-L1 agents: A meta-analysis. Crit Rev Oncol Hematol [Internet]. Elsevier Ireland Ltd; 2016;101:75–85. Available from: http://dx.doi.org/10.1016/j.critrevonc.2016.03.007
Shen X, Zhao B. Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: Meta-analysis. BMJ. 2018;362:1–9.
Puhr HC, Preusser M, Ilhan-Mutlu A. Immunotherapy for esophageal cancers: What is practice changing in 2021? Cancers (Basel). 2021;13:1–15.
de Ruiter EJ, Mulder FJ, Koomen BM, Speel EJ, van den Hout MFCM, de Roest RH, et al. Comparison of three PD-L1 immunohistochemical assays in head and neck squamous cell carcinoma (HNSCC). Mod Pathol [Internet]. Springer US; 2021;34:1125–32. Available from: http://dx.doi.org/10.1038/s41379-020-0644-7
Conforti F, Pala L, Bagnardi V, De Pas T, Martinetti M, Viale G, et al. Cancer immunotherapy efficacy and patients’ sex: a systematic review and meta-analysis. Lancet Oncol [Internet]. Elsevier Ltd; 2018;19:737–46. Available from: http://dx.doi.org/10.1016/S1470-2045(18)30261-4
Wallis CJD, Butaney M, Satkunasivam R, Freedland SJ, Patel SP, Hamid O, et al. Association of Patient Sex with Efficacy of Immune Checkpoint Inhibitors and Overall Survival in Advanced Cancers: A Systematic Review and Meta-analysis. JAMA Oncol. 2019;5:529–36.
Ye Y, Jing Y, Li L, Mills GB, Diao L, Liu H, et al. Sex-associated molecular differences for cancer immunotherapy. Nat Commun [Internet]. Springer US; 2020;11. Available from: http://dx.doi.org/10.1038/s41467-020-15679-x

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Efficacy and Safety Profile of PD-1 Inhibitors Versus Chemotherapy in the Second-line Treatment of Advanced Esophageal Squamous Cell Carcinoma: Systematic Review and Meta-Analysis of Randomized Controlled Trials

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Abstract

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1 Introduction

2 Materials And Methods

2.1 Search strategy and study selection

2.2 Inclusion and exclusion criteria

2.3 Data extraction

2.4 Quality assessment

2.5 Statistical analysis

3 Results

3.1 Search results and study characteristics

3.2 Clinical efficacy and Safety

3.3 Subgroup analysis to explore factors modifying the clinical efficacy

4 Discussions

5 Conclusions

Declarations

References

Additional Declarations

Supplementary Files

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