Esophageal cancer (EC) ranks among the most prevalent malignant tumors affecting the digestive tract. Esophageal squamous cell carcinoma (ESCC) stands as the prevailing pathological subtype, encompassing approximately 90% of all EC patients. In clinical stage II-IVA locally advanced ESCC cases, the primary approach to treatment involves a combination of neoadjuvant therapy and surgical resection. Despite concerted efforts, the long-term outcomes for ESCC patients remain unsatisfactory, with dismal prognoses. However, recent years have witnessed remarkable strides in immunotherapy, particularly in the second- and first-line treatment of advanced or metastatic ESCC, with the development of monoclonal antibodies that inhibit programmed death 1 or programmed death ligand 1 demonstrating encouraging responses and perioperative clinical benefits for various malignancies, including ESCC. This comprehensive review aims to present the current landscape of perioperative immunotherapy for resectable ESCC, focusing specifically on the role of immune checkpoint inhibitors during the perioperative period. Additionally, the review will explore promising biomarkers and offer insights into future prospects.

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.

Significant progress has been made in the investigation of neoadjuvant immune-chemoradiotherapy (NICRT) and neoadjuvant immune-chemotherapy (NICT) on the outcomes of esophageal cancer patients. To summarize the current developments, a systematic review and meta-analysis were conducted to evaluate the efficacy and safety of neoadjuvant immunotherapy combined with chemoradiotherapy or chemotherapy.

A search strategy of prospective studies on esophageal cancer receiving neoadjuvant immunotherapy was predefined to scan PubMed, Embase, Cochrane, and additional major conferences for prospective studies. Efficacy was assessed by pathological complete response (pCR), major pathological response (MPR), and R0 resection rates. Safety was evaluated based on the incidence of grade ≥ 3 treatment-related adverse events (TRAEs), neoadjuvant therapy completion rate, surgical resection rate, and surgical delay rate. Differences between the NICRT and NICT groups were also analyzed.

A total of 38 studies qualified for the analysis. The pooled pCR, MPR, and R0 resection rates were 30, 58, and 99%, respectively. The pCR and MPR in the NICRT vs. NICT group were 38% vs. 28% (p=0.078) and 67% vs. 57% (p=0.181), respectively. The pooled incidence of grade ≥ 3 TRAEs was 24% (NICRT,58%, I² = 61% vs. NICT,18%, I² = 79%; p<0.001). In addition, the pooled neoadjuvant therapy completion and surgical resection rates were 92% and 85%, respectively; the difference was not statistically significant between the NICRT and NICT groups.

Neoadjuvant immunotherapy combined with chemoradiotherapy or chemotherapy is effective and safe in the short term for locally advanced esophageal cancer. However, further randomized trials are needed to confirm which combined model is more favorable.

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021284266, identifier CRD42021284266.

A considerable number of clinical trials of neoadjuvant immunotherapy for patients with resectable esophageal cancer are emerging. However, systematic evaluations of these studies are lacking.

To provide state-of-the-art evidence and normative theoretical support for neoadjuvant immunotherapy for locally advanced resectable esophageal cancer.

PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched for relevant original articles and conference proceedings that were published in English through April 1, 2022.

Published phase 2 or 3 clinical trials that included patients with resectable stage I to IV esophageal cancer who received immune checkpoint inhibitors (ICIs) before surgery as monotherapy or in combination with other therapies.

The Preferred Reporting Items for Systematic Reviews and Meta-analyses and the Meta-analysis of Observational Studies in Epidemiology guidelines for meta-analysis were followed to extract data. A random-effects model was adopted if the heterogeneity was significant (I2 statistic >50%); otherwise, the common-effects model was used. Data analyses were conducted from April 2 to 8, 2022.

Pathological complete response (pCR) rate and major pathological response (MPR) rate were considered to be the primary outcomes calculated for the clinical outcomes of neoadjuvant immunotherapy. Incidence of treatment-related severe adverse events was set as the major measure for the safety outcome. The rate of R0 surgical resection was summarized. Subgroup analyses were conducted according to histologic subtype and ICI types.

A total of 27 clinical trials with 815 patients were included. Pooled rates were 31.4% (95% CI, 27.6%-35.3%) for pCR and 48.9% (95% CI, 42.0-55.9%) for MCR in patients with esophageal cancer. In terms of safety, the pooled incidence of treatment-related severe adverse events was 26.9% (95% CI, 16.7%-38.3%). Most patients achieved R0 surgical resection (98.6%; 95% CI, 97.1%-99.6%). Regarding histologic subtypes, the pooled pCR rates were 32.4% (95% CI, 28.2%-36.8%) in esophageal squamous cell carcinoma and 25.2% (95% CI, 16.3%-35.1%) in esophageal adenocarcinoma. The pooled MPR rate was 49.4% (95% CI, 42.1%-56.7%) in esophageal squamous cell carcinoma.

This study found that neoadjuvant immunotherapy with chemotherapy had promising clinical and safety outcomes for patients with resectable esophageal cancer. Randomized clinical trials with long-term follow-up are warranted to validate the findings and benefits of ICIs.

Toripalimab (Tuoyi™) is a selective, recombinant, humanized monoclonal antibody against programmed death protein 1 (PD-1) developed by Shanghai Junshi Bioscience Co., Ltd. Toripalimab is able to bind to PD-1 and block the interaction with its ligands. The binding of toripalimab to PD-1 is mainly attributed to the heavy chain of the former and the FG loop of the latter. Toripalimab received a conditional approval in China for the treatment of melanoma (second-line) in December, 2018. It has also received approvals to treat nasopharyngeal carcinoma (first-line and third-line) and urothelial carcinoma (second-line) in 2021. Additionally, several orphan drug designations were granted to toripalimab by the US Food and Drug Administration. Toripalimab has exhibited primary anti-tumor effects in tumors such as melanoma, lung cancer, digestive tract tumors, hepatobiliary and pancreatic tumors, neuroendocrine neoplasms, nasopharyngeal carcinoma and urothelial carcinoma. It showed a satisfactory anti-tumor effect and long-term survival benefits in Chinese melanoma patients, while the combination of axitinib with toripalimab exhibited an impressive result in metastatic mucosal melanoma. As a checkpoint inhibitor, toripalimab was generally well-tolerated in the enrolled patients. Due to different study populations, comparisons could not be made directly between toripalimab and other drugs in most cases. Nevertheless, the introduction of toripalimab may offer a valuable choice for decision-making in the treatment of tumors in the future.