Immunotherapy for esophageal cancer:Where are we now and where can we go

Immune checkpoint inhibitor therapy has dramatically improved patient prognosis,and thereby transformed the treatment in various cancer types including esophageal squamous cell carcinoma(ESCC)in the past decade.Monoclonal antibodies that selectively inhibit programmed cell death-1(PD-1)activity has now become standard of care in the treatment of ESCC in metastatic settings,and has a high expectation to provide clinical benefit during perioperative period.Further,anti-cytotoxic T-lymphocyte–associated protein 4(CTLA-4)monoclonal antibody has also been approved in the treatment of recurrent/metastatic ESCC in combination with anti-PD-1 antibody.Well understanding of the existing evidence of immune-based treatments for ESCC,as well as recent clinical trials on various combinations with chemotherapy for different clinical settings including neoadjuvant,adjuvant,and metastatic diseases,may provide future prospects of ESCC treatment for better patient outcomes.

Present situation and prospect of immunotherapy for unresectable locally advanced esophageal cancer during peri-radiotherapy

Four major studies(Checkmate577,Keynote-590,Checkmate649 and Attraction-4)of locally advanced esophageal cancer published in 2020 have established the importance of immunotherapy,represented by anti-programmed death protein(PD)-1 in postoperative adjuvant treatment and advanced first-line treatment of locally advanced or advanced esophageal cancer and esophagogastric junction cancer,from the aspects of proof of concept,long-term survival,overall survival rate and progression-free survival.For unresectable or inoperable nonmetastatic esophageal cancer,concurrent radiotherapy and chemotherapy is the standard treatment recommended by various guidelines.Because its curative effect is still not ideal,it is necessary to explore radical radiotherapy and chemotherapy in the future,and it is considered to be promising to combine them with immunotherapeutic drugs such as anti-PD-1.This paper mainly discusses how to combine radical concurrent radiotherapy and chemotherapy with immunotherapy for unresectable local advanced esophageal cancer.

Advances in radiotherapy in the treatment of esophageal cancer

Recent advancements in radiotherapy for esophageal cancer have significantly improved treatment outcomes and patient quality of life.Traditional radiotherapy techniques have been enhanced by the integration of advanced imaging and precision targeting technologies,such as intensity-modulated radiotherapy and proton therapy,which allow for more accurate tumor targeting while minimizing damage to surrounding healthy tissues.Additionally,combining radiotherapy with immunotherapy has shown promising results,leveraging the body’s im-mune response to enhance the effectiveness of cancer treatment.Studies have also highlighted the benefits of neoadjuvant chemoradiation followed by surgical resection,which has been associated with improved overall survival rates com-pared to radiotherapy alone.These innovations are paving the way for more effe-ctive and personalized treatment strategies,offering new hope for patients with esophageal cancer.

Mechanisms of tumor immunosuppressive microenvironment formation in esophageal cancer

As a highly invasive malignancy,esophageal cancer(EC)is a global health issue,and was the eighth most prevalent cancer and the sixth leading cause of cancerrelated death worldwide in 2020.Due to its highly immunogenic nature,emerging immunotherapy approaches,such as immune checkpoint blockade,have demonstrated promising efficacy in treating EC;however,certain limitations and challenges still exist.In addition,tumors may exhibit primary or acquired resistance to immunotherapy in the tumor immune microenvironment(TIME);thus,understanding the TIME is urgent and crucial,especially given the importance of an immunosuppressive microenvironment in tumor progression.The aim of this review was to better elucidate the mechanisms of the suppressive TIME,including cell infiltration,immune cell subsets,cytokines and signaling pathways in the tumor microenvironment of EC patients,as well as the downregulated expression of major histocompatibility complex molecules in tumor cells,to obtain a better understanding of the differences in EC patient responses to immunotherapeutic strategies and accurately predict the efficacy of immunotherapies.Therefore,personalized treatments could be developed to maximize the advantages of immunotherapy.

Endoscopic submucosal dissection for superficial esophageal neoplasms

Endoscopic submucosal dissection(ESD) is currently accepted as the major treatment modality for superficial neoplasms in the gastrointestinal tract including the esophagus.An important advantage of ESD is its effectiveness in resecting lesions regardless of their size and severity of fibrosis.Based on excellent outcomes for esophageal neoplasms with a small likelihood of lymph node metastasis,the number of ESD candidates has increased.On the other hand,ESD still requires highly skilled endoscopists due to technical difficulties.To avoid unnecessary complications including perforation and postoperative stricture,the indications for ESD require careful consideration and a full understanding of this modality.This article,in the highlight topic series,provides detailed information on the indication,procedure,outcome,complications and their prevention in ESD of superficial esophageal neoplasms.

Endoscopic submucosal tunnel dissection for largesuperficial esophageal squamous cell neoplasms

Endoscopic submucosal dissection(ESD)is a wellestablished treatment for superficial esophageal squamous cell neoplasms(SESCNs)with no risk of lymphatic metastasis.However,for large SESCNs,especially when exceeding two-thirds of the esophageal circumference,conventional ESD is time-consuming and has an increased risk of adverse events.Based on the submucosal tunnel conception,endoscopic submucosal tunnel dissection(ESTD)was first introduced by us to remove large SESCNs,with excellent results.Studies from different centers also reported favorable results.Compared with conventional ESD,ESTD has a more rapid dissection speed and R0 resection rate.Currently in China,ESTD for large SESCNs is an important part of the digestive endoscopic tunnel technique,as is peroral endoscopic myotomy for achalasia and submucosal tunnel endoscopic resection for submucosal tumors of the muscularis propria.However,not all patients with SESCNs are candidates for ESTD,and postoperative esophageal strictures should also be taken into consideration,especially for lesions with a circumference greater than three-quarters.In this article,we describe our experience,review the literature of ESTD,and provide detailed information on indications,standard procedures,outcomes,and complications of ESTD.

Short term results of endoscopic submucosal dissection in superficial esophageal squamous cell neoplasms

AIM: To evaluate the efficacy of endoscopic submucosal dissection for superficial esophageal squamous cell neoplasms. METHODS: Between July 2007 and March 2009, 27 consecutive superficial esophageal squamous cell neoplasms in 25 enrolled patients were treated by endoscopic submucosal dissection. The therapeutic efficacy, complications, and follow-up results were assessed. RESULTS: The mean size of the lesions was 21 ± 13 mm (range 2-55 mm); the mean size of the resection specimens was 32 ± 12 mm (range 10-70 mm). The enblock resection rate was 100% (27/27), and en block resection with tumor-free lateral/basal margins was 88.9% (24/27). Perforation occurred in 1 patient who was managed by conservative medical treatments. None of the patients developed local recurrence or distant metastasis in the follow-up period. CONCLUSION: Endoscopic submucosal dissection is applicable to superficial esophageal squamous cell neoplasms with promising results.

Endoscopic submucosal dissection for superficial esophageal squamous cell neoplasms

Endoscopic resection is an effective treatment for noninvasive esophageal squamous cell neoplasms(ESCNs).Endoscopic mucosal resection(EMR)has been developed for small localized ESCNs as an alternative to surgical therapy because it shows similar effectiveness and is less invasive than esophagectomy.However,EMR is limited in resection size and therefore piecemeal resection is performed for large lesions,resulting in an imprecise histological evaluation and a high frequency of local recurrence.Endoscopic submucosal dissection(ESD)has been developed in Japan as one of the standard endoscopic resection techniques for ESCNs.ESD enables esophageal lesions,regardless of their size,to be removed en bloc and thus has a lower local recurrence rate than EMR.The development of new devices and the establishment of optimal strategies for esophageal ESD have resulted in fewer complications such as perforation than expected.However,esophageal stricture after ESD may occur when the resected area is larger than three-quarters of the esophageal lumen or particularly when it encompasses the entire circumference;such a stricture requires multiple sessions of endoscopic balloon dilatation.Recently,oral prednisolone has been reported to be useful in preventing post-ESD stricture.In addition,a combination of chemoradiotherapy(CRT)and ESD might be an alternative therapy for submucosal esophageal cancer that has a risk of lymph node metastasis because esophagectomy is extremely invasive;CRT has a higher local recurrence rate than esophagectomy but is less invasive.ESD is likely to play a central role in the treatment of superficial esophageal squamous cell neoplasms in the future.

Endoscopic submucosal dissection for early esophageal neoplasms using the stag beetle knife

AIM To determine short-and long-term outcomes of endoscopic submucosal dissection(ESD) using the stag beetle(SB) knife, a scissor-shaped device.METHODS Seventy consecutive patients with 96 early esophageal neoplasms, who underwent ESD using a SB knife at Kure Medical Center and Chugoku Cancer Center, Japan, between April 2010 and August 2016, were retrospectively evaluated. Clinicopathological characteristics of lesions and procedural adverse events were assessed. Therapeutic success was evaluated on the basis of en bloc, histologically complete, and curative or non-curative resection rates. Overall and tumor-specific survival, local or distant recurrence, and 3-and 5-year cumulative overall metachronous cancer rates were also assessed.RESULTS Eligible patients had dysplasia/intraepithelial neoplasia(22%) or early cancers(squamous cell carcinoma, 78%). The median procedural time was 60 min and on average, the lesions measured 24 mm in diameter, yielding 33-mm tissue defects. The en bloc resection rate was 100%, with 95% and 81% of dissections deemed histologically complete and curative, respectively. All procedures were completed without accidental incisions/perforations or delayed bleeding. During follow-up(mean, 35 ± 23 mo), no local recurrences or metastases were observed. The 3-and 5-year survival rates were 83% and 70%, respectively, with corresponding rates of 85% and 75% for curative resections and 74% and 49% for noncurative resections. The 3-and 5-year cumulative rates of metachronous cancer in the patients with curative resections were 14% and 26%, respectively.CONCLUSION ESD procedures using the SB knife are feasible, safe, and effective for treating early esophageal neoplasms, yielding favorable short-and long-term outcomes.

Risk factors for Mallory-Weiss Tear during endoscopic submucosal dissection of superficial esophageal neoplasms

BACKGROUND Adverse events during endoscopic submucosal dissection(ESD)of superficial esophageal neoplasms,such as perforation and bleeding,have been welldocumented.However,the Mallory-Weiss Tear(MWT)during esophageal ESD remains under investigation.AIM To investigate the incidence and risk factors of the MWT during esophageal ESD.METHODS From June 2014 to July 2017,patients with superficial esophageal neoplasms who received ESD in our institution were retrospectively analyzed.The clinicopathological characteristics of the patients were collected.Patients were divided into an MWT group and non-MWT group based on whether MWT occurred during ESD.The incidence of MWTs was determined,and the risk factors for MWT were then further explored.RESULTS A total of 337 patients with 373 lesions treated by ESD were analyzed.Twenty patients developed MWTs during ESD(5.4%).Multivariate analysis identified that female sex(OR=5.36,95%CI:1.47-19.50,P=0.011)and procedure time longer than 88.5 min(OR=3.953,95%CI:1.497-10.417,P=0.005)were independent risk factors for an MWT during ESD.The cutoff value of the procedure time for an MWT was 88.5 min(sensitivity,65.0%;specificity,70.8%).Seven of the MWT patients received endoscopic hemostasis.All patients recovered satisfactorily without surgery for the laceration.CONCLUSION The incidence of MWTs during esophageal ESD was much higher than expected.Although most cases have a benign course,fatal conditions may occur.We recommend inspection of the stomach during and after the ESD procedure for timely management in cases of bleeding MWTs or even perforation outside of the procedure region.

Perioperative immunotherapy for esophageal squamous cell carcinoma:Now and future

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 secondand 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.

Role of ferroptosis in esophageal cancer and corresponding immunotherapy

Esophageal cancer(EC)is one of the most common digestive system malignancies in the world.The combined modality treatment of EC is usually surgery and radiation therapy,however,its clinical efficacy for advanced patients is relatively limited.Ferroptosis,a new type of iron-dependent programmed cell death,is different from apoptosis,necrosis and autophagy.In recent years,many studies have further enlightened that ferroptosis plays an essential role in the occurrence,development and metastasis of tumors.Targeting ferroptosis stimulates a new direction for further exploration of oncologic treatment regimens.Furthermore,ferroptosis has a critical role in the immune microenvironment of tumors.This paper reviews the mechanism of ferroptosis and the ferroptosis research progress in the treatment of EC.We further elaborate the interaction between ferroptosis and immunotherapy,and the related mechanisms of ferroptosis participation in the immunotherapy of EC,so as to provide new directions and ideas for the treatment of EC.

Prognosis value of heat-shock proteins in esophageal and esophagogastric cancer:A systematic review and meta-analysis

BACKGROUND Heat shock proteins(HSPs)are molecular chaperones that play an important role in cellular protection against stress events and have been reported to be overex-pressed in many cancers.The prognostic significance of HSPs and their regulatory factors,such as heat shock factor 1(HSF1)and CHIP,are poorly understood.AIM To investigate the relationship between HSP expression and prognosis in esophageal and esophagogastric cancer.METHODS A systematic review was conducted in accordance with PRISMA recommend-ations(PROSPERO:CRD42022370653),on Embase,PubMed,Cochrane,and LILACS.Cohort,case-control,and cross-sectional studies of patients with eso-phagus or esophagogastric cancer were included.HSP-positive patients were compared with HSP-negative,and the endpoints analyzed were lymph node metastasis,tumor depth,distant metastasis,and overall survival(OS).HSPs were stratified according to the HSP family,and the summary risk difference(RD)was calculated using a random-effect model.RESULTS The final selection comprised 27 studies,including esophageal squamous cell carcinoma(21),esophagogastric adenocarcinoma(5),and mixed neoplasms(1).The pooled sample size was 3465 patients.HSP40 and 60 were associated with a higher 3-year OS[HSP40:RD=0.22;95%confidence interval(CI):0.09-0.35;HSP60:RD=0.33;95%CI:0.17-0.50],while HSF1 was associated with a poor 3-year OS(RD=-0.22;95%CI:-0.32 to-0.12).The other HSP families were not associated with long-term survival.HSF1 was associated with a higher probability of lymph node metastasis(RD=-0.16;95%CI:-0.29 to-0.04).HSP40 was associated with a lower probability of lymph node dissemination(RD=0.18;95%CI:0.03-0.33).The expression of other HSP families was not significantly related to tumor depth and lymph node or distant metastasis.CONCLUSION The expression levels of certain families of HSP,such as HSP40 and 60 and HSF1,are associated with long-term survival and lymph node dissemination in patients with esophageal and esophagogastric cancer.

Importance of early detection of esophageal cancer before the tumor progresses too much for effective treatment

This editorial comments on an article by Qu et al published in the World Journal of Gastrointestinal Oncology.It focuses on the importance of early detection of esophageal cancer,including recurrence or secondary malignancy after chemoradiotherapy(CRT).Endoscopic resection is the first choice for treatment for esophageal cancer remaining within the mucous membrane,while surgery or radical CRT are treatment options for advanced stages depending on the patient’s general condition and desire.Although these treatments are potentially curative,they are more invasive than endoscopic resection.Early-stage esophageal cancer is often asymptomatic and difficult to detect.Uniform periodic endoscopy is unrealistic.Although less burdensome tests exist,including liquid biopsy and urinary biomarkers,these have not yet been widely used in clinical practice.Early detection is important after radical CRT because the local recurrence rate is higher than that after surgery.However,endoscopic resection or photodynamic therapy is indicated if detected in the early stages,and positive results have been reported.Early detection of esophageal cancer is crucial.Endoscopy is the main diagnostic method;however,new and less burdensome methods should be established to ensure early treatment for patients with esophageal cancer.

Sporadic gastrinoma with refractory benign esophageal stricture:A case report

BACKGROUND Gastrinoma is characterized by an excessive release of gastrin,leading to hypersecretion of gastric acid,subsequently resulting in recurrent peptic ulcers,chronic diarrhea,and even esophageal strictures.This case report aims to improve awareness and facilitate early diagnosis and treatment of gastrinoma by presenting a rare case of gastrinoma with refractory benign esophageal stricture(RBES).Additionally,it highlights the persistent challenges that gastroenterologists encounter in managing RBES.CASE SUMMARY This case demonstrates a patient with gastrinoma who developed RBES and complete esophageal obstruction despite management with maximal acid suppressive therapy,multiple endoscopic bougie dilations and endoscopic incisional therapy(EIT).CONCLUSION It is essential to diagnose gastrinoma as early as possible,as inadequately controlled acid secretion over an extended period increases the risk of developing severe esophageal strictures.In patients with esophageal strictures causing complete luminal obstruction,blind reopening EIT presents challenges and carries a high risk of perforation.

Advancements and challenges in the treatment of esophageal cancer:A comprehensive review

Esophageal cancer(EC)is an aggressive malignancy with a poor prognosis,ranking seventh in incidence and sixth cancer-related deaths globally.EC is classified in two main types,the esophageal squamous cell carcinoma(ESCC)and esophageal adenocarcinoma(EAC),with ESCC being more common in Eastern Europe,South Asia,and Africa,while EAC is prevalent in Western Europe and North America.Molecular analysis identifies three subgroups of ESCC,each with distinct genetic mutations and treatment responses.Early-stage EC is often difficult to detect,leading to late-stage diagnoses that necessitate systemic drug therapies,including molecular-targeted therapies and immunotherapies.Immunotherapy,particularly immune checkpoint inhibitor,has shown promising results in improving survival rates for metastatic or persistent EC.It is particularly important to target to multidisciplinary combination therapies,integrating surgery,chemoradiotherapy,targeted therapy and immunotherapy.Additionally,radioimmunotherapy is being explored for its potential to enhance treatment efficacy,especially in advanced and metastatic tumors.However,the pathological complete response rate to neoadjuvant chemoradiotherapy remains suboptimal,highlighting the need for novel treatment strategies.Future research should focus on optimizing treatment combinations and identifying predictive biomarkers to improve clinical outcomes for EC patients.

Combination of concurrent endoscopic submucosal dissection and modified peroral endoscopic myotomy for an achalasia patient with synchronous early esophageal neoplasms

with an increased risk for developing esophageal squamous cell carcinoma. In our paper, we introduced an achalasia patient combined with synchronous early esophageal neoplasms. We performed a combination of concurrent endoscopic submucosal dissection (ESD) and peroral endoscopic myotomy (POEM). No complications other than postoperative pain that needed morphine treatment for two days had occurred. Dysphagia was significantly improved. Neither reflux nor cough occurred. The short-term efficacy and safety of our case is favorable and suggests that concurrent ESD and POEM could be a treatment option to such patients.

Concordance between four PD-L1 immunohistochemical assays and 22C3 pharmDx assay in esophageal squamous cell carcinoma in a multicenter study

Background:The prediction of response to immunotherapy mostly depends on the programmed death-ligand 1(PD-L1)immunohistochemistry(IHC)status,and the 22C3 pharmDx assay has been approved in esophageal squamous cell carcinoma(ESCC).However,the widespread use of the 22C3 pharmDx assay is limited due to its availability.Thus,alternative PD-L1 assays are needed.We aimed to investigate the analytical and clinical diagnostic performances of four PD-L1 assays and to compare their concordances with the 22C3 pharmDx assay.Methods:The PD-L122C3 pharmDx assay was performed on the Dako Autostainer Link 48 platform,three testing assays(PD-L1 E1L3N XP antibody[Ab],PD-L1 BP6099 Ab and PD-L1 CST E1L3N Ab)on the Leica BOND-MAX/III platform,and one testing assay(PD-L1 MXR006 Ab)on the Roche VENTANA Benchmark Ultra platform.A total of 218 ESCC cases from four centers were included in this retrospective study.Professionals from each center stained and read the IHC slides independently and determined the combined positive score(CPS)and the tumor proportion score(TPS).Results:Regarding analytical performance,the four testing assays demonstrated good correlations with the 22C3 pharmDx assay when evaluated by the TPS or CPS(𝜌>0.8 for all four assays).Regarding diagnostic performance(CPS≥10 was used as the cutoff),the four testing assays showed moderate concordances with the 22C3 pharmDx assay(kappa>0.7 for all four assays).The overall percent agreements between each testing assay and the 22C3 pharmDx assay was at least 87.2%.Conclusion:This study provides insight into the potential interchangeability of the four PD-L1 assays with the 22C3 pharmDx assay.

Primary small cell esophageal carcinoma,chemotherapy sequential immunotherapy:A case report

BACKGROUND Primary small cell esophageal carcinoma(PSCEC)is aggressive and rare,with a worse prognosis than other subtypes esophageal carcinoma.No definitive and optimum standard guidelines are established for treating it.Herein,we report a case of PSCEC,including a current literature review of PSCEC.CASE SUMMARY A 79-year-old male was diagnosed PSCEC with multiple lymph node metastasis thorough computed tomography,positron emission tomography-computed tomography,endoscopy and pathology.Surgery was not suitable for this patient.He was treated with etoposide 100 mg/m2 and cisplatin 25 mg/m2 on days 1-3,every 3 wk for 4 cycles.The tumor and lymph nodes became smaller and dysphagia and vomiting symptoms improved.The patient could not tolerate subsequent chemotherapy(CT)because of hematological toxicity;therefore,we performed immunotherapy(durvalumab,1500 mg)every 4 wk.At present the patient has received 12 cycles immunotherapy over about 1 year.He is still receiving treatment and follow-up.CONCLUSION PSCEC with multiple lymph nodes metastasis does not always indicate surgery.CT may extend survival time and improve the quality of life in the absence of surgery.Immunotherapy or immunotherapy plus CT may also work as a treatment for PSCEC.

Evaluating the predictive value of endoscopic findings for residual colorectal cancer following neoadjuvant combination immunotherapy

BACKGROUND Endoscopy allows for the direct observation of primary tumor characteristics and responses after neoadjuvant treatment.However,reports on endoscopic evaluation following neoadjuvant immunotherapy remain limited.AIM To examine the predictive value of endoscopic findings of primary tumors for responses to neoadjuvant immunotherapy.METHODS This retrospective study,conducted at a tertiary center in China,evaluated 74 patients with colorectal cancer,including 17 with deficient mismatch repair(dMMR)and 15 with proficient mismatch repair(pMMR)tumors.Patients underwent neoadjuvant immunotherapy followed by surgery.Endoscopic findings before and after neoadjuvant immunotherapy were reviewed and compared with the pathology of the resected specimens.RESULTS In the pMMR group(n=57 evaluable patients),endoscopy identified 11/17 patients who achieved a complete response(CR),while misidentifying 1/40 patients with residual disease as CR(64.7%vs 2.5%,P<0.01).Conversely,22/40 patients with residual disease were accurately identified as achieving a partial response(PR),with 1/17 patients who achieved CR misclassified as PR(55.0%vs 5.9%,P<0.01).The sensitivity,specificity,and accuracy of endoscopic diagnosis for pathological CR were 64.7%,97.5%,and 87.7%,respectively.In the dMMR cohort,endoscopy classified 9/17 patients as CR and 2 of the remaining patients with residual tumors as PR(64.3%vs 66.7%,P=0.73).The method demonstrated 100%sensitivity and 82.4%accuracy in diagnosing pathological CR.CONCLUSION Endoscopic evidence of CR or PR was well correlated with postoperative pathological outcomes in the pMMR cohort.Despite endoscopic indications of tumor residue,a complete pathological response post-surgery was possible in the dMMR cohort.