As immunotherapy rises to prominence in cancer treatment, the therapeutic approach to esophageal cancer is undergoing significant transformations. This review emphasizes the necessity and optimization pathways for adjuvant postoperative radiotherapy after neoadjuvant therapy in patients with esophageal cancer in the immunotherapy era. Initially, we review the advancements in neoadjuvant treatment strategies. Subsequently, we evaluate the role of postoperative radiotherapy and the latest advancements in radiotherapy target volume definition and dose optimization following neoadjuvant therapy, as well as the implications of tumor immunotherapy on postoperative radiotherapy strategies. In conclusion, in the new era of immunotherapy, postoperative radiotherapy following neoadjuvant therapy for esophageal cancer holds significant value. Optimization strategies should follow individualized treatment principles and comprehensively consider tumor biology, patient status, and treatment resources to achieve optimal therapeutic outcomes and quality of life, thereby driving continuous innovation in esophageal cancer treatment.

Tumor metabolism has emerged as a critical target in cancer therapy, revolutionizing our understanding of how cancer cells grow, survive, and respond to treatment. Historically, cancer research focused on genetic mutations driving tumorigenesis, but in recent decades, metabolic reprogramming has been recognized as a hallmark of cancer. The TP53 inducible glycolysis and apoptosis regulator, or TIGAR, affects a wide range of cellular and molecular processes and plays a key role in cancer cell metabolism by regulating the balance between glycolysis and antioxidant defense mechanisms. Cancer cells often exhibit a shift towards aerobic glycolysis (the Warburg effect), which allows rapid energy production and gives rise to biosynthetic intermediates for proliferation. By inhibiting glycolysis, TIGAR can reduce the proliferation rate of cancer cells, particularly in early-stage tumors or specific tissue types. This metabolic shift may limit the resources available for rapid cell division, thereby exerting a tumor-suppressive effect. However, this metabolic shift also leads to increased levels of reactive oxygen species (ROS), which can damage the cell if not properly managed. TIGAR helps protect cancer cells from excessive ROS by promoting the pentose phosphate pathway (PPP), which generates NADPH-a key molecule involved in antioxidant defense. Through its actions, TIGAR decreases the glycolytic flux while increasing the diversion of glucose-6-phosphate into the PPP. This reduces ROS levels and supports biosynthesis and cell survival by maintaining the balance of nucleotides and lipids. The role of TIGAR has been emerging as a prognostic and potential therapeutic target in different types of cancers. This review highlights the role of TIGAR in different types of cancer, evaluating its potential role as a diagnostic marker and a therapeutic target.

Neoadjuvant chemotherapy with docetaxel, cisplatin plus 5-FU (DCF) has become the new standard of care for locally advanced esophageal squamous cell carcinoma (ESCC). In a real-world setting, the efficacy, recurrence, and adverse events (AEs) remain unclear.

This retrospective cohort study included 86 patients who received neoadjuvant DCF followed by esophagectomy for resectable ESCC.

Following neoadjuvant DCF treatment, 75 patients underwent R0 curative resection. At the median follow-up of 19.2 months, the median disease-free survival (DFS)/recurrence-free survival (RFS) was not yet reached, with estimated 3-year DFS/RFS rates of 65.2%, respectively. The incidence of primary tumor regression grading (TRG) grade 1a and pathological complete response (pCR) were 21.3% (16/75) and 14.7% (11/75), respectively. The estimated 1-year DFS/RFS rates were 93.8% for primary TRG grade 1a and 100% for pCR. Baseline elevated serum SCC-antigen levels were inversely associated with achieving primary TRG grade 1a or pCR. In 64 patients who did not achieve pCR, residual tumor cells in the lymph nodes (ypN; HR, 16.96; 95% CI, 2.11-136.12; P < 0.01) and Glasgow prognostic score (GPS; HR, 8.34; 95% CI, 1.73-40.31; P < 0.01) were independent predictors of shorter DFS/RFS. The most common grade ≥ 3 AEs were neutropenia (61.6%) and febrile neutropenia (26.7%), which were not associated with clinicopathological factors. The most common non-hematological AEs were appetite loss (9.3%), pulmonary embolism (8.1%), diarrhea (7.0%), and nausea (2.3%). Nine patients discontinued neoadjuvant DCF due to toxicities.

Neoadjuvant DCF was effective and well-tolerated in real-world ESCC patients. Primary TRG grade 1a or pCR showed a favorable DFS/RFS, while positive ypN and GPS were independent risk factors for worse DFS/RFS.

It remains unclear whether the lymph-node ratio (LNR) is a relevant factor for the risk of recurrence following neoadjuvant chemotherapy (nCT) with docetaxel, cisplatin, and 5-fluorouracil (DCF), which is a new standard of care for locally advanced esophageal squamous cell carcinoma (ESCC) in Japan. This study aimed to evaluate the clinical utility of LNR as a risk factor for recurrence.

We retrospectively analyzed 75 patients who underwent nCT-DCF followed by curative surgery for resectable ESCC. The cut-off for the LNR was determined using receiver-operating characteristic curve analysis for recurrence.

A higher LNR was observed in 34 (45.3%) patients. At a median follow-up of 19.2 months, the median disease-free survival (DFS)/recurrence-free survival (RFS) rate was not reached in patients with a lower LNR and was 8.0 months in those with a higher LNR (P < 0.01). The estimated 1-year DFS/RFS rate was 47.8% and 100% for patients with a higher LNR and lower LNR, respectively. LNR remained a risk factor, even when stratified by non-pathological complete response, the presence of positive ypN, or ypStage III. In those with a higher LNR, the median DFS/RFS was 18.3 versus 8.0 months with and without adjuvant nivolumab treatment, respectively.

Higher LNR indicates a more aggressive phenotype with worse DFS/RFS rates and increased recurrence following nCT-DCF treatment and curative surgery for ESCC.

The efficacy of consolidation chemotherapy (CCT) following concurrent chemoradiotherapy (CCRT) has not been clearly defined in esophageal squamous cell carcinoma (ESCC). This study determined which patients with stage II-IVA ESCC benefitted from CCT.

351 patients with ESCC were retrospectively reviewed. 185 patients received CCRT alone and 166 received CCRT plus CCT. Subset analyses were conducted on all patients' characteristics. Factors associated with survival were analyzed using the Kaplan-Meier method and a Cox proportional hazards model. The Propensity score matching (PSM) technique was used to compensate for differences in patients' characteristics.

The median OS were 17.7 months and 38.4 months in the CCRT alone group and CCRT+CCT group (p = 0.002), respectively. Multivariable Cox regression analysis determined that CCT was associated with improved OS (p = 0.002, HR 0.592, 95% CI 0.423-0.829); After PSM, relative to the CCRT group, patients who received CCT experienced improved OS (17.7 months vs. 38.4 months, p = 0.0139). Subgroup analysis showed that CCT was more effective in radiation dose < 60 Gy (p = 0.002, HR 0.368, 95% CI 0.194-0.700). After matching between radiation dose, in the low dose cohort, the median OS was 13.2 months and 20.7 months in the CCRT alone group and CCRT+CCT group, respectively (p = 0.0028), the multivariate analysis results showed that CCT retained its statistical significance (p = 0.002, HR 0.353, 95% CI 0.183-0.681). In the high dose cohort, the median OS were 21.6 months and 23.6 months in the CCRT alone group and CCRT+CCT group, respectively (p = 0.5512).

We recommend that CCT treatment should be considered for ESCC patients who underwent CCRT using < 60 Gy. Further studies are needed to confirm these results.

Esophageal cancer (EC) continues to be a significant global health concern, with two main subtypes: esophageal squamous cell carcinoma and esophageal adenocarcinoma. Prevention and changes in etiology, improvements in early detection, and refinements in the treatment have led to remarkable progress in the outcomes of EC patients in the past two decades. This seminar provides an in-depth analysis of advances in the epidemiology, disease biology, screening, diagnosis, and treatment landscape of esophageal cancer, focusing on the ongoing debate surrounding multimodality therapy. Despite significant advancements, EC remains a deadly disease, underscoring the need for continued research into early detection methods, understanding the molecular mechanisms, and developing effective treatments.

In the Western hemisphere, nonmetastatic locally advanced esophageal carcinoma is mostly treated in multimodal therapy protocols according to current therapy guidelines. In squamous cell carcinoma of the esophagus, neoadjuvant chemoradiation is the favorable option. Unimodal surgical and chemoradiation treatment alternatives show inferior results on this entity. For locally advanced adenocarcinoma of the esophagus perioperative chemotherapy and neoadjuvant chemoradiation have been competing treatment approaches in the recent past. Both are evidence based (class I evidence) and superior compared to unimodal surgery. However, the latest results of head-to-head comparative therapy studies show superior overall survival results for the FLOT regimen of perioperative chemotherapy. Furthermore, immunotherapy and targeted therapy with monoclonal antibodies have become a strong focus of current clinical research. Nivolumab as well as trastuzumab are already an important part of the current standard therapies. In both entities - SCC and AC - a significant quota of patients shows a locoregional complete remission of the tumor in the specimen after modern neoadjuvant therapy and surgical resection. The addition of immunotherapy and targeted therapy to neoadjuvant therapy further increases complete remission rates in defined subgroups according to the results of current studies. Currently, three prospective randomized trials are ongoing on the subject of future possibilities for organ-preserving concepts in case of complete clinical remission ("surgery as needed," "watch and wait"). It is to be expected for the future that curative short-term and long-term treatment results in locally advanced esophageal carcinoma will significantly improve, particularly due to the additional possibilities of immunotherapy and organ-preserving therapy concepts in postneoadjuvant complete remission.

Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies.

Purpose: We constructed a prediction model to predict a 2-year locoregional recurrence based on the clinical features and radiomic features extracted from the machine learning method using computed tomography (CT) before definite chemoradiotherapy (dCRT) in locally advanced esophageal cancer. Patients and methods: A total of 264 patients (156 in Beijing, 87 in Tianjin, and 21 in Jiangsu) were included in this study. All those locally advanced esophageal cancer patients received definite radiotherapy and were randomly divided into five subgroups with a similar number and divided into training groups and validation groups by five cross-validations. The esophageal tumor and extratumoral esophagus were segmented to extract radiomic features from the gross tumor volume (GTV) drawn by radiation therapists before radiotherapy, and six clinical features associated with prognosis were added. T stage, N stage, M stage, total TNM stage, GTV, and GTVnd volume were included to construct a prediction model to predict the 2-year locoregional recurrence of patients after definitive radiotherapy. Results: A total of 264 patients were enrolled from August 2012 to April 2018, with a median age of 62 years and 81% were males. The 2-year locoregional recurrence rate was 52.6%, and the 2-year overall survival rate was 45.6%. About 66% of patients received concurrent chemotherapy. In total, we extracted 786 radiomic features from CT images and the Principal Component Analysis (PCA) method was used to screen out the maximum 30 features. Finally, the Support Vector Machine (SVM) method was used to construct the integrated prediction model combining radiomics and clinical features. In the five training groups for predicting locoregional recurrence, the mean value of C-index was 0.9841 (95%CI, 0.9809-0.9873), and in the five validation groups, the mean value was 0.744 (95%CI, 0.7437-0.7443). Conclusions: The integrated radiomics model could predict the 2-year locoregional recurrence after dCRT. The model showed promising results and could help guide treatment decisions by identifying high-risk patients and enabling strategies to prevent early recurrence.

Esophageal cancer is a major problem in India. The incidence has a geographic variation, being more common in some parts of south India and pockets in the north. The patients usually present in late stages as the symptoms are non-specific, hence patients are treated for other causes over prolonged periods. There has been marked improvement due to the incorporation of a multi-modality approach in the management of these cancers over the last decade.

This study included patients with non-metastatic esophageal cancer who presented to the department of medical oncology between January 2020 and December 2023. The aim was to analyze the clinical and demographic profiles and survival outcomes of patients.

This is a retrospective study conducted at a tertiary cancer care center in southern India, primarily serving patients from rural areas. Approval from the Institutional Ethics Committee was secured prior to the study (GSLMC/RC:1259A-EC/1259A-05/2024). Case files for all esophageal cancer patients treated at our center between January 2020 and December 2023 were collected from the medical records department and analyzed. We focused on patients diagnosed with non-metastatic esophageal cancer who had received treatment.

A total of 47 patients participated in our study, with a mean age of 55 years. The male-to-female ratio was 2:3. Among the participants, 18 (38.3%) were smokers and 12 (25.5%) were alcohol users. The most frequently affected site was the middle thoracic esophagus, with 22 patients (46.8%), followed by the lower third in 15 patients (31.9%), and both the upper one-third and gastroesophageal junction cancers each accounting for five patients (10.6%). Squamous cell carcinoma was the predominant histological type, representing 82% of cases. Stage 2 was the most common stage at presentation, seen in 22 patients (46.8%), followed by stage 3 in 17 patients (36.2%). Twenty patients received neoadjuvant chemoradiotherapy (NACRT), with 13 (65%) receiving a weekly regimen of paclitaxel and carboplatin, while seven (35%) were treated with a CAPEOX (capecitabine and oxaliplatin) regimen alongside radiation (41.4 to 45 Gray). Of these, only eight patients (40%) proceeded to surgery, while 12 patients (60%) did not. Among those who underwent surgery, five patients (62.5%) achieved a pathological complete response. Additionally, 24 patients received definitive CRT, resulting in a complete response in 14 patients (58.3%) and a partial response in 10 patients (41.6%). Three patients defaulted on treatment. The median overall survival for the analyzed group was 10.5 months, with a subset analysis showing that those who had surgery had a survival duration of 12 months, compared to eight months for those who did not undergo surgery.

The study concluded that the middle thoracic esophagus is the most prevalent site for esophageal cancer, with squamous cell carcinoma being the predominant histological type. Stage 2 is frequently observed at presentation, followed by stage 3. The standard treatment for locally advanced esophageal malignancies now involves a combined approach with NACRT. Despite advancements in multimodal treatments, the prognosis for esophageal cancer remains poor and requires significant improvement.

This phase II trial investigated the safety and efficacy of chemoradiotherapy (CRT) followed by immunochemotherapy (iCT) and surgery in unresectable locally advanced esophageal squamous cell carcinoma (ESCC).

Patients with unresectable locally advanced ESCC received radiotherapy (50 Gy/25f, 5 days/week) and nab-paclitaxel (100 mg on day 1/week) plus cisplatin (25 mg/m2 on day 1/week) for 5 weeks, followed by tislelizumab (200 mg on day 1/cycle) plus chemotherapy (nab-paclitaxel 150 mg/m2 and cisplatin 75 mg/m2 on day 2/cycle) for two 21-day cycles. Patients who converted to resectable underwent surgery 2 to 4 weeks afterward. The primary endpoint was a 1-year progression-free survival (PFS) rate.

Thirty patients were enrolled and underwent CRT (median follow-up: 21 months), of whom 24 received iCT. Twenty (66.7%) patients achieved resectability (R0: 95.2%; pathologic complete response: 65.0%; major pathologic response: 90.0%). One-year PFS and overall survival (OS) rates were 79.4% and 89.6%, respectively. The R0 resection group exhibited longer PFS (median, not reached vs. 8.4 months; HR = 0.28; 95% confidence interval, 0.08-0.84; P = 0.02) and OS (median, not reached vs. 19.2 months; HR = 0.18; 95% confidence interval, 0.04-0.73; P < 0.01) than the nonsurgery group. Grade 3 to 4 adverse events were observed in 11 (11/30, 36.7%) patients, and immune-related pneumonitis was observed in 5 (5/24, 20.8%) patients. Post-CRT minimal residual disease before surgery was associated with unfavorable PFS and OS.

Our study met the primary endpoint. Conversion CRT and subsequent iCT followed by surgery was a promising treatment strategy for unresectable locally advanced ESCC.

Several studies have shown that the survival outcomes of chemoradiotherapy (CRT) are not inferior to surgery alone in patients with esophageal squamous cell carcinoma (ESCC). This study aimed to compare survival outcomes of ESCC treated with immunochemotherapy (ICT) followed by surgery or definitive CRT and to explore subgroups of patients who could benefit from one treatment strategy.

Pooled data were obtained from two prospectively registered clinical trials of patients with ESCC at the Affiliated Cancer Hospital of Nanjing Medical University. One trial involved treatment with neoadjuvant ICT followed by surgery, while the other involved induction ICT followed by definitive CRT. To balance potential biases, we conducted an overlap weighting (OW) analysis to compare the rates of 2-year progression-free survival (PFS), locoregional relapse-free survival (LRRFS), distant relapse-free survival (DRFS), and overall survival (OS). Additionally, propensity score matching (PSM) was performed to analyze failure pattern.

The median follow-up time of the survivors was 39.3 months. After overlap weighting, the rates of 2-year PFS, LRRFS, DRFS, and OS for patients undergoing surgery and CRT were 61.5 % and 59.7 %, 67.2 % and 69.9 %, 81.3 % and 90.7 %, 84.6 % and 79.1 %, respectively (P>.05 for all). A trend for improved 2-year OS was observed in the surgery group in patients who did not respond to ICT (P=.07).

The differences in the rates of 2-year PFS, LRRFS, DRFS, and OS between the surgery group and the chemoradiotherapy group did not reach statistical significance.

Definitive chemoradiotherapy (dCRT) is a potentially curative therapy for esophageal cancer. As indications for dCRT differ widely, it is challenging to draw conclusions on outcomes and survival. The aim of this study was to evaluate overall survival (OS) and recurrence patterns according to indications for treatment. Patients who underwent dCRT (50.4 Gy concomitant with carboplatin/paclitaxel) for esophageal cancer between 2012 and 2022 were identified. Indications for dCRT were: cervical tumor, irresectable disease, unfit for surgery, and patient and/or physician preference. The primary endpoint was OS calculated with the Kaplan-Meier method. Secondary endpoints included the proportion of patients that completed the dCRT regimen, 30- and 90-day mortality, and disease recurrence. One hundred and fifty-seven patients were included (72.6% esophageal squamous cell carcinoma) with a median follow-up of 20 months (IQR 10.0-43.9). The full dCRT regimen was completed by 116 patients (73.9%). Thirty- and 90-day mortality were 2.5% and 8.3%, respectively. Median and 5-year OS for all patients were 22.9 months (95% CI 18.0-27.9) and 31.4%, respectively. The median OS per indication was 23.7 months (95% CI 6.5-40.8) for patients with cervical tumors, 10.9 months (95% 0.0-23.2) for irresectable disease, 28.2 months (95% CI 12.3-44.0) for unfit patients, and 22.9 months (95% CI 15.4-30.5) for patients' preference for dCRT (P = 0.11). Disease recurrence was observed in 74 patients (46%), located locoregionally (46%), distant (19%), or combined (35%). Patients who underwent dCRT had a 5-year OS of 31.4%, but OS differed according to indications for treatment with patients who had irresectable disease having the worst prognosis.

Existing clinical trials favor neoadjuvant chemoradiation therapy (NCRT) followed by surgery alone for locally advanced esophageal cancer (EC) and perioperative chemotherapy as the preferred modality for esophageal adenocarcinoma (EAC). However, it is unclear whether these trial findings are reflected in the patterns of care and survival outcomes among patients in the clinical setting.

To investigate survival outcomes in the clinical setting among patients with EC after various treatment modalities.

This retrospective cohort study examined data from the National Cancer Database maintained by the American College of Surgeons and focused on patients with clinical stage II or III EC, excluding those with gastroesophageal junction cancer, who underwent trimodality therapy (NCRT followed by esophagectomy), definitive chemoradiation therapy (DCRT), radiotherapy (RT) alone, or perioperative chemotherapy from January 2006 to December 2020. Analyses were conducted from December 2023 to August 2024.

Perioperative chemotherapy, trimodality therapy, DCRT, and single-modality RT.

A Cox proportional hazards regression model was used to compare overall survival (OS) between treatment groups in the entire cohort, among patients with squamous cell carcinoma or adenocarcinoma, and among those older than 65 years. Landmark survival analysis at 6 months was performed to reduce survivorship bias.

The study included 57 116 patients (median age, 64 [IQR, 57-72] years; 45 410 [79.5%] male); 21 619 patients (37.9%) received trimodality therapy, 32 493 (57.1%) received DCRT, 2692 (4.7%) received single-modality RT, and 312 (0.5%) received perioperative chemotherapy. In the overall study population, 37 698 patients (66.0%) had EAC, and of the 312 patients that received perioperative chemotherapy, 283 (90.7%) had EAC. In adjusted survival analysis, perioperative chemotherapy (adjusted hazard ratio [AHR], 0.33; 95% CI, 0.28-0.39; P <.001) and trimodality therapy (AHR, 0.45; 95% CI, 0.44-0.46; P < .001) were associated with improved OS compared with DCRT. In contrast, RT alone was associated with worse outcomes compared with DCRT (AHR, 1.37; 95% CI, 1.30-1.45; P < .001). The median OS for perioperative chemotherapy of 66.2 months (95% CI, 43.1-111.9 months; P < .001) was longer compared with that for DCRT alone (18.1 months; 95% CI, 17.8-18.4 months; P < .001). Trimodality therapy was associated with a median OS of 43.9 months (95% CI, 42.8-45.5 months; P < .001), which was shorter than that for perioperative chemotherapy but improved compared with DCRT and RT alone, which was associated with a median OS of 13.5 months (95% CI, 12.8-14.0 months; P < .001). In the subgroup of patients older than 65 years, those who received perioperative chemotherapy had longer median OS (56.7 months; 95% CI, 36.4-115.2 months; P < .001) compared with those receiving other treatment modalities (eg, trimodality therapy: 40.1 months; 95% CI, 38.1-42.0 months; P < .001). Patients who received RT alone had the worst median OS (13.6 months; 95% CI, 12.8-14.4 months; P < .001).

In this cohort study of patients with stage II to III EC, trimodality therapy was associated with improved OS compared with DCRT or RT alone for locally advanced EC and perioperative chemotherapy was associated with improved OS for adenocarcinoma.

NRG/RTOG 0436 evaluated cetuximab added to chemoradiation (CRT) for non-operative esophageal cancer management. PRO objectives assessed improvement in the FACT-Esophageal cancer subscale (ECS), version 4, with cetuximab, and if improved ECS correlated with clinical complete response (cCR).

Patients were randomized to cisplatin/paclitaxel/radiation ± cetuximab. Overall survival (OS) was the primary endpoint, with a 420 patient target, which also provided 82% power to detect ≥ 15 increase in the proportion of cetuximab patients with ECS improvement from baseline to 6-8 weeks post-CRT; α = 0.05, using a χ2 test. Improvement in ECS and its Swallowing and Eating Indices (SI, EI) was defined as 5, 4 and 2 point increases, respectively, from baseline to 6-8 weeks post-CRT. Univariate logistic regression assessed if cCR was associated with improved ECS.

This study was stopped early for not meeting a pre-specified OS endpoint and did not show survival benefit. Of 420 planned patients, 344 enrolled and 281 consented to PROs. ECS was completed by 261 (93%) at baseline, 173 (66%) 6-8 weeks post-CRT, and 117 (64%) at 1 year. At 6-8 weeks, patients receiving CRT + Cetuximab didn't have improved ECS; they experienced a lower proportion of improvement compared to standard CRT (37% vs. 53%; P = 0.04). The proportion of CRT patients with improvement in SI was 9% higher than with cetuximab, but not statistically significant (39% vs. 30%, P = 0.22). There was no association between treatment and EI. When examining ECS scores at 1 year by cCR vs. residual disease, a higher proportion of cCR patients improved, but not statistically significant (48% vs. 45%, P = 0.74).

The addition of cetuximab to CRT for the nonoperative management of esophageal cancer did not improve PROs.

The average five-year survival rate for esophageal cancer, a common malignant tumor of the digestive system, is barely 20%. The majority of esophageal squamous cell carcinoma (ESCC) patients had already progressed to a locally advanced or even advanced stage at initial diagnosis, making routine surgery ineffective. Chemotherapy and immunotherapy are important neoadjuvant treatments for ESCC, however, it remains unknown how treatment will affect the immunological microenvironment, especially at the spatial level. Here, we presented the TME characters of ESCC from the temporal and spatial dimensions using scRNA-seq and ST, investigated the changes of immune cell clusters in the TME under neoadjuvant chemotherapy and preoperative immunotherapy, and explored the potential mechanisms. It was found that compared with chemotherapy, immunotherapy combined with chemotherapy increased the level of T cell proliferation, partially restored the function of exhausted T cells, induced the expansion of specific exhausted CD8 T cells, increased the production of dendritic cells (DCs), and supported the immune hot microenvironment of the tumor. We also found that CD52 and ID3 have potential as biomarkers of ESCC. Particularly, CD52 may be served as a predictor of the efficacy to screen the advantaged population of different regimens. Through multiple pathways, CAF2 and CAF5's antigen-presenting role affected the other fibroblast clusters, resulting in malignant transformation. We analyzed the immune microenvironment differences between the two regimens to provide a more thorough description of the ESCC microenvironment profile and serve as a foundation for customized neoadjuvant treatment of ESCC.

Pembrolizumab plus cisplatin and 5-fluorouracil administered as first-line therapy for advanced esophageal cancer patients has shown a better objective response and survival than conventional chemotherapy with less severe hematological adverse events. The safety and efficacy of this regimen were evaluated in patients with T4b esophageal squamous cell carcinoma (ESCC).

Eight consecutive patients with T4b ESCC received this regimen according to KEYNOTE-590 as induction, and they were evaluated after 1-3 courses. The programmed death-ligand 1 (PD-L1) combined positive score (CPS) was also evaluated before chemotherapy. Efficacy for the primary lesion was evaluated by our original formula for the tumor reduction rate.

The numbers of patients with partial response (PR), stable disease, and progressive disease (PD) were 5, 1, and 2, respectively. The tumor reduction rate ranged from 69 to 87% in PR patients, and all PR patients had relief from T4b. Two patients underwent conversion surgery with R0 resection. PD-L1 CPS was over 90 in 2 PR patients, but under 10 in 2 other PR patients. PD-L1 CPS was under 10 in PD patients. One patient had hyperprogression, resulting in an esophago-pulmonary fistula. Greater than grade 3 adverse events were bleeding gastric ulcer in one patient (12.5%), neutropenia without G-CSF in 3 patients (37.5%), and hypopotassemia in 1 patient (12.5%). No patient had febrile neutropenia.

Marked tumor reduction was confirmed in 62.5% of patients with pembrolizumab plus cisplatin and 5-fluorouracil with less adverse events. This regimen could be administered as induction chemotherapy for patients with T4b ESCC.

Although esogastric cancers often affect patients over 75, there are no specific age-related guidelines for the care of these patients. Esogastric cancers have a poor prognosis and require multimodal treatment to obtain a cure. The morbidity and mortality of these multimodal treatments can be limited if care is optimized by selecting patients for neoadjuvant treatment and surgery. This can include a geriatric assessment, prehabilitation, renutrition, and more extensive use of minimally invasive surgery. Denutrition is frequent in these patients and is particularly harmful in older patients. While older patients may be provided with neoadjuvant chemotherapy or radiotherapy, it must be adapted to the patient's status. A reduction in the initial dose of palliative chemotherapy should be considered in patients with metastases. These patients tolerate immunotherapy better than systemic chemotherapy, and a strategy to replace chemotherapy with immunotherapy whenever possible should be evaluated. Finally, better supportive care is needed in patients with a poor performance status. Prospective studies are needed to improve the care and prognosis of elderly patients.

The optimal management of patients with locally advanced esophageal adenocarcinoma is unclear. Neoadjuvant chemoradiotherapy followed by esophagectomy (trimodality therapy) is supported as a standard of care, but definitive chemoradiotherapy is frequently given in practice to patients who may have been surgical candidates. This multi-institutional retrospective cohort study compared the outcomes of consecutive patients diagnosed with stage II to IVA esophageal adenocarcinoma between 2004 and 2018 who planned to undergo trimodality therapy or definitive chemoradiotherapy. A total of 493 patients were included, of whom 435 intended to undergo trimodality therapy and 56 intended to undergo definitive chemoradiotherapy. After a median follow-up of 7.3 years, trimodality therapy was associated with a lower risk of locoregional failure (5-year risk, 30.5% vs. 61.3%; HR, 0.39; 95% CI, 0.24-0.62; p<0.001) but not distant metastases (5-year risk, 58.2% vs. 53.9%; HR, 1.21; 95% CI, 0.77-1.91; p=0.40). There were no differences in overall survival (HR, 0.78; 95% CI, 0.56-1.09; p=0.14) or cancer-specific survival (HR, 0.83; 95% CI, 0.57-1.21; p=0.33). Findings were consistent on propensity score-matched sensitivity analyses. In conclusion, trimodality therapy was associated with a lower risk of locoregional failure, but this did not translate into a significantly lower risk of distant failure or improved survival. Further studies are required to accurately estimate the trade-offs between the two treatment strategies.

In patients with esophageal squamous cell carcinoma (ESCC), accurately predicting a pathologic complete response (pCR) to preoperative chemoradiotherapy (PCRT) has the potential to enable an active surveillance strategy without esophagectomy. We aimed to establish a reliable multiparameter nomogram model that combines tumor characteristics, imaging modalities, and hematologic markers to predict pCR in patients with ESCC who underwent PCRT and esophagectomy.

We retrospectively reviewed the medical records of 457 patients with ESCC who received PCRT followed by esophagectomy between January 2005 and October 2020. The nomogram model was developed using logistic regression analysis with a training cohort and externally validated with a validation cohort.

In the training and validation cohorts, 44.2% (126/285) and 48.3% (83/172) of patients, respectively, achieved pCR after PCRT. The 5-year rates of overall survival, progression-free survival, and freedom from local progression in the training cohort were 51.6%, 48.5%, and 77.6%, respectively. The parameters included in the nomogram were histologic grade, clinical N stage, maximum standardized uptake value on positron emission tomography, and post-PCRT biopsy. Hematologic markers were significantly associated with survival outcomes but not with pCR. The area under the receiver operating characteristic curve of the nomogram was 0.717, 0.704, and 0.707 for the training cohort, internal validation cohort, and external validation cohort, respectively.

Our nomogram model based on four parameters obtained from standard clinical practice demonstrated good performance in both the training and validation cohorts and could be useful to aid clinical decision-making to determine whether surgery or active surveillance strategy should be pursued.

Esophageal cancer is the seventh most common malignancy worldwide, with over 470 000 new cases diagnosed each year. Two distinct histological subtypes predominate, and should be considered biologically separate disease entities.1 These subtypes are esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). Outcomes remain poor regardless of subtype, with most patients presenting with late stage disease.2 Novel strategies to improve early detection of the respective precursor lesions, squamous dysplasia, and Barrett's esophagus offer the potential to improve outcomes. The introduction of a limited number of biologic agents, as well as immune checkpoint inhibitors, is resulting in improvements in the systemic treatment of locally advanced and metastatic esophageal cancer. These developments, coupled with improvements in minimally invasive surgical and endoscopic treatment approaches, as well as adaptive and precision radiotherapy technologies, offer the potential to improve outcomes still further. This review summarizes the latest advances in the diagnosis and management of esophageal cancer, and the developments in understanding of the biology of this disease.

Radiation therapy is an effective treatment modality in the management of patients with esophageal cancer regardless of tumor location (proximal, middle, or distal esophagus) or histology (squamous cell vs adenocarcinoma). The addition of neoadjuvant CRT to surgery in patients who are surgical candidates has consistently shown a benefit in terms of locoregional recurrence, pathologic downstaging, and overall survival. For patients who are not surgical candidates, CRT has a role as definitive treatment.

Esophageal cancer is among the top causes of cancer-related mortality worldwide, and the main treatment modality for locally advanced esophageal cancer is concurrent chemoradiotherapy. The current photon-based radiotherapy modalities and procedures have increased the incidence of treatment-related cardiac and pulmonary complications. Additionally, anatomical changes in the esophagus resulting from diaphragmatic movement, weight loss, and tumor progression present challenges for radiotherapy. These challenges have spurred interest in particle therapies, such as proton beam therapy (PBT) and heavy-ion therapy, for esophageal cancer. This paper comprehensively reviews the dosimetric advantages, clinical efficacy, and limitations of PBT and heavy-ion therapy for esophageal cancer and discusses their prospects. This highlights the unique dosimetric benefits of these therapies, particularly their ability to deliver high-dose radiation precisely to the tumor while sparing the surrounding normal organs and tissues. Although PBT and heavy-ion therapy demonstrate superior clinical efficacy compared to photon therapy, they are not without limitations. Multiple studies are needed to further validate and supplement the existing clinical and preclinical data to better exploit the benefits of PBT and thereby provide improved survival advantages to these patients.

Esophageal cancer (EC) is a major global health burden, with a particularly high incidence in East Asia. The authors aimed to investigate the effect of metastasis in cervical paraesophageal lymph nodes (station 101) and supraclavicular lymph nodes (station 104) on the survival of patients who underwent esophagectomy for esophageal squamous cell carcinoma (ESCC).

Data were obtained from the database of the authors' hospital. The authors retrospectively analyzed the patients with EC who underwent esophagectomy from January 2010 to December 2017. These patients were allocated into two groups based on the presence of lymph node metastasis (LNM) in the cervical paraesophageal or supraclavicular regions. Clinical outcomes and survival data were compared using the TNM staging system of the 8th edition of the American Joint Committee on Cancer (AJCC).

After a median follow-up of 62.1 months, 122 patients with LNM in the supraclavicular region were included in the study. Among these patients, 53 showed cervical paraesophageal LNM and an overall survival (OS) of 19.9 months [95% confidence interval (CI): 16.3-23.5]. In contrast, 69 patients showed supraclavicular LNM with an OS of 34.9 months (95% CI 25.7-44.1). The OS rates at 1, 3, and 5 years were 77%, 29%, and 21%, respectively, for patients with cervical paraesophageal LNM. Moreover, patients with supraclavicular LNM demonstrated OS rates of 88%, 48%, and 34%, respectively [Hazard ratio (HR): 0.634, 95% CI: 0.402-1.000, P=0.042].

Patients with ESCC with cervical paraesophageal LNM had significantly worse OS than those with supraclavicular LNM. This study underscores the importance of accurately identifying and managing ESCC with cervical paraesophageal LNM, as it may require more tailored and aggressive treatment strategies to prolong patient survival.

Esophageal cancer in one of the most malignant and hard-to-treat cancers. Esophageal squamous carcinoma (ESCC) is most common in Asian countries, whereas adenocarcinoma at the esophago-gastric junction (EGJ AC) is more prevalent in the Western countries. Due to differences in both genetic background and response to chemotherapy and radiotherapy, both histologic subtypes need different paradigms of management. Since the landmark CROSS study has demonstrated the superior survival benefit of tri-modality including neoadjuvant chemoradiotherapy prior to esophagectomy, the tri-modality becomes the standard of care; however, it is suitable for a highly-selected patient. Tri-modality should be offered for every ESCC patient, if a patient is fit for surgery with adequate cardiopulmonary reserve, regardless of ages. Definitive chemoradiotherapy remains the best option for a patient who is not a surgical candidate or declines surgery. On the contrary, owing to doubtful benefits of radiotherapy with potentially more toxicities related to radiotherapy in EGJ AC, either neoadjuvant chemotherapy or peri-operative chemotherapy would be more preferable in an EGJ AC patient. In case of very locally advanced disease (cT4b), the proper management is more challenging. Even though, palliative care is the safe option, multi-modality therapy with curative intent like neoadjuvant chemotherapy with conversion surgery may be worthwhile; however, it should be suggested on case-by-case basis.

With the rising life expectancy and an aging population, it has become increasingly important to investigate treatments suitable for older adult patients with esophageal cancer. This study investigated whether older adult patients who underwent esophagectomy had better clinical outcomes than those who were nonsurgically treated.

We retrospectively analyzed patients with esophageal squamous cell carcinoma (ESCC) who were 70 years or older and underwent esophagectomy, radiotherapy (RT), and/or chemoradiotherapy (CRT) between January 2018 and December 2019. Patients were divided into 2 groups: the surgery group (S group) and the nonsurgery group (NS group). We then compared the clinical outcomes of the 2 groups.

After a median follow-up duration of 36.6 months, the S group showed better overall survival (OS). The 3-year OS was 59% in the S group and 27% in the NS group (hazard ratio [HR], 0.397; 95% CI, 0.278-0.549; P < .0001). In the S group, the median progression-free survival was 38.3 months (95% CI, 30.6-46.1) compared with 12.3 months in the NS group (HR, 0.511; 95% CI, 0.376-0.695; P < .0001). In addition, the number of adverse events in the NS group was higher than that in the S group (P < .001).

Overall, patients with ESCC at the age of ≥70 years who underwent esophagectomy had significantly better clinical outcomes than those who underwent nonsurgical treatment with RT and/or CRT.

This study aims to evaluate the efficacy of various treatment approaches in stage T4b esophageal cancer patients.

Data were extracted from the Surveillance, Epidemiology, and End Results databases, covering patients diagnosed with esophageal cancer between 2000 and 2020. Kaplan-Meier analysis was used to assess cancer-specific survival (CSS) and overall survival (OS) across different treatment patterns.

The study included 482 patients: 222 (46.1%) received chemoradiotherapy, 58 (12.0%) underwent radiotherapy alone, 37 (7.7%) received chemotherapy alone, 50 (10.4%) underwent surgery, and 115 (23.8%) received no treatment. Median CSS were 12, 4, 6, 18, and 1 month for chemoradiotherapy, radiotherapy alone, chemotherapy alone, surgery, and non-treatment groups. Median OS for these groups were 11, 3, 6, 17, and 1 month, respectively. Multivariable proportional hazard regression analysis revealed that patients who underwent surgery experienced significantly improved CSS (hazard ratio [HR] = 0.42, 95% confidence interval [CI]: 0.24-0.72; P = 0.002) and OS (HR = 0.45, 95% CI: 0.28-0.74; P = 0.002) compared to those receiving chemoradiotherapy after propensity score matching.

Esophagectomy, with or without radiotherapy and/or chemotherapy, results in better survival outcomes than chemoradiotherapy in patients with stage T4b esophageal cancer.

Oesophageal squamous cell carcinoma is a common malignancy worldwide. Definitive chemoradiotherapy is the standard treatment for patients with resectable stage oesophageal squamous cell carcinoma who cannot undergo surgery, as well as those with locally advanced unresectable oesophageal squamous cell carcinoma. However, it has several disadvantages such as poor survival, radiation-related toxicities and severe and lethal complications related to salvage treatment for residual or recurrent disease. Numerous clinical trials on chemoradiotherapy have been conducted to confirm the optimal combination of irradiation and chemotherapy. For advanced disease, multimodal treatment strategies including salvage surgery are essential. Palliative chemoradiotherapy is also crucial for dysphagia in locally advanced oesophageal squamous cell carcinoma with or without metastatic lesions. Recently, the synergistic mechanism of radiotherapy combined with immunotherapy has been reported. Early phase clinical trials suggest that a combination of immunotherapy and chemoradiotherapy can improve clinical outcomes with manageable side effects, but further investigations are needed. Here, we reviewed the existing clinical data and current development of chemoradiotherapy combined with immunotherapy in patients with oesophageal squamous cell carcinoma.

Diagnosis and therapy of esophageal carcinoma is challenging and requires a multidisciplinary approach. The purpose of the updated German guideline "Diagnosis and Treatment of Squamous Cell Carcinoma and Adenocarcinoma of the Esophagus-version 3.1" is to provide practical and evidence-based advice for the management of patients with esophageal cancer. Recommendations were developed by a multidisciplinary expert panel based on an extensive and systematic evaluation of the published medical literature and the application of well-established methodologies (e.g. Oxford evidence grading scheme, grading of recommendations). Accurate diagnostic evaluation of the primary tumor as well as lymph node and distant metastases is required in order to guide patients to a stage-appropriate therapy after the initial diagnosis of esophageal cancer. In high-grade intraepithelial neoplasia or mucosal carcinoma endoscopic resection shall be performed. Whether endoscopic resection is the definitive therapeutic measure depends on the histopathological evaluation of the resection specimen. Esophagectomy should be performed minimally invasive or in combination with open procedures (hybrid technique). Because the prognosis in locally advanced esophageal carcinoma is poor with surgery alone, multimodality therapy is recommended. In locally advanced adenocarcinomas of the esophagus or esophagogastric junction, perioperative chemotherapy or preoperative radiochemotherapy should be administered. In locally advanced squamous cell carcinomas of the esophagus, preoperative radiochemotherapy followed by complete resection or definitive radiochemotherapy without surgery should be performed. In the case of residual tumor in the resection specimen after neoadjuvant radiochemotherapy and R0 resection of squamous cell carcinoma or adenocarcinoma, adjuvant immunotherapy with nivolumab should be given. Systemic palliative treatment options (chemotherapy, chemotherapy plus immunotherapy, immunotherapy alone) in unresectable or metastastic esophageal cancer depend on histology and are stratified according to PD-L1 and/or Her2 expression.

Large primary tumor volume has been identified as a poor prognostic factor of esophageal squamous cell carcinoma (ESCC) treated with definitive concurrent chemoradiotherapy (CCRT). However, when neoadjuvant CCRT and surgery are adopted, the prognostic impact of primary tumor and lymph node (LN) volume on clinical outcomes in ESCC remains to be elucidated. This study included 107 patients who received neoadjuvant CCRT and surgery for ESCC. The volume of the primary tumor and LN was measured using radiotherapy planning computed tomography scans, and was correlated with overall survival (OS), disease-free survival (DFS), and cancer failure pattern. The median OS was 24.2 months (IQR, 11.1-93.9) after a median follow-up of 18.4 months (IQR, 8.1-40.7). The patients with a baseline LN volume > 7.7 ml had a significantly worse median OS compared to those with smaller LN volume (18.8 vs. 46.9 months, p = 0.049), as did those with tumor regression grade (TRG) 3-5 after CCRT (13.9 vs. 86.7 months, p < 0.001). However, there was no association between OS and esophageal tumor volume (p = 0.363). Multivariate analysis indicated that large LN volume (HR 1.753, 95% CI 1.015-3.029, p = 0.044) and high TRG (HR 3.276, 95% CI 1.556-6.898, p = 0.002) were negative prognostic factors for OS. Furthermore, large LN volume was linked to increased locoregional failure (p = 0.033) and decreased DFS (p = 0.041). In conclusion, this study demonstrated that large LN volume is correlated with poor OS, DFS, and locoregional control in ESCC treated with neoadjuvant CCRT and esophagectomy.

The efficacy of concurrent chemoradiotherapy (CCRT) or esophagectomy for locally advanced esophageal squamous cell carcinoma (ESCC) is unclear. This study compared the survival and recurrence of patients with locally advanced ESCC after definitive CCRT and surgery.

A retrospective study was conducted on patients with locally advanced ESCC who underwent CCRT or esophagectomy at Kosin University Gospel Hospital from January 2010 to December 2016. The patients' baseline characteristics, pathology, recurrence rate, and three-year/five-year overall survival were obtained.

This study evaluated ESCC patients with cT1-T2, N+ or cT3-T4, or N, who were treated by definitive CCRT (n=14) or esophagectomy (n=32). No significant difference was noted between the two groups, except for the location of the cancer and performance state. The respective three- and five-year overall survival rates were 30.8% and 23.1% in the CCRT group and 40.2% and 22.5% in the esophagectomy group (p=0.685). In the CCRT group, three patients (21.4%) had a complete response, and two (66.7%) had a recurrence. In the esophagectomy group, an R0 resection was achieved in 28 (87.5%) patients, and a recurrence occurred in 18 (64.3%). The median disease-free survival in the CCRT and esophagectomy groups was 14 and 17 months, respectively (p=0.882).

These results showed no significant difference in survival between the definitive CCRT and surgery as the initial treatment. Nevertheless, larger prospective studies will be needed because of the retrospective nature and small number of patients in this study.

Definitive concurrent chemoradiotherapy (dCCRT) is the gold standard for the treatment of locally advanced esophageal squamous cell carcinoma (ESCC). However, the potential benefits of consolidation chemotherapy after dCCRT in patients with esophageal cancer remain debatable. Prospective randomized controlled trials comparing the outcomes of dCCRT with or without consolidation chemotherapy in patients with ESCC are lacking. In this study, we aim to generate evidence regarding consolidation chemotherapy efficacy in patients with locally advanced, inoperable ESCC.

This is a multicenter, prospective, open-label, phase-III randomized controlled trial comparing non-inferiority of dCCRT alone to consolidation chemotherapy following dCCRT. In total, 600 patients will be enrolled and randomly assigned in a 1:1 ratio to receive either consolidation chemotherapy after dCCRT (Arm A) or dCCRT alone (Arm B). Overall survival will be the primary endpoint, whereas progression-free survival, locoregional progression-free survival, distant metastasis-free survival, and treatment-related toxicity will be the secondary endpoints.

This study aid in further understanding the effects of consolidation chemotherapy after dCCRT in patients with locally advanced, inoperable ESCC.

ChiCTR1800017646.

To assess the tolerability and oncological results of chemoradiation in elderly patients with locally advanced adenocarcinoma of the esophagus or gastroesophageal junction.

This multi-center retrospective analysis included 86 elderly patients (≥ 65 years) with esophageal or gastroesophageal junction adenocarcinoma (median age 73 years; range 65-92 years) treated with definitive or neoadjuvant (chemo)radiotherapy. The treatment was performed at 3 large comprehensive cancer centers in Germany from 2006 to 2020. Locoregional control (LRC), progression-free survival (PFS), distant metastasis-free survival (DMFS), overall survival (OS), and treatment-associated toxicities according to CTCAE criteria v5.0 were analyzed, and parameters potentially relevant to patient outcomes were evaluated.

Thirty-three patients (38%) were treated with neoadjuvant chemoradiation followed by surgery, while the remaining patients received definitive (chemo)radiation. The delivery of radiotherapy without dose reduction was possible in 80 patients (93%). In 66 patients (77%), concomitant chemotherapy was initially prescribed; however, during the course of therapy, 48% of patients (n = 32) required chemotherapy de-escalation due to treatment-related toxicities and comorbidities. Twenty-nine patients (34%) experienced higher-grade acute toxicities and 14 patients (16%) higher-grade late toxicities. The 2-year LRC, DMFS, PFS, and OS amounted to 72%, 49%, 46%, and 52%, respectively. In multivariate analysis, neoadjuvant chemoradiation followed by surgery was shown to be associated with significantly better PFS (p = 0.006), DMFS (p = 0.006), and OS (p = 0.004) compared with all non-surgical treatments (pooled definitive radiotherapy and chemoradiation). No such advantage was seen over definitive chemoradiation. The majority of patients with neoadjuvant therapy received standard chemoradiotherapy without dose reduction (n = 24/33, 73%). In contrast, concurrent chemotherapy was only possible in 62% of patients undergoing definitive radiotherapy (n = 33/53), and most of these patients required dose-reduction or modification of chemotherapy (n = 23/33, 70%).

In our analysis, omission of chemotherapy or adjustment of chemotherapy dose during definitive radiotherapy was necessary for the overwhelming majority of elderly esophageal cancer patients not eligible for surgery, and hence resulted in reduced PFS and OS. Therefore, optimization of non-surgical approaches and the identification of potential predictive factors for safe administration of concurrent chemotherapy in elderly patients with (gastro)esophageal adenocarcinoma is required.