Neoadjuvant immunotherapy combined with chemotherapy or chemoradiotherapy has emerged as a promising approach in the treatment of esophageal cancer. However, there is a lack of comprehensive understanding regarding the clinical factors that can predict patient response to this therapy. The aim of this study was to develop a predictive model for assessing the efficacy of neoadjuvant immunotherapy in patients undergoing surgical treatment.

This study retrospectively enrolled 220 consecutive patients with preoperative immunotherapy combined chemotherapy or chemoradiotherapy. A logistic regression was used to evaluate the association between pathologic complete response (pCR) and endoscopic ultrasound parameters, constructing a predictive model for treatment response. Additional, overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method, and Cox regression analyses were introduced to explore the associations between EUS factors after neoadjuvant immunotherapy.

Logistic regression analysis identified that the significant predictors of pCR were treatment regimen, negative biopsy findings, RECIST assessment, endoscopic ultrasound responder, and downstaging in uN. A predictive model including above five variables was generated, and area under the curve was 0.840(95%CI 0.78-0.89), this nomogram was also adequately validated internally. In the cox regression analyses, EUS responder was found to be a significant predictor of overall survival with a hazard ratio (HR) of 0.38(95%CI 0.15-0.98), whereas only pCR status was a significant predictor of PFS (HR 0.80; 95%CI 0.01-0.60).

EUS responder can serve as a valuable predictor of the efficacy of adjuvant immunotherapy combined with chemotherapy or chemoradiotherapy, as well as of survival outcomes.

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.

Although neoadjuvant chemotherapy and immunotherapy show promise in treating oesophageal squamous cell carcinoma (OSCC), long-term survival data are limited. This randomized, multicenter phase 2 study evaluated the efficacy of perioperative Nivolumab with chemotherapy, followed by surgery and adjuvant immunotherapy, in patients with locally advanced resectable OSCC, and explored the prognostic role of circulating tumor DNA (ctDNA) status.

In this trial, participants recruited from five centers were randomly assigned in a 2:1 ratio to receive either perioperative Nivolumab or a placebo in addition to chemotherapy (cisplatin and paclitaxel), followed by minimally invasive esophagectomy. For those who did not achieve a pathological complete response (pCR), adjuvant treatment with Nivolumab was administered. The main measure of success was the pCR rate, with secondary endpoints including the R0 resection rate, event-free survival, and overall survival. All outcomes and safety measures were assessed based on the intention-to-treat population. ctDNA levels were monitored as exploratory endpoints.

Ninety patients were enrolled and randomized to Nivolumab or placebo plus chemotherapy. The pCR rate was slightly higher in the Nivolumab group (15%) compared to the control group (13.3%) (relative risk, 1.13; 95% CI, 0.38 to 3.36). No significant differences were observed in R0 resection rates (96.4% vs. 96.6%; P > 0.05). The median follow-up duration was 24.9 months (interquartile range: 22.8 to 26.7 months). Two-year event-free survival rates were 63.11% in the Nivolumab group versus 60.47% in the chemo group (hazard ratio, 0.97; 95% CI, 0.49 to 1.92). Two-year overall survival rates were 83.32% and 79.4%, respectively (hazard ratio, 0.82; 95% CI, 0.29 to 2.31). All participants were ctDNA positive at baseline, but post-treatment, 89% of the Nivolumab group and 62.5% of the placebo group turned ctDNA negative (P = 0.01). Those negative for ctDNA at all testing points showed significantly better disease-free survival (P < 0.001).

Perioperative Nivolumab plus chemotherapy is a viable and safe option for systemically treating locally advanced resectable OSCC. Monitoring minimal residual disease through ctDNA could be potentially valuable for assessing the effectiveness of adjuvant therapy and for prognostic evaluation in a systemic manner.

ClinicalTrials.gov registration NCT05213312.

This study proposes a modified lymph node (LN) staging category (BALN) on the basis of the number of positive LNs before (prepN) and after (ypN) neoadjuvant chemoradiotherapy (nCRT) to improve prognostic stratification in esophageal squamous cell carcinoma (ESCC).

A total of 381 patients with ESCC who underwent nCRT at three medical centers were retrospectively enrolled. The ypN categories were scored according to the eighth edition of the American Joint Committee of Cancer (AJCC) staging manual. LNs with regression changes or vital tumor cells were used for interpretation of the prepN stage, reflecting the estimated number of originally involved LNs. BALN category was organized on the basis of the sum of the number of positive LNs in prepN and ypN categories.

BALN category revealed clearer survival classification and prognostic value of disease-free survival (DFS) in patients with ESCC (p < 0.0001). Multivariate cox proportional risk model identified BALN stage as a significant risk factor of DFS of patients with ESCC (p < 0.001). The results of 5-year time-area under the curve (AUC) demonstrated better predictive ability of the BALN category than the ypN category (AUC 0.755 versus 0.707, p = 0.004). The rypTNM system based on BALN category exhibited comparable survival discrimination and better predictive performance than ypTNM system (AUC 0.799 versus 0.756, p = 0.020).

The BALN stage and the revised ypTNM system showed preferable prognosis outcomes to the ypN stage and the ypTNM system, respectively. Evaluating LN status before and after nCRT could allow for more accurate esophageal cancer staging.

With the annual increase in the incidence and mortality rates of gastric cancer, it has gradually become one of the significant threats to human health. Approximately 90% of gastric cancer patients are diagnosed with adenocarcinoma. Although the 5-year survival rate for early-stage gastric cancer can exceed 90%, due to its concealed symptoms, less than half of the patients are eligible for radical surgical treatment upon diagnosis. For gastric cancer patients receiving palliative treatment, the current expected survival time is only about one year. In China, the majority of gastric cancer patients, accounting for about 80% of the total, are in the locally advanced stage. For these patients, radical surgery remains the primary treatment option; however, surgery alone is often inadequate in controlling tumor progression. In the pivotal MAGIC study, the recurrence rate was as high as 75%, and similar results were obtained in the French ACCORD07-FFCD9703 study. Numerous clinical trials are currently exploring preoperative neoadjuvant therapy for patients with locally advanced gastric cancer. Data indicates that preoperative neoadjuvant therapy can not only reduce the size of the local tumor but also shrink surrounding lymph nodes, thereby downstaging the tumor and improving the R0 resection rate. Additionally, it can decrease tumor cell activity and eliminate potential micrometastases. The emergence of various immunotherapies has ushered in a new era for neoadjuvant treatment options for gastric cancer.

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.

Combination of anti-PD-1 monoclonal antibody with chemotherapy has been widely used as a first-line treatment for metastatic esophageal squamous cell carcinoma (ESCC). However, the efficacy of this therapeutic combination as a neoadjuvant intervention for resectable ESCC remains inadequately explored. This study aims to evaluate the efficacy and safety of sintilimab in combination with chemotherapy as a neoadjuvant therapy for ESCC.

In this single-arm, phase II study, patients with histopathologically diagnosed resectable ESCC who had clinical cT1-3/N0-1M0 (stage II-III) were recruited. Sintilimab (200mg, iv, d1) in combined with chemotherapy (nab-paclitaxel 260 mg/m2, d1 and cisplatin 75 mg/m2, d1-3) were administered every 3 weeks for 2 cycles. The primary endpoint was pathological complete response (pCR).

From November 2020 through November 2022, 29 patients were enrolled and 27 completed the two cycles of neoadjuvant therapy. A total of 21 patients underwent surgery. The pCR rate was 28.6% (6/21) and the major pathologic response (MPR) rate was 42.9% (9/21). The most common Grade 3 or 4 treatment-related adverse events were leukopenia (26.7%) and neutropenia (20%). No delays in surgical procedures or unexpected surgical complications attributable to the treatment were reported.

The combination of sintilimab and chemotherapy as a neoadjuvant regimen was tolerable and associated with favorable responses for ESCC patients. Given these favorable results, this regimen could serve as a viable alternative in the neoadjuvant treatment landscape for ESCC, with particular applicability to Chinese patient populations.

https://www.chictr.org.cn/, identifier ChiCTR2000040345.

To investigate the utility of combined tumour and lymph node (LN) radiomics features in predicting disease-free survival (DFS) among patients with locally advanced esophageal squamous cell carcinoma (ESCC) after neoadjuvant chemotherapy and resection.

We retrospectively enrolled 176 ESCC patients from January 2013 to December 2016. Tumour and targeted LN segmentation were performed on venous phase CT images. Models were constructed using LASSO Cox regression: a clinical model, a clinical-tumour radiomics model, and a clinical-tumour-LN radiomics model. Model fitting was evaluated using Akaike information criterion and likelihood ratio (LR), while performance was assessed using Harrell's concordance index (C-index) and time-dependent receiver operating characteristic analysis.

The clinical model included clinical stage and neutrophil-to-lymphocyte ratio (NLR). Integration of tumour features significantly improved prognostic accuracy (clinical-tumour model vs. clinical model, LR: 17.84 vs. 11.84, P = 0.049). Subsequent integration of LN features further augmented model performance (clinical-tumour-LN model vs. clinical-tumour model, LR: 24.48 vs. 17.84, P = 0.009). The final model included clinical stage, NLR, two tumour features (Conventional_mean and GLZLM_HGZE), and one LN feature (GLCM_entropy). The C-index was 0.68 for the training set and 0.70 for the test set. The nomogram based on these features effectively stratified patients into high- and low-risk groups (P < 0.001).

The clinical-tumour-LN model, integrating clinical stage, NLR, and radiomics features, outperformed simpler models in predicting DFS among ESCC patients after neoadjuvant chemotherapy and resection. This underscores the potential of radiomics data to enhance prognostic models, offering clinicians a more robust tool for assessment.

This study aimed to evaluate the clinical significance of four-dimensional dynamic ventilation CT (4DCT) for assessing resectability in borderline resectable locally advanced esophageal cancer (BR-LAEC) and confirmed the pathological validity of the 4DCT results in surgery without prior treatment.

We retrospectively reviewed 128 patients (107 men; median age, 68 [range, 43-89] years) diagnosed with BR-LAEC on initial conventional CT (i-CT). These patients were initially classified into three categories: BR1 (closer to resectable), BR2 (resectability not assessable), or BR3 (closer to unresectable). Subsequent 4DCT reclassified patients as either resectable or unresectable within 1 week of i-CT. We analyzed the diagnostic shift induced by 4DCT. Additionally, 18 patients who underwent surgery without prior treatment were evaluated using 4DCT and pathological outcomes.

4DCT reclassified patients with BR-LAEC as resectable (57.0%; 73/128) and unresectable (43.0%; 55/128). Of 53 patients initially classified as BR1, 32.1% (17/53) were reclassified as unresectable, and of 47 patients initially classified as BR3, 46.8% (22/47) were reclassified as resectable. Among 28 patients initially classified as BR2, 53.6% (15/27) were reclassified as resectable and 46.4% (13/27) as unresectable. In the surgery-only cohort of 18 patients, 9 were initially classified as BR1 and 9 as BR2, and all were reclassified as resectable. These patients were pathologically confirmed to have resectable disease.

4DCT may provide information complementary to that provided by initial conventional CT in assessing resectability among patients with BR-LAEC, and could be a useful adjunct tool for guiding clinical decisions in this patient population.

Regional lymph node (LN) status is a key prognostic factor in oesophageal cancer (OeC). Tumour-derived antigens can activate immune reactions in LNs, potentially reflecting the host's anti-tumour immune response. It remains unclear whether this response is homogeneous across all tumour negative LNs (LNneg) within individual OeC patients.

To investigate the hypotheses: (1) the host anti-tumour immune response is similar in all LNneg from an individual OeC patient reflected in a similar microarchitecture in all LNneg; and (2) immune response measured in the largest LNneg can represent that of all LNnegs.

(y)pN0 patients from the Oe02 trial with at least two LNneg were included. Microarchitectural LN features (germinal centres (GermC), lymphocytes outside GermCs (lymphocytes), histiocytes) were morphometrically quantified. Linear mixed-effects models, intraclass correlation coefficients (ICC) and Bland-Altman plots were used to determine systematic bias, reliability/variability and agreement of LNneg microarchitecture measurements.

Linear mixed-effects models showed no systematic bias in LNneg microarchitectural features within a patient. The ICC revealed moderate variability for lymphocytes (ICC: 0.39; 95 %CI: 0.01- 0.61, p = 0.02)) and GermC (ICC: 0.50; 95 %CI: 0.22-0.68, p < 0.001), and high variability for histiocytes (ICC: 0.07 (95 %CI: -0.45-0.40, p = 0.38). Bland-Altman plots showed that 5.0 % of GermC, 5.0 % of histiocytes and 8.5 % of lymphocyte measurements were outside the 95 % limits of agreement.

This is the first study to systematically assess agreement of microarchitectural features in LNneg within an individual (y)pN0 OeC patient. The absence of systematic bias supports using largest LNneg as surrogate for OeC patient's overall anti-tumour immune response.

The present study aimed to develop a nomogram model for predicting overall survival (OS) in esophageal squamous cell carcinoma (ESCC) patients.

A total of 205 patients with ESCC were enrolled and randomly divided into a training cohort (n = 153) and a test cohort (n = 52) at a ratio of 7:3. Multivariate Cox regression was used to construct the radiomics model based on CT data. The mutation signature was constructed based on whole genome sequencing data and found to be significantly associated with the prognosis of patients with ESCC. A nomogram model combining the Rad-score and mutation signature was constructed. An integrated nomogram model combining the Rad-score, mutation signature, and clinical factors was constructed.

A total of 8 CT features were selected for multivariate Cox regression analysis to determine whether the Rad-score was significantly correlated with OS. The area under the curve (AUC) of the radiomics model was 0.834 (95% CI, 0.767-0.900) for the training cohort and 0.733 (95% CI, 0.574-0.892) for the test cohort. The Rad-score, S3, and S6 were used to construct an integrated RM nomogram. The predictive performance of the RM nomogram model was better than that of the radiomics model, with an AUC of 0. 830 (95% CI, 0.761-0.899) in the training cohort and 0.793 (95% CI, 0.653-0.934) in the test cohort. The Rad-score, TNM stage, lymph node metastasis status, S3, and S6 were used to construct an integrated RMC nomogram. The predictive performance of the RMC nomogram model was better than that of the radiomics model and RM nomogram model, with an AUC of 0. 862 (95% CI, 0.795-0.928) in the training cohort and 0. 837 (95% CI, 0.705-0.969) in the test cohort.

An integrated nomogram model combining the Rad-score, mutation signature, and clinical factors can better predict the prognosis of patients with ESCC.

Esophageal cancer (EC) is one of the leading causes of cancer-related deaths globally. Surgery is the standard treatment for resectable EC after preoperative chemoradiotherapy or chemotherapy, followed by postoperative adjuvant chemotherapy in certain cases. Upper gastrointestinal endoscopy and computed tomography (CT) are predominantly performed to evaluate the efficacy of these treatments, but their sensitivity and accuracy for evaluating minimal residual disease remain unsatisfactory, thereby requiring the development of alternative methods. In recent years, interest has been increasing in using liquid biopsy to assess treatment responses. Liquid biopsy is a noninvasive technology for detecting cell components in the blood and other body fluids. It involves collecting a small sample of body fluid, which is then analyzed for the presence of components, including circulating tumor DNA (ctDNA), microRNA (miRNA), or circulating tumor cells (CTCs). Further, ctDNA and miRNA are analyzed with various techniques, including digital polymerase chain reaction (dPCR) and next-generation sequencing (NGS). CTCs are isolated by determining surface antigens using immunomagnetic techniques or by filtering the blood according to cell size and rigidity. Several studies indicate that investigating these materials helps predict EC prognosis and recurrence and possibly stratifies high-risk groups. Liquid biopsy may also apply to the selection of cases that have achieved a complete response through preoperative treatment to prevent surgery and preserve the esophagus, as well as identifying the suitability of postoperative chemotherapy and the timing of conversion surgery for unresectable EC. The potential of liquid biopsy to enhance treatment decisions will further advance EC treatment.

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.

The current guidelines for the treatment of esophageal cancer recommend a multimodal approach that includes chemotherapy, targeted therapy and immunotherapy, radiation, and surgery. Despite advances in treatment, rates of treatment failure, pathologic incomplete response, tumor metastasis, and death remain unacceptably high.

This study was a narrative literature review using the terms "resectable esophageal cancer" and "multimodal therapy" to identify prospective trials of neoadjuvant radiation and chemotherapy, individually or combined with surgery, for esophageal cancer. Trials performed between 1984 and 2022 were identified and analyzed.

gov was queried to identify ongoing studies.

Twenty-one clinical studies were identified: 15 randomized controlled trials and 6 prospective nonrandomized trials. The results of the randomized trials suggest that multimodal therapy-in the form of neoadjuvant chemotherapy in combination with radiation or chemotherapy alone, followed by surgery-is associated with better rates of local disease control and partial clinical response and, potentially, longer survival than is surgery alone. Immunotherapy is an emerging option for the treatment of patients with esophageal cancer.

The treatment of patients with resectable esophageal cancer is rapidly evolving. Although previous treatment options have had only limited benefits for patients, significant progress has been made during last 3 decades. The results of the available studies suggest that advances in the treatment of esophageal cancer have the potential to improve survival in these patients; however, questions remain regarding mechanisms of action, patient selection, and the use of personalized approaches that are based on genetics.

The incidence of oesophageal adenocarcinoma (OAC) has risen six-fold in western countries over the last forty years but survival rates have only marginally improved. Hyperactivation of the PI3K-AKT-mTOR pathway is a common occurrence in OAC, driving cell survival, proliferation and resistance to chemotherapeutic agents. Inhibition of AKT has been explored as a treatment strategy with limited success and current inhibitors have failed to progress through clinical trials. Our study, describes a novel allosteric AKT inhibitor, ALM301, and demonstrates an enhancement of the efficacy of conventional chemotherapy when combined with ALM301 in OAC. Reduced sensitivity to ALM301 is associated with high expression of the Inhibitor of Apoptosis (IAP) family of proteins, particularly XIAP. Combined AKT and IAP inhibition synergistically enhanced OAC cell death and successfully re-sensitized ALM301 and chemotherapy resistant cell lines. A high degree of synergism was also observed in patient-derived OAC organoids indicating the potential clinical relevance of the combination. This study demonstrates the role for dual AKT/IAP inhibition in OAC and provides a strong rationale for the further investigation of this highly efficacious combination strategy.

The clinicoradiological staging for esophageal cancer is fraught with variable accuracy, potentially depriving patients who have been understaged of the benefit of neoadjuvant therapy, which has been shown to improve long-term survival in locally advanced malignancies. It is imperative to identify these high-risk tumors for tailored treatment.

Retrospective analysis of a prospective database of patients undergoing esophagectomy for carcinoma esophagus between 2011 and 2019. Patients with clinicoradiological early-stage esophageal carcinoma (T1/2 and N0), staged with EUS and fluoro-deoxy-glucose positron emission tomography with contrast-enhanced computed tomography (FDG PET-CECT), and undergoing upfront surgery were included. Demographic profile, staging, perioperative outcomes, and follow-up data were extracted from electronic records and analyzed using SPSS 26.0.

During this period, we performed 1496 esophagectomies, of which 68 patients (4.5%) underwent upfront surgery for early-stage tumors. The overall concordance between clinical and surgical staging was 55.8%. The positive predictive value (PPV) of EUS for T1, T2, and N0 was 81.6%, 46.7%, and 82.4%, respectively, with 10.2% and 17% upstaging to T3 and N + , respectively. On multivariate analysis, T2 on EUS and tumors longer than 3.5 cm and having standardized uptake value (SUVmax) > 3.05 on FDG PET were strong predictors of stage migration. The 3-year overall survival (OS) of the entire cohort was 74.2%, while those who were understaged had a worse outcome, with a 3-year survival of 48.2%.

Endoscopic T2 stage, length more than 3.5 cm, and SUVmax more than 3.05 are associated with significant understaging and hence should be considered for neoadjuvant therapy.

Esophageal cancer remains a significant global health challenge. Several treatment modalities were explored in randomized controlled trials (RCTs) in recent decades. This study evaluates the robustness of RCTs focusing on esophageal cancer treatment using the fragility index (FI) and reverse fragility index (RFI).

A systematic review of RCTs studying different treatment modalities for esophageal cancer from 2000 to 2023 was conducted. The FI and RFI were utilized to gauge the robustness of statistically significant and non-significant outcomes, respectively. The FI represents the minimal number of patient outcomes that would need to alter to overturn a trial's statistical significance, while RFI indicates the minimal changes required to achieve significance in non-significant results.

Out of 4028 studies retrieved, 21 RCTs were included for final analysis. The studies spanned 2001 to 2023 with a mean followup of 66 months (range, 29-108 months) and median number of patients of 194 (range, 45-802). The most common treatment modalities examined in these studies were neoadjuvant chemoradiotherapy (n = 7, 33.3%), neoadjuvant chemotherapy (n = 4, 19.0%), and neoadjuvant immunotherapy (n = 2, 9.5%). Only 5 studies (23.8%) had a statistically significant primary outcome result with a median FI of 6 (IQR, 2.5-8.5). Non-significant primary outcomes were seen in 16 studies (76.2%) with a median RFI of 4 (IQR 1-11) and lost to followup of 0 (IQR 0-4). In the study with the highest FI (10), the FI was lower than the number of patients lost to followup (13).

Our findings demonstrate that most RCTs on esophageal cancer treatments did not report significant primary outcomes. The few studies that reported significant results had a low fragility index, suggesting a vulnerability in their findings.

Oesophageal cancer (EC), ranking 11th in incidence and 7th in mortality globally, presents a significant health challenge, with a notable prevalence in India, especially in the northeastern region. This article examines the efficacy of neoadjuvant chemoradiotherapy (NACRT) versus neoadjuvant chemotherapy (NACT) in treating locally advanced EC, analyzing data from randomized controlled trials (RCTs) between 2000 and 2024. NACRT, involving preoperative chemoradiotherapy followed by surgery, has shown improved survival rates, notably in the CROSS trial, which reported a 10-year overall survival benefit of 13%. Conversely, NACT is supported by key trials like the OE02 and MAGIC trials, demonstrating comparable survival outcomes. Key points of debate include compliance, complications, response and resection status, survival rates, and health-related quality of life (HRQOL). Compliance rates are similar for both modalities, though disease progression is more common after NACT. Postoperative complications and mortality rates are comparable, with NACTRT showing higher pathologic complete response (pCR) and R0 resection rates, potentially avoiding additional adjuvant radiation. While NACRT shows marginally better 3-year survival rates, particularly for squamous cell carcinoma, 5-year survival rates and HRQOL outcomes are similar for both treatments. NACTRT is associated with more respiratory symptoms, whereas NACT patients experience more gastrointestinal issues. Both NACT and NACTRT are viable options, with the choice depending on patient-specific factors and a thorough assessment of potential benefits and risks. Further research is needed to optimize treatment protocols for EC.

There is controversy about the benefit of administering adjuvant therapy to esophageal cancer (EC) patients after preoperative neoadjuvant therapy and surgical treatment. This study aims to investigate the clinical benefit of postoperative adjuvant therapy in EC patients with neoadjuvant therapy and surgery.

The study included EC patients diagnosed from 2007 to 2020 in the Surveillance, Epidemiology, and End Results (SEER) database. Patients who received neoadjuvant therapy (NCRT) were defined as those who underwent neoadjuvant chemotherapy or neoadjuvant radiotherapy before surgery, while patients who received adjuvant therapy (ACRT) were defined as those who underwent adjuvant chemotherapy or adjuvant radiotherapy after surgery. Propensity score matching (PSM) method was employed to establish matched cohorts, and Kaplan-Meier analysis, COX regression model, and Fine-Gray model were used for survival analysis.

The study included a total of 5805 EC patients, with 837 (14.4%) in the ACRT group and 4968 (85.4%) in the no-ACRT group. After PSM, a cohort of 1660 patients who received NCRT was enrolled for analysis, with 830 patients in each group. Kaplan-Meier analysis revealed no significant differences between the two groups in terms of median overall survival (OS) (34.0 vs. 36.0 months, p = 0.89) or cancer-specific survival (CSS) (40.0 vs. 49.0 months, p = 0.16). Multivariate Cox models and Fine-Gray models indicated that ACRT was not a predictive factor for OS or CSS (p > 0.05). Subgroup analysis for CSS suggested a protective effect of ACRT in the N2 (Cox model: HR = 0.640, p = 0.090; Fine-Gray model: HR = 0.636, p = 0.081) and the N3 subgroup (Cox model: HR = 0.302, p = 0.018; Fine-Gray model: HR = 0.306, p = 0.034).

Only for esophageal cancer patients with a more advanced N stage, postoperative adjuvant therapy after completing neoadjuvant therapy and curative surgical treatment may be beneficial.

Oesophageal cancer is the seventh leading cause of cancer mortality worldwide. Two major pathological subtypes exist: oesophageal squamous cell carcinoma and oesophageal adenocarcinoma. Epidemiological studies in the last decade have shown a gradual increase in the incidence of oesophageal adenocarcinoma worldwide. The prognosis of oesophageal cancer has greatly improved due to breakthroughs in screening, surgical procedures, and novel treatment modalities. The success achieved with combined modality therapies, including surgery, chemotherapy, and radiotherapy, to treat locally advanced oesophageal cancer is particularly notable. Immunotherapy has become a crucial treatment for oesophageal cancer, with immune checkpoint inhibitor-based therapies now established as the standard of care in adjuvant and metastatic first-line settings. This Seminar provides an overview of advances in the screening, diagnosis, and treatment of oesophageal squamous cell carcinoma and oesophageal adenocarcinoma, with a particular focus on neoadjuvant therapies for locally advanced oesophageal cancer and immune checkpoint inhibitor-based therapies.

In the era of immunotherapy, neoadjuvant immunochemotherapy (NAIC) for the treatment of locally advanced esophageal squamous cell carcinoma (ESCC) is used clinically but lacks of high-level clinical evidence. This study aimed to compare the safety and long-term efficacy of NAIC followed by minimally invasive esophagectomy (MIE) with those of neoadjuvant chemotherapy (NAC) followed by MIE.

A prospective, single-center, open-label, randomized phase III clinical trial was conducted at Henan Cancer Hospital, Zhengzhou, China. Patients were randomly assigned to receive either neoadjuvant toripalimab (240 mg) plus paclitaxel (175 mg/m2) + cisplatin (75 mg/m2) (toripalimab group) or paclitaxel + cisplatin alone (chemotherapy group) every 3 weeks for 2 cycles. After surgery, the toripalimab group received toripalimab (240 mg every 3 weeks for up to 6 months). The primary endpoint was event-free survival (EFS). The pathological complete response (pCR) and overall survival (OS) were key secondary endpoints. Adverse events (AEs) and quality of life were also assessed.

Between May 15, 2020 and August 13, 2021, 252 ESCC patients ranging from T1N1-3M0 to T2-3N0-3M0 were enrolled for interim analysis, with 127 in the toripalimab group and 125 in the chemotherapy group. The 1-year EFS rate was 77.9% in the toripalimab group compared to 64.3% in the chemotherapy group (hazard ratio [HR] = 0.62; 95% confidence interval [CI] = 0.39 to 1.00; P = 0.05). The 1-year OS rates were 94.1% and 83.0% in the toripalimab and chemotherapy groups, respectively (HR = 0.48; 95% CI = 0.24 to 0.97; P = 0.037). The patients in the toripalimab group had a higher pCR rate (18.6% vs. 4.6%; P = 0.001). The rates of postoperative Clavien-Dindo grade IIIb or higher morbidity were 9.8% in the toripalimab group and 6.8% in the chemotherapy group, with no significant difference observed (P = 0.460). The rates of grade 3 or 4 treatment-related AEs did not differ between the two groups (12.5% versus 12.4%).

The interim results of this ongoing trial showed that in resectable ESCC, the addition of perioperative toripalimab to NAC is safe, may improve OS and might change the standard treatment in the future.

Radical surgery for esophageal cancer requires macroscopic and microscopic clearance of all malignant tissue. A critical element of the procedure is achieving a negative circumferential margin (CRM) to minimize local recurrence. The utility of minimally invasive surgery poses challenges in replicating techniques developed in open surgery, particularly for hiatal dissection in esophago-gastrectomy. In this study, the technical approach and clinical and oncological outcomes for open and laparoscopic esophago-gastrectomy are described with particular reference to CRM involvement.

This cohort study included all patients undergoing either open or laparoscopic esophago-gastrectomy between January 2004 and June 2022 in a single tertiary center. A standard surgical technique for hiatal dissection of the esophago-gastric junction developed in open surgery was adapted for a laparoscopic approach. Clinical parameters, length of stay (LOS), postoperative complications, and mortality data were collected and analyzed by a Mann-Whitney U or Fisher's exact method.

Overall 447 patients underwent an esophago-gastrectomy in the study with 219 open and 228 laparoscopic procedures. The CRM involvement was 18.8% in open surgery and 13.6% in laparoscopic surgery. The 90-day-mortality for open surgery was 4.1 compared with 2.2% for laparoscopic procedures. Median Intensive care unit (ITU), inpatient LOS and 30-day readmission rates were shorter for laparoscopic compared with open esophago-gastrectomy (ITU: 5 versus 8 days, P= 0.0004; LOS: 14 versus 20 days, P= 0.022; 30-day re-admission 7.46 versus 10.50%). Postoperative complication rates were comparable across both cohorts. The rates of starting adjuvant chemotherapy were 51.8 after open and 74.4% in laparoscopic esophago-gastrectomy.

This study presents a standardized surgical approach to hiatal dissection for esophageal cancer. The authors present equivalence between open and laparoscopic esophago-gastrectomy in clinical, oncological, and survival outcomes with similar rates of CRM involvement. The authors also observe a significantly shorter hospital length of stay with the minimally invasive approach.

Epithelial-mesenchymal transition (EMT) has been identified as a driver of therapy resistance, particularly in esophageal adenocarcinoma (EAC), where transforming growth factor beta (TGF-β) can induce this process. Inhibitors of TGF-β may counteract the occurrence of mesenchymal, resistant tumor cell populations following chemo(radio)therapy and improve treatment outcomes in EAC. Here, we aimed to identify predictive biomarkers for the response to TGF-β targeting. In vitro approximations of neoadjuvant treatment were applied to publicly available primary EAC cell lines. TGF-β inhibitors fresolimumab and A83-01 were employed to inhibit EMT, and mesenchymal markers were quantified via flow cytometry to assess efficacy. Our results demonstrated a robust induction of mesenchymal cell states following chemoradiation, with TGF-β inhibition leading to variable reductions in mesenchymal markers. The cell lines were clustered into responders and non-responders. Genomic expression profiles were obtained through RNA-seq analysis. Differentially expressed gene (DEG) analysis identified 10 positively- and 23 negatively-associated hub genes, which were bioinformatically identified. Furthermore, the correlation of DEGs with response to TGF-β inhibition was examined using public pharmacogenomic databases, revealing 9 positively associated and 11 negatively associated DEGs. Among these, ERBB2, EFNB1, and TNS4 were the most promising candidates. Our findings reveal a distinct gene expression pattern associated with the response to TGF-β inhibition in chemo(radiated) EAC. The identified DEGs and predictive markers may assist patient selection in clinical studies investigating TGF-β targeting.

Textbook outcome is a composite quality measurement in esophageal cancer surgery. This study aimed to estimate the rate of textbook outcome esophagectomies at a high-volume center and investigate associations between textbook outcome and overall and recurrence-free survival.

A retrospective single-center study was conducted at Copenhagen University Hospital, Rigshospitalet, Denmark, analyzing esophagectomies performed from November 1, 2016, to December 31, 2021. Patients with primary carcinoma of the gastroesophageal junction who underwent elective and curative esophagectomy were included. The rate of textbook outcome esophagectomies was calculated, and the impact of textbook outcome on overall and recurrence-free survival was analyzed using Kaplan-Meier and Cox regression.

A total of 433 patients were included in the study. Textbook outcome was achieved in 195 patients (45%). Achieving textbook outcome was independently associated with improved overall survival (HR 0.67; P = .011) and with a median overall survival of 57 months and 32 months for patients with or without textbook outcome, respectively. A trend for improved recurrence-free survival was observed for patients with textbook outcome (HR 0.74; P = .064).

The present study found a consensus-based textbook outcome rate of 45%. Textbook outcome was found to be directly associated with improved overall survival. These results emphasize the association between improved short-term outcomes and long-term survival.

As a substantial waiting time is usually required for radical surgery, safe and effective preoperative neoadjuvant chemotherapy (NAC) is desired for the treatment of locally advanced head and neck squamous cell carcinoma (HNSCC). However, the significance of NAC in advanced HNSCC is still unclear. This study aimed to assess the safety and efficacy of NAC using the paclitaxel, carboplatin, and cetuximab (PCE) regimen.

We retrospectively evaluated the background characteristics, incidence of adverse events, overall response rate (ORR), pathological response, recurrence-free survival (RFS), and overall survival (OS) in 26 patients. Patients receiving the PCE regimen were further divided into two groups based on the number of chemotherapy cycles (one cycle or more) and eligibility for cisplatin. Patients aged ≥ 75 years and those with an estimated glomerular filtration rate (eGFR) < 60 mL/min were classified as ineligible for cisplatin.

The median age was 70 (27-81) years. The median eGFR at treatment initiation was 63.2 (41.1-89.7) mL/min. Fourteen (53.8%) patients were ineligible for cisplatin. Grade 3 or higher neutropenia was observed in 11 of 25 (42.3%) patients. No delay in or withdrawal from surgery was observed. The ORR was 65.4%. The 2-year RFS and OS were 61.5% and 76.7%, respectively. No significant differences in safety and efficacy between the number of chemotherapy cycles and cisplatin eligibility were observed.

NAC using the PCE regimen for patients with locally advanced HNSCC, including cisplatin-ineligible patients, has acceptable toxicity and favorable efficacy.

The higher pathologic complete response (pCR) after neoadjuvant chemoradiotherapy compared with neoadjuvant chemotherapy for locally advanced esophageal squamous cell carcinoma (ESCC) has not translated into significant gains in overall survival. Data on the long-term survival of patients who obtained a pCR after neoadjuvant chemotherapy are scarce. Therefore, this study aimed to evaluate the long-term prognosis and recurrence patterns in these patients.

The study enrolled patients with locally advanced ESCC after neoadjuvant chemotherapy followed by surgery in the authors' hospital between January 2007 and December 2020. The factors predictive of pCR were analyzed. Furthermore, propensity score-matching was performed for those who did and those who did not have a pCR using 1:5 ratio for a long-term survival analysis. Finally, the survival and recurrence patterns of patients obtaining pCR after neoadjuvant chemotherapy were analyzed.

A pCR was achieved for 61 (8.70%) of the 701 patients in the study. Univariate analysis showed that the patients without alcohol drinking had a higher possibility of obtaining a pCR, although multivariate analysis failed to confirm the difference as significant. After propensity score-matching, the 5-year overall survival was 84.50% for the patients who had a pCR and 52.90% for those who did not (p < 0.001). Among the 61 patients with a pCR, 9 patients (14.80%) experienced recurrence, including 6 patients with locoregional recurrence and 3 patients with distant metastasis.

Advanced ESCC patients with pCR after neoadjuvant chemotherapy had a favorable prognosis, yet some still experienced recurrence, particularly locoregional recurrence. Therefore, for this group of patients, regular follow-up evaluation also is needed.

The prognosis of patients with adenocarcinoma of the esophagus and esophagogastric junction (AEG) is poor. From current evidence, it remains unclear to what extent preoperative chemoradiotherapy (CRT) or preoperative and/or perioperative chemotherapy achieve better outcomes than surgery alone.

To assess the association of preoperative CRT and preoperative and/or perioperative chemotherapy in patients with AEG with overall survival and other outcomes.

Literature search in PubMed, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, ClinicalTrials.gov, and International Clinical Trials Registry Platform was performed from inception to April 21, 2023.

Two blinded reviewers screened for randomized clinical trials comparing preoperative CRT plus surgery with preoperative and/or perioperative chemotherapy plus surgery, 1 intervention with surgery alone, or all 3 treatments. Only data from participants with AEG were included from trials that encompassed mixed histology or gastric cancer. Among 2768 initially identified studies, 17 (0.6%) met the selection criteria.

The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed for extracting data and assessing data quality by 2 independent extractors. A bayesian network meta-analysis was conducted using the 2-stage approach.

Overall and disease-free survival, postoperative morbidity, and mortality.

The analyses included 2549 patients (2206 [86.5%] male; mean [SD] age, 61.0 [9.4] years) from 17 trials (conducted from 1989-2016). Both preoperative CRT plus surgery (hazard ratio [HR], 0.75 [95% credible interval (CrI), 0.62-0.90]; 3-year difference, 105 deaths per 1000 patients) and preoperative and/or perioperative chemotherapy plus surgery (HR, 0.78 [95% CrI, 0.64-0.91]; 3-year difference, 90 deaths per 1000 patients) showed longer overall survival than surgery alone. Comparing the 2 modalities yielded similar overall survival (HR, 1.04 [95% CrI], 0.83-1.28]; 3-year difference, 15 deaths per 1000 patients fewer for CRT). Similarly, disease-free survival was longer for both modalities compared with surgery alone. Postoperative morbidity was more frequent after CRT plus surgery (odds ratio [OR], 2.94 [95% CrI, 1.01-8.59]) than surgery alone. Postoperative mortality was not significantly more frequent after CRT plus surgery than surgery alone (OR, 2.50 [95% CrI, 0.66-10.56]) or after chemotherapy plus surgery than CRT plus surgery (OR, 0.44 [95% CrI, 0.08-2.00]).

In this meta-analysis of patients with AEG, both preoperative CRT and preoperative and/or perioperative chemotherapy were associated with longer survival without relevant differences between the 2 modalities. Thus, either of the 2 treatments may be recommended to patients.

Esophagectomy remains a procedure with one of the highest complication rates. Given the advances in medical and surgical management of patients and increased patient survival, the number of complications reported has increased. There are different grading systems for complications which vary based on severity or organ system, with the Esophageal Complications Consensus Group unifying them. Management involves conservative intervention and dietary modification to endoscopic interventions and surgical reintervention. Treatment is etiology specific but rehabilitation and patient optimization play a significant role in managing these complications by preventing them. Management is a step-up approach depending on the severity of symptoms.

Progression of the physical weakness during neoadjuvant therapy (NAT) in patients with esophageal or gastroesophageal junction cancer is a serious problem; however, prehabilitation during NAT has the potential to overcome the unmet need. Nevertheless, systematic reviews on this topic have not been summarized. Therefore, this systematic review aimed to determine prehabilitation's effectiveness, acceptability, and safety during NAT for patients with esophageal or gastroesophageal junction cancer. An electronic search was performed in the MEDLINE, Web of Science, CENTRAL, CINAHL, and PEDro databases. A meta-analysis was conducted to assess the effectiveness of prehabilitation during NAT, along with a descriptive analysis of acceptance and safety. This study analyzed data from three randomized controlled trials (RCTs) and nine non-RCTs involving 664 patients. The meta-analysis of two RCTs demonstrated that prehabilitation during NAT may be more effective than usual care in enhancing tolerance to NAT and grip strength; moreover, one RCT and three non-RCTs revealed that prehabilitation may reduce the risk of postoperative complications. The adherence rates for exercise programs in two RCTs and seven non-RCTs were 55-76%. Additionally, two studies reported a 76% adherence rate for multimodal prehabilitation programs, including exercise, dietary, and psychological care. Six studies reported no serious prehabilitation-related adverse events during NAT. Prehabilitation during NAT may be a safe and beneficial intervention strategy for patients with esophageal or gastroesophageal junction cancer. However, the investigation of strategies to enhance adherence is essential. Furthermore, additional high-quality RCTs are needed to examine the effect of prehabilitation during NAT.

Radiotherapy combined with fluorouracil (5FU) and cisplatin for locally advanced esophageal cancer is associated with a 20-25% pathologic complete response (pCR) rate. Cetuximab increases the efficacy of radiotherapy in patients with head and neck carcinomas. The aim of this phase I/II trial was to determine the optimal doses and the pCR rate with chemoradiotherapy (C-RT) plus cetuximab.

A 45-Gy radiotherapy regimen was delivered over 5 weeks. The phase I study determined the dose-limiting toxicity and the maximum tolerated dose of 5FU-cisplatin plus cetuximab. The phase II trial aimed to exhibit a pCR rate > 20 % (25 % expected), requiring 33 patients (6 from phase I part plus 27 in phase II part). pCR was defined as ypT0Nx.

The phase I study established the following recommended doses: weekly cetuximab (400 mg/m2 one week before, and 250 mg/m2 during radiotherapy); 5FU (500 mg/m2/day, d1-d4) plus cisplatin (40 mg/m2, d1) during week 1 and 5. In the phase II part, 32 patients received C-RT before surgery, 31 patients underwent surgery, and resection was achieved in 27 patients. A pCR was achieved in five patients (18.5 %) out of 27. After a median follow-up of 19 months, the median progression-free survival was 13.7 months, and the median overall survival was not reached.

Adding cetuximab to preoperative C-RT was toxic and did not achieve a pCR > 20 % as required. The recommended doses, determined during the phase I part, could explain these disappointing results due to a reduction in chemotherapy dose-intensity.

This trial was registered with EudraCT number 2006-004770-27.

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.

While surgery is the primary curative treatment for resectable gastric and gastroesophageal junction (GEJ) cancer, rates of locoregional and distant recurrence remain high with surgery alone, especially in more advanced disease. Multimodal approaches with perioperative therapy including chemotherapy and/or radiation therapy (RT) have thus evolved as ways to reduce the rates of disease recurrence and improve survival outcomes. This review article provides a comprehensive literature review on the role of preoperative RT for resectable gastric and GEJ cancer.

A literature review on the role of preoperative RT for resectable gastric and GEJ cancer was conducted.

Preoperative RT has the potential to facilitate tumor downstaging and improved R0 resection, allowing for better locoregional control and thereby survival. For resectable locally advanced GEJ cancer, preoperative chemoradiotherapy (CRT) is currently a standard of care option along with perioperative chemotherapy, based on evidence from randomized trials. In resectable gastric cancer, however, the role of preoperative CRT is less defined with no randomized data to date, although phase II single-arm studies have shown promising results. Current standard of care for gastric cancer remains perioperative chemotherapy, with consideration for preoperative CRT in select cases.

Results from ongoing and future randomized controlled trials are expected to help define the role of preoperative CRT compared to perioperative chemotherapy alone as well as postoperative CRT for gastric and GEJ cancer.