Elderly patients, particularly those aged 70 and above, often present with comorbidities such as coronary heart disease (CHD), chronic obstructive pulmonary disease (COPD), diabetes mellitus (DM), and high blood pressure (HBP). These comorbid diseases complicate treatment. However, the impact of these comorbidities on survival outcomes and complications in elderly patients undergoing esophagectomy for esophageal squamous cell carcinoma (ESCC) remains under-researched.

This cohort study examined ESCC patients aged 70 and older who underwent esophagectomy. Patients were divided into two cohorts: those without preoperative comorbid diseases (NCD group) and those with preoperative comorbid diseases (CD group). Data were obtained from the Sichuan Cancer Hospital and Institute Esophageal Cancer Case Management Database between May 2016 and August 2021, with follow-up concluding on December 20, 2023.

A total of 469 patients met the inclusion criteria, with 206 patients in the comorbid diseases (CD group) and 263 patients without (NCD group). The median follow-up period was 47.5 months, the median overall survival (OS) was 51.6 months and median disease-free survival (DFS) was 33.0 months, with no statistically significant difference in OS and DFS in 2 groups. The incidence of grade 3 or higher complications in the NCD and CD groups was similar, with no statistically significant difference. The most common grade 3 or higher complications were pulmonary infection, hydrothorax, anastomotic stenosis, and anastomotic leakage.

Preoperative comorbidities, including CHD, COPD, DM, and HBP, did not significantly impact the long-term survival or disease-free survival of elderly ESCC patients undergoing esophagectomy.

This study aimed to compare the survival outcomes of paclitaxel liposome-based chemoradiotherapy, with or without rhEndostatin, in patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC).

Patients with ESCC treated with paclitaxel liposome-based definitive chemoradiotherapy (dCRT), with or without rhEndostatin (E), between February 2015 and June 2020 were included. Patients received induction chemotherapy followed by concurrent chemoradiotherapy, with or without rhEndostatin. The chemotherapy regimen consisted of platinum-based doublet (paclitaxel liposome + cisplatin/nedaplatin). RhEndostatin was administered at a dose of 30 mg/d from day 1 to day 5 of each chemotherapy cycle. Total radiotherapy dose was 66-68 Gy, delivered in fractions of 2.0-2.2 Gy/d. Follow-up continued until December 2023. The primary endpoints were 3-year progression-free survival (PFS) rate. Secondary endpoints included 3-year overall survival (OS) rate, objective response rate (ORR), disease control rate (DCR), and toxicity.

A total of 80 patients were included, with 34 in the dCRT group and 46 in the E + dCRT group. The 3-year PFS was 26.47% (95% confidence interval [CI] 13.19-41.81) in the dCRT group and 56.29% (95% CI 40.79-69.20) in the E + dCRT group (Hazard ratio (HR), 0.50; 95% CI 0.28-0.89, P = 0.012). Patients in the E + dCRT group had a superior 3-year OS compared to those in the dCRT group (80.44% [95% CI 65.77-89.30] vs. 47.06% [95% CI 29.83-62.52]; HR, 0.40; 95% CI 0.21-0.72; P = 0.003). The ORR was 91.18% in the dCRT group and 95.65% in the E + dCRT group. The most common grade 3-4 toxicities were leukopenia, neutropenia, and thrombocytopenia.

The addition of rhEndostatin to paclitaxel liposome-based dCRT may improve clinical outcomes for patients with unresectable ESCC while maintaining manageable toxicities. However, further prospective randomized controlled studies are necessary to confirm the survival benefits of this treatment strategy.

Esophageal cancer is one of the most common malignant tumors, with China accounting for 50% of the world's total incidence. Concurrent chemoradiotherapy (cCRT) with platin-based dual-drug regimen is the standard treatment for inoperable, locally advanced esophageal cancer in patients with a good performance status. However, certain patients possess risk factors that heighten toxicity and reduce their tolerance to cCRT, thereby challenging the feasibility of standard treatment. This study evaluates an alternative therapeutic approach combining programmed cell death protein 1 inhibitor (PD-1 inhibitor), definitive radiotherapy, and immunonutrition support for patients with unresectable non-metastatic esophageal cancer expressing PD-L1 who are intolerant to cCRT.

This is a phase II, single-arm, multicenter clinical trial involving patients with histologically confirmed unresectable esophageal squamous cell carcinoma (ESCC), who exhibit positive PD-L1 and are unsuitable for cCRT. Participants will receive a total radiotherapy dose of 50-60 Gy in 25-30 fractions, sintilimab (200 mg every three weeks), alongside, supplemented by enteral nutritional emulsion (600-1600 ml/day). The primary endpoint is the 1-year progression-free survival rate, with secondary endpoints including objective response rate, overall survival and incidence of adverse events.

This research has the potential to redefine treatment for inoperable ESCC patients who cannot tolerate conventional therapies. By evaluating a less toxic regimen that combines immunotherapy, radiotherapy, and nutritional support, we aim to determine if this approach can improve both survival rates and quality of life. The synergistic effects of immunonutrition support and PD-1 inhibitor will also be explored.

NCT06342167.

Esophageal cancer (ESCA) poses a significant challenge in oncology because of the limited treatment options and poor prognosis. Therefore, enhancing the therapeutic effects of radiotherapy for ESCA and identifying relevant therapeutic targets are crucial for improving both the survival rate and quality of life of patients.

To define the role of the transcription factor Snail family transcriptional repressor 1 (SNAI1) in ESCA, particularly its regulation of radiosensitivity.

A comprehensive analysis of TCGA data assessed SNAI1 expression in ESCA. Survival curves correlated SNAI1 levels with radiotherapy outcomes. Colony formation assays, flow cytometry, and a xenograft model were used to evaluate tumor radiosensitivity and apoptosis. Western blot validated protein expression, while Chromatin immunoprecipitation assays examined SNAI1's role in regulating epithelial-mesenchymal transition (EMT).

SNAI1 expression in ESCA cell lines and clinical specimens emphasizes its central role in this disease. Elevated SNAI1 expression is correlated with unfavorable outcomes in radiotherapy. Downregulation of SNAI1 enhances the sensitivity of ESCA cells to ionizing radiation (IR), resulting in remarkable tumor regression upon IR treatment in vivo. This study underscores the direct involvement of SNAI1 in the regulation of EMT, particularly under IR-induced conditions. Furthermore, inhibiting deacetylation effectively suppresses EMT, suggesting a potential avenue to enhance the response to radiotherapy in ESCA.

This study highlights SNAI1's role in ESCA radiosensitivity, offering prognostic insights and therapeutic strategies to enhance radiotherapy by targeting SNAI1 and modulating EMT processes.

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.

The standard treatment for elderly patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC) is definitive chemoradiotherapy with S-1. However, the 3-year overall survival (OS) is limited to approximately 40%. Tislelizumab is the first- and second-line standard treatment for advanced ESCC with tolerable toxicity. In this study, we aimed to explore a new curative strategy for locally advanced unresectable ESCC in the elderly by combining tislelizumab with chemoradiotherapy.

This study is an open-label, multicenter, investigator-initiated phase II clinical trial in older patients with inoperable locally advanced ESCC evaluating tislelizumab plus concurrent chemoradiotherapy compared with concurrent chemoradiotherapy. The main inclusion criteria were pathological confirmation of locally advanced inoperable ESCC at clinical cT1N2-3M0 or cT2-4bN0-3M0 (stage II-IVA), age ≥ 70 years, absence of previous systemic anti-tumor therapy, and adequate organ function. A total of 136 patients will be recruited from approximately seven centers (in Tianjin, Chengdu, Taiyuan, Zhengzhou, Shijiazhuang, Changsha, Nanjing) over a period of 18 months and randomized in a 1:1 ratio to receive tislelizumab in combination with concurrent chemoradiotherapy (tislelizumab + S-1 + radiotherapy) or concurrent chemoradiotherapy (S-1 + radiotherapy). The efficacy and safety of the treatment will be evaluated during the therapy and follow-up period until disease progression, death, or the end of the trial. The primary study endpoint was investigator-assessed progression-free survival (PFS), and secondary study endpoints were OS, objective response rate (ORR), duration of remission (DOR), and safety. Fresh or archival tumor tissues and peripheral blood samples will be used in exploratory studies.

This study is the first "programmed death-1 (PD-1) inhibitor combined with concurrent chemoradiotherapy" for elderly patients with inoperable locally advanced ESCC (NCT06061146). The synergistic efficacy of combined definitive concurrent chemoradiotherapy with tislelizumab is expected to result in survival benefits for elderly patients with inoperable locally advanced ESCC. Because S-1 plus concurrent radiotherapy is the standard treatment option for locally advanced ESCC in older patients, the combination of definitive concurrent chemoradiotherapy and tislelizumab has the potential to change the standard ESCC therapeutic strategy with comparable safety.

ClinicalTrials.gov NCT06061146.Registered 9/10/2023.

Definitive concurrent chemoradiotherapy (DCRT) is the standard treatment for locally advanced unresectable esophageal cancer (EC). However, acute fatal radiation pneumonitis (AFRP) is one of the most harmful complications and it is still controversial which factors pose a greater risk.

This case-control study aims to investigate the relationship between AFRP and lung volume-dose parameters in patients with esophageal cancer undergoing DCRT.

Cases are patients who died of AFRP after DCRT, whereas controls are patients who did not develop RP. Participants were enrolled using the International Classification of Diseases Codes Searching and then verified by medical record review. One-to-three propensity score matching was performed between EC patients undergoing DCRT who died from AFRP and those who did not develop radiation pneumonitis(RP). Prognostic factors were determined using univariate and multivariate analyses. The exposure factors were lung volume-dose parameters, including V5, V20, V30, and mean lung dose (MLD). Overall survival was compared between the two groups of patients before and after propensity score matching.

17 cases were confirmed with AFRP among 568 EC patients were treated with DCRT between June 2008 and June 2013, and 51 cases with no RP matched by PSM method in the control group. The median V5 and MLD values in the case group were significantly higher than the control group: 88.39% versus 65.045% and 17.325 gray (Gy) versus 14.38 Gy, respectively. V5 > 60%, V20 > 25%, and MLD > 15 Gy were identified as independent risk factors for AFRP. V5 > 80% significantly increased the susceptibility to AFRP and predicted worse overall survival.

V5 > 60%, V20 > 25% and MLD > 15 Gy are key risk factors for AFRP in EC patients undergoing DCRT. Furthermore, V5 > 80% is a strong indicator of mortality risk.

Our goal is to develop a nomogram model to predict overall survival (OS) for elderly esophageal squamous cell carcinoma (ESCC) patients receiving definitive radiotherapy (RT) or concurrent chemoradiotherapy (CRT), aiding clinicians in personalized treatment planning with a risk stratification system.

A retrospective study was conducted on 718 elderly ESCC patients treated with RT or CRT at 10 medical centers (3JECROG) from January 2004 to November 2016. We identified independent prognostic factors using univariate and multifactorial Cox regression to construct a nomogram model. Its effectiveness was evaluated using concordance statistics (C-index), area under the curve (AUC), net reclassification index (NRI), and integrated discrimination improvement (IDI), and compared against the AJCC staging. Additionally, decision curve analysis (DCA) assessed the model's clinical benefit. Patients were stratified into low, intermediate, and high-risk groups using the nomogram, and their prognoses in various disease stages were analyzed.

Significant prognostic factors identified included diabetes, tumor volume (GTVp), tumor length, location, and clinical stages (T, N, M), and RT response. Multivariate analysis confirmed these as independent factors for OS. The nomogram outperformed AJCC staging in prediction accuracy and discrimination, evidenced by a higher C-index, better AUC, and significant NRI and IDI values. Patients categorized by the nomogram demonstrated distinct 5-year OS rates, with a higher C-index than AJCC staging (0.597 vs. 0.562) .

The study identified key prognostic factors for elderly ESCC patients receiving RT or CRT. The nomogram model, based on these factors, showed enhanced prediction performance, discrimination, and clinical utility compared to AJCC staging. This risk stratification provided more accurate survival predictions and aided in personalized risk management.

Esophageal cancer (EC) often occurs in the elderly, with approximately 33% of patients aged ≥ 75 years at the time of diagnosis.

To evaluate the prognostic factors for radiotherapy (RT) in elderly patients with unresectable EC.

We retrospectively analyzed the clinical characteristics, toxic reactions, and survival information of EC patients aged ≥ 75 years who underwent intensity-modulated RT at Lu'an Hospital of Anhui Medical University between January 2016 and September 2023. Kaplan-Meier analysis was used to draw the overall survival (OS) curves, and Cox regression analysis was employed to evaluate the influence of various clinical factors on the prognosis.

A total of 139 patients were enrolled. The median follow-up time was 52.0 months. The median OS was 20.0 months. The 1-year, 2-year, 3-year, and 5-year OS rates were 69.8%, 38.7%, 28.2%, and 17.5%, respectively. Univariate analysis showed that age, radiation dose, and chemotherapy had no significant impact on prognosis. Multivariate analysis indicated that clinical stage [III-IVa vs I-II, hazard ratio (HR) = 2.421, 95% confidence interval (CI): 1.242-4.718, P = 0.009; IVb vs I-II, HR = 4.222, 95%CI: 1.888-9.438, P < 0.001), Charlson comorbidity index (CCI) (0 vs ≥ 1, HR = 1.539, 95%CI: 1.015-2.332, P = 0.042), and nutritional risk screening 2002 (NRS2002) (< 3 vs ≥ 3, HR = 2.491, 95%CI: 1.601-3.875, P < 0.001) were independent prognostic factors for OS.

Our results suggest that CCI and NRS2002 were independent prognostic factors of OS for unresectable elderly EC patients undergoing RT. For elderly patients with EC, full attention should be given to biological age-related indicators, such as comorbidities and nutrition, when formulating treatment protocols. These factors should be considered in future clinical practice.

Elderly patients with esophageal cancer can benefit from concurrent chemoradiotherapy (CCRT). However, the optimal concurrent chemotherapy regimen remains undetermined. We aimed to compare the efficacy and safety of CCRT with paclitaxel-based or S-1 regimens in treating elderly patients with esophageal squamous cell carcinoma (ESCC).

From January 2016 to November 2022, a total of 349 patients aged 70 and above with ESCC were included. The patient population was divided into two treatment groups: patients receiving paclitaxel-based CCRT were allocated to the TP group, and those receiving S-1 regimen CCRT were allocated to the S-1 group. Propensity score matching (PSM) was used to balance potential biases. Survival outcomes, overall response rate, and treatment-related toxicities were assessed.

After PSM, there were 82 patients in each group. The median follow up of the surviving patients was 42.6 months (IQR 28.0-58.8 months). The 2-year overall survival (OS) rate (71.4% vs 65.4%; log-rank P = 0.010) and progression-free survival (PFS) rate (64.4% vs 58.0%; log-rank P = 0.048) were significantly higher in the TP group. Compared with the S-1 group, the TP group experienced a higher rate of grade 3 and above hematologic toxicities, such as leukopenia (47.6% vs 15.9%, P < 0.001) and neutropenia (35.4% vs 6.1%, P < 0.001). One patient in the TP group and two patients in the S-1 group had grade 5 toxic effects.

Our findings suggest that paclitaxel-based CCRT was well tolerated in elderly patients with ESCC and provided significant survival benefits over S-1 regimen.

Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC). However, the optimal radiotherapy regimen, particularly in terms of total dose and planned range of irradiation field, remains unclear. This phase III clinical trial aimed to compare the survival benefits between different radiation doses and different target fields.

This trial compared two aspects of radiation treatment, total dose and field, using a two-by-two factorial design. The high-dose (HD) group received 59.4 Gy radiation, and the standard-dose (SD) group received 50.4 Gy. The involved field irradiation (IFI) group and elective nodal irradiation (ENI) group adopted different irradiation ranges. The participants were assigned to one of the four groups (HD+ENI, HD+IFI, SD+ENI and SD+IFI). The primary endpoint was overall survival (OS), and the secondary endpoints included progression-free survival (PFS). The synergy indexwas used to measure the interaction effect between dose and field.

The interaction analysis did not reveal significant synergistic effects between the dose and irradiation field. In comparison to the target field, patients in IFI or ENI showed similar OS (hazard ratio [HR] = 0.99, 95% CI: 0.80-1.23, p = 0.930) and PFS (HR = 1.02, 95% CI: 0.82-1.25). The HD treatment did not show significantly prolonged OS compared with SD (HR = 0.90, 95% CI: 0.72-1.11, p = 0.318), but it suggested improved PFS (25.2 months to 18.0 months). Among the four groups, the HD+IFI group presented the best survival, while the SD+IFI group had the worst prognosis. No significant difference in the occurrence of severe adverse events was found in dose or field comparisons.

IFI demonstrated similar treatment efficacy to ENI in CCRT of ESCC. The HD demonstrated improved PFS, but did not significantly improve OS. The dose escalation based on IFI (HD+IFI) showed better therapeutic efficacy than the current recommendation (SD+ENI) and is worth further validation.

Neoadjuvant chemoradiotherapy (nCRT) followed by surgery remains a standard of care for resectable esophageal cancer (EC), and definitive chemoradiotherapy (dCRT) is an alternative for unresectable diseases. However, it is controversial for the use of the two aggressive regimens in elderly patients.

We systematically searched multiple databases for studies comparing overall survival (OS) and/or progression-free survival (PFS) between dCRT and surgery (nCRT + surgery or surgery alone) or between dCRT and radiotherapy (RT) alone in elderly patients (age ≥ 65 years) until March 28, 2024. Statistical analysis was performed using random-effects model.

Fourty-five studies with 33,729 patients were included. dCRT significantly prolonged OS (hazard ratio [HR] = 0.64, 95% confidence interval [CI]: 0.58-0.70) and PFS (HR = 0.67, 95% CI: 0.60-0.76) compared to RT alone for unresectable EC, and resulted in a worse OS compared to surgery for resectable cases (HR = 1.34, 95% CI: 1.23-1.45). Similar results of OS were also observed when the multivariate-adjusted HRs were used as the measure of effect (dCRT vs. RT alone: HR = 0.65, 95% CI: 0.58-0.73; dCRT vs. surgery: HR = 1.49, 95% CI: 1.28-1.74). Subgroup analyses according to age group (≥ 70, ≥ 75, or ≥ 80 years), study design, study region, histological type, radiation field, chemotherapy regimen revealed comparable results.

nCRT + surgery is likely a preferred strategy for elderly patients with good physiological conditions; and dCRT is a better alternative for unresectable cases. Advanced age alone does not appear to be a key predictor for the tolerability of the two aggressive treatments.

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.

Explore the efficacy and safety of involved-field irradiation (IFI) combined with S-1 as definitive concurrent chemoradiotherapy (dCRT) for locally advanced elderly esophageal squamous cell carcinoma (ESCC), under the premise of intensity-modulated radiotherapy (IMRT).

We designed a prospective single-arm phase II study. The study enrolled 91 patients aged 75 to 92 years. Eligible participants had histologically confirmed squamous cell carcinoma, stage II to IV disease based on the 8th edition of the American Joint Committee on Cancer (AJCC). All elderly patients (EPs) received dCRT with S-1. which was administered orally twice daily for 28 days. The radiotherapy dose was 61.2 Gy delivered in 34 fractions or 50.4 Gy delivered in 28 fractions. The primary endpoint was 2-year overall survival (OS), and the secondary endpoints were progression-free survival (PFS), local control rate (LCR), and safety.

From July 2017 to July 2021, we enrolled EPs with ESCC who were treated at the Jiangsu Cancer hospital. As of August 1, 2023, the median follow-up of surviving EPs was 31.4 months (IQR: 25.2 to 72.6 months). 83 patients (91.2%) completed the whole course of treatment. The 2-year OS rate was 59.2%, and the PFS rate was 43.7%. The most common grade 1 to 2 adverse effects (AEs) were radiation esophagitis (79.1%), and then were radiation pneumonia (46.2%). Anemia (41.8%) was the most common of grade 1 to 2 hematologic toxicity. The incidence of grade 3 or above AEs was 24.2%, and the incidence of leukopenia was the highest (11.0%). There was not one death due to treatment-related toxicity. In a subgroup analysis of radiotherapy doses, we found no statistically significant differences in PFS (P = 0.465) and OS (P = 0.345) in EPs with ESCC who received 50.4 Gy and 61.2 Gy, and that patients in the 50.4 Gy group had lower dermatitis (P = 0.045) and anemia (P = 0.004).

IF-IMRT combined with S-1 is a promising regimen for elderly ESCC. And the radiotherapy dose of 50.4 Gy remains the standard dose for EPs with ESCC undergoing CCRT.

In older patients, esophageal squamous cell carcinoma (ESCC) is difficult to treat using standard therapies, including surgery and cisplatin-based chemoradiotherapy. Paclitaxel (PTX) has radiosensitizing activity. We conducted a phase I trial of PTX combined with radiotherapy to establish a standard therapy for locally advanced ESCC in older patients.

Enrollment was conducted at six centers in Japan from April 2016 to September 2019. The participants were aged ≥ 70 years, had locally advanced ESCC, and were intolerant to surgery or unwilling. A fixed 60-Gy radiation dose was administered in 30 fractions. PTX dosing levels started at 30 mg/m2 weekly for 6 weeks. Depending on the number of DLTs, the dose was set to be increased by 10 mg/m2 or switched to biweekly. A geriatric assessment was performed before treatment using the Geriatric-8 screening tool. The primary endpoint was dose-limiting toxicity (DLT).

We enrolled 24 patients (6 per group); DLT was observed in one (grade 4 hypokalemia), one (grade 3 aspiration), two (grade 3 radiodermatitis, grade 3 esophageal hemorrhage), and two (grade 3 anorexia, grade 5 pneumonitis) patients in the weekly PTX 30, 40, 50, and 60 mg/m2 groups, respectively. All adverse events, except death in the 60 mg/m2 group, showed reversible improvement, and the safety profile was considered acceptable. The 2-year survival and complete response rates were 40.0% and 54.2%, respectively. There was a significant difference in survival between favorable and unfavorable Geriatric-8 scores.

The recommended PTX dose with concomitant radiation was determined to be 50 mg/m2 weekly. Phase II trials at this dose are underway.

Current studies have substantiated the sparing effect of ultra-high dose rate irradiation (FLASH) in various organs including the brain, lungs, and intestines. Whether this sparing effect extends to esophageal tissue remains unexplored. This study aims to compare the different responses of esophageal tissue in histological and protein expression levels following conventional dose rate irradiation (CONV) and FLASH irradiation to ascertain the presence of a sparing effect.

C57 female mice were randomly divided into three groups: control, CONV, and FLASH groups. The chest region of the mice in the radiation groups was exposed to a prescribed dose of 20 Gy using a modified electron linear accelerator. The CONV group received an average dose rate of 0.1 Gy/s, while the FLASH group received an average dose rate of 125 Gy/s. On the 10th day after irradiation, the mice were euthanized and their esophagi were collected for histopathological analysis. Subsequently, label-free proteomic quantification analysis was performed on esophageal tissue. The validation process involved analyzing transmission electron microscopy images and utilizing the parallel reaction monitoring method.

Histopathology results indicated a significantly lower extent of esophageal tissue damage in the FLASH group compared to the CONV group (p < 0.05). Label-free quantitative proteomic analysis revealed that the sparing effect observed in the FLASH group may be attributed to a reduction in radiation-induced protein damage associated with mitochondrial functions, including proteins involved in the tricarboxylic acid cycle and oxidative phosphorylation, as well as a decrease in acute inflammatory responses.

Compared with CONV irradiation, a sparing effect on esophageal tissue can be observed after FLASH irradiation. This sparing effect is associated with alleviated mitochondria damage and acute inflammation.

This phase 3 trial aimed to compare the efficacy and safety of capecitabine or capecitabine plus oxaliplatin (XELOX) with those of fluorouracil plus cisplatin (PF) in definitive concurrent chemoradiotherapy (DCRT) for inoperable locally advanced esophageal squamous cell carcinoma (ESCC).

Patients were randomly assigned to receive two cycles of capecitabine, XELOX, or PF along with concurrent intensity-modulated radiation therapy. Patients in each arm were again randomly assigned to receive two cycles of consolidation chemotherapy or not. The primary end points were 2-year overall survival (OS) rate and incidence of grade ≥3 adverse events (AEs).

A total of 246 patients were randomly assigned into the capecitabine (n = 80), XELOX (n = 85), and PF (n = 81) arms. In capecitabine, XELOX, and PF arms, the 2-year OS rate was 75%, 66.7%, and 70.9% (capecitabine v PF: hazard ratio [HR], 0.91 [95% CI, 0.61 to 1.35]; nominal P = .637; XELOX v PF: 0.86 [95% CI, 0.58 to 1.27]; P = .444); the median OS was 40.9 (95% CI, 34.4 to 49.9), 41.9 (95% CI, 28.6 to 52.1), and 35.4 (95% CI, 30.4 to 45.4) months. The incidence of grade ≥3 AEs during the entire treatment was 28.8%, 36.5%, and 45.7%, respectively. Comparing the consolidation chemotherapy with the nonconsolidation chemotherapy groups, the median OS was 41.9 (95% CI, 34.6 to 52.8) versus 36.9 (95% CI, 28.5 to 44) months (HR, 0.71 [95% CI, 0.52 to 0.99]; nominal P = .0403).

Capecitabine or XELOX did not significantly improve the 2-year OS rate over PF in DCRT for inoperable locally advanced ESCC. Capecitabine showed a lower incidence of grade ≥3 AEs than PF did.

We report here a case of postoperative recurrent adenosquamous carcinoma (ASC) of the esophagogastric junction (EGJ) treated with S-1 therapy. A 79-year-old woman was diagnosed with carcinoma of the EGJ. Thoracoscopic subtotal esophagectomy was performed, and pathological examination revealed advanced ASC with lymph node metastasis. Five months after surgery, multiple lung metastases and multiple lymph node metastases were observed, and the patient was treated with S-1 monotherapy, which showed partial response and may be effective for advanced ASC of the EGJ. On the other hand, immunohistological analysis of the tumors showed a relatively wide range of areas that could differentiate into both adenocarcinoma and squamous cell carcinoma, suggesting that tumor cells with multidifferentiation potential, or at least the ability to differentiate into both adeno-epithelial and squamous epithelial cells, were the likely source of the tumors.

The gold standard for resectable, locally advanced esophageal squamous cell carcinoma (ESCC) is surgery-based treatment; however, it is unclear whether esophagectomy or chemoradiotherapy is suitable for older patients. This retrospective study aimed to identify the treatment outcomes of surgery-based therapy versus definitive chemoradiotherapy (dCRT) as an initial treatment for older patients with resectable, locally advanced ESCC.

Data from 434 patients who received radical treatment for resectable, locally advanced ESCC were collected from January 2011 to December 2020. Of the patients >75 years of age, 49 underwent radical esophagectomy and 26 received dCRT. Survival was compared between the surgery and dCRT groups.

The mean ages of the surgery and chemoradiotherapy groups were 77.3 and 78.8 years, respectively. Differences in overall survival (OS) between the two groups were not statistically significant (3-year OS: surgery 66.2%, dCRT 55.7%, p = 0.236). Multivariate analysis for OS showed a hazard ratio of 1.229 for dCRT versus surgery (90% confidence interval 0.681-2.217). OS did not differ between the groups in any of the performance statuses. For patients who were able to receive chemotherapy using fluorouracil and cisplatin, OS tended to be better in the surgery group, but the difference was not statistically significant (3-year OS: surgery 68.1%, dCRT 51.8%, p = 0.117).

There was no clear difference in survival outcome between surgery-based therapy and dCRT as an initial treatment for esophageal cancer in older patients. Either treatment may be an option for older patients.

Esophagus cancer as a second primary malignancy (esophagus-2) is increasingly common, but its prognosis is poorly understood. This study aims to examine the overall, non-cancer related and cancer-specific survival of patients diagnosed with esophagus-2 compared to the first primary esophagus cancer (esophagus-1).

We included primary esophagus cancer patients diagnosed from 1975 to 2019 in the Surveillance, Epidemiology, and End Results program. Esophagus-2 was identified in patients with a previous diagnosis of non-esophageal primary malignancy. Hazard ratios of overall, esophagus cancer-specific and non-cancer related mortality were estimated among patients with esophagus-2 compared to esophagus-1, adjusting for age, gender, tumor stage and other demographic and clinical characteristics.

A total of 74,521 and 14,820 patients were identified as esophagus-1 and esophagus-2 respectively. Esophagus-2 patients suffered lower risk of esophagus cancer-specific mortality in initial 5 years but with similar risk thereafter, independent of tumor characteristics and treatment. In the first 5 years after diagnosis, patients with esophagus-2 had similar risk of overall mortality with those with esophagus-1 but increased risk thereafter. As for non-cancer related mortality, esophagus-2 patients had higher risk all along.

Esophagus-2 patients should not be entirely excluded from clinical trial and a 3-year exclusion window is suggested. A conservative approach to manage esophagus-2 solely based on malignancy history is not supported but effort should be put into surveillance, prevention and management of the comorbidities and complications for the first malignancy.

Definitive chemoradiotherapy (dCRT) is the standard treatment for unresectable locally advanced esophageal cancer. However, this treatment is associated with substantial toxicity, and most malnourished or elderly patients are unable to complete this therapy. Therefore, there is a need for a more suitable radiotherapy combination regimen for this population. This study was aimed to evaluate the efficacy and safety of a combination regimen comprising chemotherapy with nimotuzumab and S-1 and concurrent radiotherapy for patients with fragile locally advanced esophageal cancer with a high Nutritional Risk Screening 2002 (NRS-2002) score.

Eligible patients with unresectable esophageal carcinoma who had an NRS-2002 score of 2 or higher were enrolled. They were treated with S-1 and nimotuzumab with concurrent radiotherapy, followed by surgery or definitive radiotherapy. The primary endpoint was the locoregional control (LRC) rate.

A total of 55 patients who met the study criteria were enrolled. After completion of treatment, surgery was performed in 15 patients and radiotherapy was continued in 40 patients. The median follow-up period was 33.3 [95% confidence interval (95% CI), 31.4-35.1)] months. The LRC rate was 77.2% (95% CI, 66.6%-89.4%) at 1 year in the entire population. The overall survival (OS) rate and event-free survival (EFS) rate were 57.5% and 51.5% at 3 years, respectively. Surgery was associated with better LRC [hazard ratio (HR)=0.16; 95% CI, 0.04-0.70; P=0.015], OS (HR=0.19; 95% CI, 0.04-0.80; P=0.024), and EFS (HR=0.25; 95% CI, 0.08-0.75; P=0.013). Most adverse events were of grade 1 or 2, and no severe adverse events occurred.

For malnourished or elderly patients with locally advanced esophageal cancer, radiotherapy combined with nimotuzumab and S-1 is effective and has a good safety profile.

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.

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.

Chimeric antigen receptor natural killer (CAR-NK) cells have been found to be successful in treating hematologic malignancies and present potential for usage in solid tumors.

In this study, we created CD276-targeted CAR-expressing NK cells from pluripotent stem cells (iPSC CD276-targeted CAR-NK cells) and evaluated their cytotoxicity against esophageal squamous cell carcinoma (ESCC) using patient-specific organoid (PSO) models comprising of both CD276-positive and CD276-negative adjacent epithelium PSO models (normal control PSO, NC PSO) as well as primary culture of ESCC cell models. In addition, in vitro and in vivo models such as KYSE-150 were also examined. iPSC NK cells and NK-free media were used as the CAR-free and NK-free controls, respectively.

The positive CD276 staining was specifically detected on the ESCC membrane in 51.43% (54/105) of the patients of all stages, and in 51.35% (38/74) of stages III and IV. The iPS CD276-targeted CAR-NK cells, comparing with the iPS NK cells and the NK-free medium, exhibited specific and significant cytotoxic activity against CD276-positive ESCC PSO rather than CD276-negative NC PSO, and exhibited significant cytotoxicity against CD276-expressing cultured ESCC cells, as well as against CD276-expressing KYSE-150 in vitro and in BNDG mouse xenograft.

The efficacy of the iPSC CD276-targeted CAR-NK cells demonstrated by their successful treatment of CD276-expressing ESCC in a multitude of pre-clinical models implied that they hold tremendous therapeutic potential for treating patients with CD276-expressing ESCC.

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.

A pathologic complete response (pCR) to neoadjuvant chemoradiotherapy (nCRT) is seen in up to 40% of the patients with esophageal squamous cell carcinoma (ESCC). No nomogram has been constructed for the prediction of pCR for patients whose primary chemotherapy was a taxane-based regimen. The aim is to identify characteristics associated with a pCR through analyzing multiple pre- and post-nCRT variables and to develop a nomogram for the prediction of pCR for these patients by integrating clinicopathological characteristics and hematological biomarkers.

We analyzed 293 patients with ESCC who underwent nCRT followed by esophagectomy. Clinicopathological factors, hematological parameters before nCRT, and hematotoxicity during nCRT were collected. Univariate and multivariate logistic regression analyses were performed to identify predictive factors for pCR. A nomogram model was built and evaluated for both discrimination and calibration.

After surgery, 37.88% of the study patients achieved pCR. Six variables were included in the nomogram: sex, cN stage, chemotherapy regimen, duration of nCRT, pre-nCRT neutrophil-to-lymphocyte ratio (NLR), and pre-nCRT platelet-to-lymphocyte ratio (PLR). The nomogram indicated good accuracy and consistency in predicting pCR, with a C-index of 0.743 (95% confidence interval: 0.686, 0.800) and a p value of 0.600 (>0.05) in the Hosmer-Lemeshow goodness-of-fit test.

Female, earlier cN stage, duration of nCRT (< 62 days), chemotherapy regimen of taxane plus platinum, pre-nCRT NLR (≥2.199), and pre-nCRT PLR (≥99.302) were significantly associated with a higher pCR in ESCC patients whose primary chemotherapy was a taxane-based regimen for nCRT. A nomogram was developed and internally validated, showing good accuracy and consistency.

The need for adjuvant therapy (AT) following neoadjuvant chemoimmunotherapy (nICT) and surgery in esophageal squamous cell cancer (ESCC) remains uncertain. This study aims to investigate whether AT offers additional benefits in terms of recurrence-free survival (RFS) for ESCC patients after nICT and surgery.

Retrospective analysis was conducted between January 2019 and December 2022 from three centers. Eligible patients were divided into two groups: the AT group and the non-AT group. Survival analyses comparing different modalities of AT (including adjuvant chemotherapy and adjuvant chemoimmunotherapy) with non-AT were performed. The primary endpoint was RFS. Propensity score matching(PSM) was used to mitigate inter-group patient heterogeneity. Kaplan-Meier survival curves and Cox regression analysis were employed for recurrence-free survival analysis.

A total of 155 nICT patients were included, with 26 patients experiencing recurrence. According to Cox analysis, receipt of adjuvant therapy emerged as an independent risk factor(HR:2.621, 95%CI:[1.089,6.310], P=0.032), and there was statistically significant difference in the Kaplan-Meier survival curves between non-AT and receipt of AT in matched pairs (p=0.026). Stratified analysis revealed AT bring no survival benefit to patients with pathological complete response(p= 0.149) and residual tumor cell(p=0.062). Subgroup analysis showed no significant difference in recurrence-free survival between non-AT and adjuvant chemoimmunotherapy patients(P=0.108). However, patients receiving adjuvant chemotherapy exhibited poorer recurrence survival compared to non-AT patients (p= 0.016).

In terms of recurrence-free survival for ESCC patients after nICT and surgery, the necessity of adjuvant therapy especially the adjuvant chemotherapy, can be mitigated.

Cutaneous squamous cell carcinoma is usually treated with surgery; however, locoregionally advanced cutaneous squamous cell carcinoma can be difficult to resect. Although recent guidelines from Western countries recommend using anti-programmed cell death protein 1 (PD-1) antibodies, including cemiplimab and pembrolizumab, there are no approved anti-PD-1 antibodies for locoregional cutaneous squamous cell carcinoma in Asian countries. S-1 is an oral drug with a low incidence of severe toxicity that can be used for head and neck cancers, including head and neck locoregional cutaneous squamous cell carcinoma, in Japan. We retrospectively evaluated patients with head and neck locoregional cutaneous squamous cell carcinoma treated with S-1 at two Japanese institutions (2008-2022). The initial dosage was determined by the body surface area (<1.25 m2 : 80 mg/day, 1.25-1.5 m2 : 100 mg/day, ≥1.5 m2: 120 mg/day) for 28 consecutive days. The outcome measures were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Fourteen patients were included. The ORR was 78%, and the complete response (CR) rate was 64.3%. The median PFS and OS were not reached (NR) (95% confidence interval [CI], 5.9 months-NR) and NR (95% CI, 13.8 months-NR), respectively. The 12-month PFS and OS rates were 51% and 85%, respectively. Six of the nine patients who achieved CR showed no recurrence during the follow-up period (median follow-up, 24.7 months). After CR, three patients experienced recurrence. Among these, two resumed S-1 treatment and subsequently underwent salvage surgery, resulting in a sustained absence of recurrence. One patient developed lung metastasis and died, although S-1 therapy was resumed. Only one patient (7.1%) developed grade 3 anemia. S-1 showed favorable efficacy and low toxicity in patients with head and neck locoregionally advanced cutaneous squamous cell carcinoma. S-1 may be a good alternative to the anti-PD-1 antibody for treating head and neck locoregionally advanced squamous cell carcinoma.