Published papers

Background: Although docetaxel-based triplet neoadjuvant chemotherapy has yielded promising results for locally advanced esophageal cancer, there are concerns that the triplet regimen can increase perioperative adverse events in older patients. This retrospective study assessed the perioperative outcomes following doublet or docetaxel-based triplet chemotherapy and esophagectomy in older patients. Methods: The data of patients aged 70–79 years who received cisplatin and 5-fluorouracil (CF) or docetaxel, cisplatin, and 5-fluorouracil (DCF) before esophagectomy were extracted from a nationwide Japanese inpatient database (April 2012–March 2022). The primary outcomes were major and respiratory complications. The secondary outcomes included anastomotic leakage, 30-day unplanned readmission, and 30- and 90-day mortality. Analyses were conducted using overlap propensity score weighting, propensity score matching, and instrumental variable methods to adjust for potential confounders. Results: Of 5229 eligible patients, 3457 (66%) and 1772 (34%) patients received neoadjuvant CF and DCF, respectively. Major and respiratory complications occurred in 5229 (40%) and 1388 (27%) patients, respectively. After overlap weighting, DCF was not associated with a higher frequency of major (odds ratio 0.99 [95% confidence interval 0.87–1.12]) and respiratory complications (odds ratio 1.04 [0.90–1.19]) compared with CF. The frequencies of anastomotic leakage, 30-day unplanned readmission, and 30- and 90-day mortality did not differ between the groups. Propensity score matching and instrumental variable analyses yielded similar results. Conclusions: Neoadjuvant DCF was not associated with a higher frequency of perioperative adverse events compared with CF after esophagectomy in patients aged 70–79 years.

Temperature monitoring is significant and fundamental in the fields of healthcare and medicine. In surgery, ultrasonic cutting devices are used for cutting, coagulation, and hemostasis. However, surgeons are concerned about the collateral thermal damages. For example, due to the limited space during endoscopic surgery, thermal damage is caused by touching the surrounding tissues of the targeted organ with the heated shaft of the ultrasonic cutting device. The present work exhibits thermoresponsive and reversible color-change coatings for temperature-distribution imaging. The phase-separated structures of the layered conjugated and matrix polymers enable both the tuned thermoresponsivity and large-scale coating. Layered polydiacetylene (PDA) with intercalated guests exhibits reversible and thermoresponsive gradual color changes from blue to red. A matrix polymer facilitates formation of the phase-separated layered PDA and large-scale coating. Spraying the precursor solution containing the diacetylene monomer, guest molecule, and matrix polymer provides the self-organized large-scale coatings on substrates. The temperature distribution on the shaft of an ultrasonic cutting device is monitored using the coatings. The phase-separated structure of thermoresponsive and matrix polymers can be applied to tunable temperature monitoring in a variety of fields.

Background: Plasma fibrinogen (FNG) is a prognostic marker in esophageal squamous cell carcinoma (ESCC). However, its predictive value for immune checkpoint inhibitor (ICI) efficacy and the underlying mechanisms remain unclear. This study aimed to evaluate the clinical significance of plasma FNG levels in ICI-treated ESCC patients and investigate its association with tumor-associated neutrophils (TANs) and genomic alterations. Methods: A retrospective, multicenter analysis of 167 ESCC patients treated with ICIs was performed. TANs were quantified via immunohistochemistry using CD11b and CD66b staining, and PD-L1 expression was assessed using the tumor proportion score (TPS). Whole-exome and RNA sequencing were conducted to analyze genomic and transcriptomic profiles. Results: Elevated plasma FNG levels correlated with lower ICI response rates and decreased survival. In first-line treatment, chemo-ICI therapy demonstrated superior efficacy compared to dual-ICI therapy in high-FNG patients, while the reverse trend was observed in low-FNG patients. High-FNG tumors showed increased TAN infiltration, independent of PD-L1 expression. RNA sequencing revealed enrichment of neutrophil activation and extravasation pathways in high-FNG tumors. Conclusions: Elevated plasma FNG levels predict poor prognosis and reduced ICI efficacy in ESCC. They may be potential biomarkers for first-line ICI-based therapy and correlate with TAN infiltration. Further validation and mechanistic investigations are warranted.

Racemose hemangioma of the bronchial artery is a rare disease. The diagnosis of racemose hemangioma is difficult when affected patients are asymptomatic and causes unexplained hemoptysis. Selective bronchial artery embolization has become the firstline treatment for this rare disease. However, feasibility and safety of bronchial artery embolization was not reported in the case with permanent tracheostomy. A 44-year-old woman underwent endoscopic screening during which a circular tumor was detected in the cervical esophagus, which was confirmed as squamous cell carcinoma on biopsy. She underwent cervical esophagectomy with pharyngolaryngectomy through a cervical incision. Reconstruction was performed by free jejunal transfer and permanent tracheostomy. Six weeks after surgery, hemoptysis from permanent tracheostomy was observed. Computed tomography (CT) scan revealed no bleeding around the tracheostomy, and bronchoscopy could not identify the origin of the bleeding due to a large amount of blood clots obscuring the visual field. Bronchial arteriography showed a bent, meandering and dilated bronchial artery, extending to the right bronchus with vascular hyperplasia.We diagnosed primary racemose hemangioma of the bronchial artery, which was successfully treated by transcatheter arterial embolization of the bronchial artery. After embolization, bronchoscopy revealed no bleeding. Findings from this case suggest that bronchial angiography is essential for diagnosis of this disease, and selective bronchial artery embolization appears to be effective in treating this disease in patients with permanent tracheostomy. Accumulation of similar cases will help to elucidate the optimal diagnosis and treatment strategy for this condition.

Introduction: Despite the development of surgical instruments combining ultrasonic scissors and an advanced bipolar device, thermal management has still been considered a persistent issue, similar to that in conventional ultrasonic scissors. To address this issue, the next-generation hybrid device (NGHD) with a new tip and handle design has been devised while maintaining the high cutting and sealing performance of combined surgical instruments (THUNDERBEAT Type S, TBS). We compared them in an ex vivo and nonclinical in vivo environment and investigated their perceived clinical usefulness. Methods: Ex vivo testing included measurements of cutting speed, posterior thermal spread from the jaw, and lateral thermal spread. The nonclinical in vivo study involved evaluations such as cutting capability while maintaining the tissue layer, and handle ergonomics. Results: The NGHD demonstrated a significantly faster cutting speed than did TBS (2.41 [2.31–2.50] vs. 3.04 [2.94–3.13] s, p < 0.01) with 5–7 mm arteries, as well as significant improvements in the posterior thermal spread on arteries during activation (5.67 [0–12.84] vs. 84.22 [35.34–133.10] μm, p < 0.01) and lateral thermal spread (2.22 [2.06–2.38] vs. 2.79 [2.55–3.03] mm, p < 0.05). Surgeon assessments indicated more improvements with the NGHD than with TBS, especially regarding cutting while maintaining the tissue layer and handle ergonomics. Conclusion: The NGHD promoted improvements in thermal management generally associated with TBS and maintained the benefits of combining devices capable of ultrasonic and advanced bipolar output. The NGHD has the potential to support safe and efficient endoscopic procedures, pending further clinical evaluation.

Purpose: Esophagectomy is a highly invasive procedure, associated with several postoperative complications including pneumonia, anastomotic leakage, and sepsis, which may result in multiorgan failure. Pneumonia is considered a major predictor of poor long-term prognosis, so its prevention is important for patients undergoing surgery for esophageal cancer. Methods: The subjects of this study were 137 patients who underwent esophagectomy at Keio University Hospital, Tokyo, Japan, between January, 2012 and December, 2016. Patients who underwent R0 or R1 resection or esophagectomy with organ excision were included. Patients who underwent salvage surgery or resection of recurrent laryngeal nerve, and those with preoperative recurrent laryngeal nerve palsy, were excluded. We investigated the effect of the maximum phonation time on the development of postoperative pneumonia. Results: Pneumonia developed more frequently in patients with a long operative time, clinically left recurrent nerve lymph node metastasis, and a short preoperative maximum phonation time (p = 0.074, 0.046, and 0.080, respectively). Pneumonia was also more common in men with an abnormal maximum phonation time (p = 0.010). Conclusions: The maximum phonation time is a significant predictor of postoperative pneumonia after esophagectomy in men.

Background: Our previous study reported the prognostic significance of endoscopic response (ER) evaluation, defined ER, and revealed ER as an independent prognostic factor of overall survival (OS) and recurrence-free survival (RFS) for esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant chemotherapy (NAC) and surgery. The present study aimed to validate the prognostic impact of ER using a nationwide database from the authorized institute for board-certified esophageal surgeons by the Japan Esophageal Society. Methods: This study retrospectively reviewed patients with ESCC who underwent subtotal esophagectomy at 85 authorized institutes for esophageal cancer from 2010 to 2015. Patients were classified as ER when the tumor size was markedly reduced post-NAC compared to pre-NAC. The correlation between OS and RFS was investigated. Results: Of 4781 patients initially enrolled, 3636 were selected for subsequent analysis. Of them, 642 (17.7%) patients were classified as the ER group. Patients with ER showed significantly better OS and RFS. Subgroup analysis revealed the statistical difference in OS and RFS in cStage II and III, while the magnitude of survival difference between ER and non-ER was not evident in cStage I and IV. The percentage of ER varied from 46 to 87% among groups when institutions were classified into 3 subgroups based on the hospital volume, which would indicate the interinstitutional inconsistency. Conclusions: The prognostic impact of ER was validated using a nationwide database. Standardization of ER evaluation is required to improve the interinstitutional consistency and clinical validity of the ER evaluation.

Aim: We have previously reported the existence of lymph nodes surrounding the thoracic duct (TDLN) and transthoracic esophagectomy (TTE) with thoracic duct (TD) resection increased the number of lymph nodes (LNs) retrieved. The current study aims to evaluate the prognostic impact of TDLN metastasis in esophageal cancer patients subdivided by its location and comparing the patients’ survival with those with extra-regional LN metastasis. Methods: Patients who underwent TTE with TD resection for esophageal squamous cell carcinoma (ESCC) were reviewed. Patients were classified into those with or without TDLN metastasis, and clinicopathological factors were compared between groups. TDLN was further divided into TDLN-Ut/Mt/Lt based on the location in the mediastinum. The relapse-free survival (RFS) and overall survival (OS) were compared between groups. Results: Of 232 patients, TDLN metastasis was observed in 17 (7%). RFS and OS were significantly worse in the TDLN metastasis group. TDLN metastasis was shown to be an independent prognostic factor for RFS and OS in the multivariate analysis. The negative prognostic impact of TDLN metastasis was evident in TDLN-Mt/Lt. The RFS and OS of patients with TDLN metastasis were almost identical to those with positive LN metastasis in extra-regional LNs. Conclusion: TDLN metastasis was proven to be a strong prognostic indicator. Although the TDLN has been included in the classification of regional LN in the current staging systems, it could be independently classified from the current regional LNs. Given that neoadjuvant therapy has been a standard, we might need to introduce adjuvant therapy when TDLN metastasis is observed.

Background: Although several studies have investigated whether thoracic duct (TD) resection improves prognosis, the conclusion remains controversial. JCOG1109 is a three-arm randomized phase III trial to confirm the survival advantage of docetaxel, cisplatin, 5-fluorouracil (DCF), and cisplatin plus 5-fluorouracil (CF) combined with radiotherapy (CF-RT) over CF as neoadjuvant treatment. The study aimed to evaluate the survival impact of TD resection and its association with neoadjuvant treatment and pathological response in patients enrolled in JCOG1109. Patients and Methods: Clinicopathological factors, surgical results, and prognosis were compared between TD preserved and resected groups. The survival impact of TD resection was also evaluated in the subgroups on the basis of combinations of preoperative therapy and pathological response. Results: Between December 2012 and July 2018, 601 patients were randomized (CF/DCF/CF-RT; 199/202/200) in JCOG1109. Of them, 541 patients underwent esophagectomy (183/181/177), and TD was resected in 265 patients (93/91/81). For the entire cohort, TD resection was not a significant prognostic factor for overall survival in the multivariable analysis (HR 1.20, 95% CI 0.91–1.57). In the subgroup analyses by combinations of neoadjuvant treatment and pathological response, TD resected group had a significantly better overall survival compared with TD preserved group in patients who received DCF and achieved pathological response (HR 0.20, 95% CI 0.07–0.61). Conclusions: The survival benefit of TD resection was not demonstrated in patients with surgically resectable esophageal squamous cell carcinoma enrolled in JCOG1109. The residual tumor burden after neoadjuvant treatment might be linked to the survival impact of TD resection.

Aim: Serum autoantibodies have been reported to react with tumor-associated antigens in various cancers. This study evaluated the diagnostic and prognostic significance of six autoantibody panels in esophageal squamous cell carcinoma. Methods: In this study, 193 patients with esophageal squamous cell carcinoma and 78 healthy controls were enrolled. Serum antibodies were detected using originally developed enzyme-linked immunosorbent assays to detect autoantibodies against the following tumor antigens: c-myc, p62, RalA, p53, Sui1, and NY-ESO-1. The positive rates of the six-autoantibody panel were compared with those of SCC antigen (SCC-Ag). The prognostic significance of these autoantibodies was also evaluated. Results: The overall positive rate was significantly higher in the six-autoantibody panel than in SCC-Ag (72% vs. 28%; p < 0.01). The positive rates of the six-autoantibody panel were 71% in stage 0/I, 73% in stage II, and 71% in stage III. No clinicopathological factors were associated with autoantibodies. Although the difference was not significant, the overall survival of the autoantibody-positive group was worse than that of the autoantibody-negative group (p = 0.14). Conclusion: The six-autoantibody panel was useful for detecting esophageal squamous cell carcinoma, particularly in stage 0/I; however, it showed limited prognostic significance.

Purpose: Risk stratification to select appropriate candidates for adjuvant therapy is required for esophageal cancer patients based on adjuvant therapy advancement including immunotherapy. The current study aims to develop a novel staging system using pathological stage (pStage) and response to neoadjuvant chemotherapy (NAC) for esophageal squamous cell carcinoma (ESCC). Methods: ESCC patients who received NAC and underwent transthoracic esophagectomy at two Japanese high-volume esophageal centers were retrospectively reviewed. The prognostic value of NAC response was evaluated within the same pStage, and a novel risk stratification to predict cancer-specific survival (CSS) was developed. Results: The HR (95% CI) of pathological responders in pStage 0–I, II, III, and IV was 0.29 (0.07–1.17), 0.37 (0.12–1.10), 0.37 (0.15–0.92), and 0.24 (0.06–0.98), respectively. Responders in pStage 0–II were classified to be in the same class and those in pStage III/IV in another group, because the 5-year CSS (5y-CSS) rate of responders in pStage 0–I, II, III, and IV was 94%, 92%, 76%, and 71%, respectively. Combining nonresponders in pStage 0–II as the same group, all patients were subdivided into five groups. Intriguingly, the 5y-CSS in pStage III–IV responders was 75%, almost identical to that of nonresponders in pStage 0–II (78%). Conclusions: The histological response influenced the long-term outcomes of patients who underwent esophagectomy after NAC, even within groups stratified by pathologic stage. The current risk stratification system will contribute to selecting appropriate candidates for adjuvant therapy.

Background: The tumor, node, metastasis staging system of the Union for International Cancer Control (UICC) has been used worldwide for esophageal cancer, and, in Japan, the Japan Esophageal Society Japanese Classification of Esophageal Cancer (JES) has also been used; however, there is a big difference between the two classifications with regard to node staging. We hypothesized that these two node staging systems may lead to different outcome predictions in terms of tumor location. Methods: This study enrolled 409 patients who underwent esophagectomy at Keio University Hospital, Tokyo, Japan, between January 2005 and December 2017. We included those who underwent R0 or R1 resection or esophagectomy with additional organ excision, and excluded those who underwent salvage surgery. Thereafter, we investigated how the number or spread of metastatic lymph nodes affected the prognosis. Results: For all 409 patients, the 5-year overall survival rate was 64.1% and the 5-year recurrence-free survival rate was 58.4%. The concordance indices were 0.756 for UICC 8th edition pathological node staging and 0.732 for JES 11th edition pathological node staging (p = 0.06). Based on tumor location, the difference in the concordance indices between these two classifications was greatest for lower thoracic esophageal tumors (p = 0.02). Conclusions: For all patients, the UICC 8th edition node staging system tended to reflect survival more precisely than that of the JES 11th edition. For lower thoracic esophageal tumors in particular, the former node staging system could be more useful.

BACKGROUND: The proportion of early extubation after esophagectomy varies among hospitals; however, the impact on clinical outcomes is unclear. The aim of this retrospective study was to evaluate associations between the proportion of early extubation in hospitals and short-term outcomes after esophagectomy. Because there is no consensus regarding the optimal timing for extubation, the authors considered that hospitals' early extubation proportion reflects the hospital-level extubation strategy. MATERIALS AND METHODS: Data of patients who underwent oncologic esophagectomy (July 2010-March 2019) were extracted from a Japanese nationwide inpatient database. The proportion of patients who underwent early extubation (extubation on the day of surgery) at each hospital was assessed and grouped by quartiles: very low- (<11%), low- (11-37%), medium- (38-83%), and high-proportion (≥84%) hospitals. The primary outcome was respiratory complications; secondary outcomes included reintubation, anastomotic leakage, other major complications, and hospitalization costs. Multivariable regression analyses were performed, adjusting for patient demographics, cancer treatments, and hospital characteristics. A restricted cubic spline analysis was also performed for the primary outcome. RESULTS: Among 37 983 eligible patients across 545 hospitals, early extubation was performed in 17 931 (47%) patients. Early extubation proportions ranged from 0-100% across hospitals. Respiratory complications occurred in 10 270 patients (27%). Multivariable regression analyses showed that high- and medium-proportion hospitals were significantly associated with decreased respiratory complications [odds ratio, 0.46 (95% CI, 0.36-0.58) and 0.43 (0.31-0.60), respectively], reintubation, and hospitalization costs when compared with very low-proportion hospitals. The risk of anastomotic leakage and other major complications did not differ among groups. The restricted cubic spline analysis demonstrated a significant inverse dose-dependent association between the early extubation proportion and the risk of respiratory complications. CONCLUSION: A higher proportion of early extubation in a hospital was associated with a lower occurrence of respiratory complications, highlighting a potential benefit of early extubation after esophagectomy.

Although the efficacy of postoperative therapy with nivolumab after preoperative chemoradiotherapy for locally advanced oesophageal cancer has been proven in Western countries, the survival benefits of postoperative therapy after preoperative chemotherapy with docetaxel, cisplatin and 5-FU or cisplatin plus 5-FU as the Japanese standard therapy remain controversial. This randomized Phase III trial was designed to confirm the superiority of postoperative therapy with nivolumab over observation alone and S-1 over observation alone in patients with locally advanced oesophageal squamous cell carcinoma with no pathological complete response after preoperative chemotherapy followed by curative esophagectomy. A total of 450 patients will be enrolled from 56 hospitals in Japan over 5.5 years. The primary endpoint is relapse-free survival, and the secondary endpoints are disease-free survival, overall survival, adverse events and incremental cost-effectiveness ratio. This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031230219 (https://jrct.niph.go.jp/latest-detail/jRCTs031230219).

SUMMARY. Clinical practice guidelines for esophagogastric junction cancer (EGJ GLs) were published in 2023. In order to evaluate how EGJ GLs have been adopted into clinical practice worldwide and to identify any outstanding clinical questions to be addressed in the next edition, this survey was conducted. An electronic questionnaire was developed. The questionnaire comprised 16 questions designed to assess the adoption of the guideline. Responses were collected online. The survey was conducted by the EGJ working group of International Gastric Cancer Association (IGCA) following approval from the guideline committee of The International Society for Diseases of the Esophagus (ISDE). As results, we received 344 valid and complete responses. 55% of respondents were from East Asia followed by Europe, Central/South America, and Central/West Asia. 80% of respondents recognized and followed the guidelines to some extent. There was still diversity in the extent of lymphadenectomy for EGJ cancers with an esophageal invasion of 2–4 cm. Although white light imaging (WLE) alone was recommended in the EGJ GLs, both WLE and image enhanced endoscopy were used in 86% of respondents. The perioperative treatment was shown to be highly diverse worldwide. While 50% of respondents provided perioperative chemotherapy, preoperative chemotherapy without adjuvant treatment and upfront surgery were still the first treatment option in 15% of respondents. In conclusion, the current survey conducted by IGCA and ISDE identified the current standard and remaining issues of EGJ cancers.

Esophageal cancer is common worldwide, including in Japan, and its major histological subtype is squamous cell carcinoma. However, there are some rare esophageal cancers, including neuroendocrine neoplasm, gastrointestinal stromal tumor, carcinosarcoma and malignant melanoma. The biological and clinical features of these cancers differ from those of esophageal squamous cell carcinoma. Therefore, different treatment strategies are needed for these cancers but are based on limited evidence. Neuroendocrine neoplasm is mainly divided into neuroendocrine tumor and neuroendocrine carcinoma by differentiation and the Ki-67 proliferation index or mitotic index. Epidemiologically, the majority of esophageal neuroendocrine neoplasms are neuroendocrine carcinoma. The treatment of neuroendocrine carcinoma is similar to that of small cell lung cancer, which has similar morphological and biological features. Gastrointestinal stromal tumor is known to be associated with alterations in the c-KIT and platelet-derived growth factor receptor genes and, if resectable, is treated in accordance with the modified Fletcher classification. Carcinosarcoma is generally resistant to both chemotherapy and radiotherapy and requires multimodal treatments such as surgery plus chemotherapy to achieve cure. Primary malignant melanoma is resistant to cytotoxic chemotherapy, but immune checkpoint inhibitors have recently demonstrated efficacy for malignant melanoma of the esophagus. This review focuses on the current status and future perspectives for rare cancer of the esophagus.

Objective: We aimed to evaluate the efficacy of neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy over cisplatin and 5-fluorouracil (CF) in patients with surgically resectable advanced esophageal squamous cell carcinoma (ESCC), using real-world data from 85 esophageal centers. Background: JCOG1109 trial, which assessed the superiority of DCF over CF, and the superiority of chemoradiotherapy with CF over CF alone demonstrated the significant survival advantage of neoadjuvant DCF in overall survival (OS) over CF for ESCC. Methods: The ESCC patients who received neoadjuvant CF or DCF at 85 Japanese esophageal centers certified by the Japan Esophageal Society were retrospectively reviewed. After propensity score (PS) matching, the OS and recurrence-free survival were compared between CF and DCF. Results: We initially enrolled 4781 patients. After data cleaning and PS matching using pretreatment variables, 1074 patients for each group were selected for subsequent analysis. There was no significant difference in the incidence of postoperative pneumonia and anastomotic leakage. In the survival analysis, OS was significantly longer in DCF group than CF group (hazard ratio, 0.868; 95% confidence interval, 0.770-0.978; P=0.02), as well as recurrence-free survival (hazard ratio, 0.850; 95% confidence interval, 0.761-0.949; P=0.004). The survival advantage of DCF was not observed in patients with 76 years old or older. Conclusions: Neoadjuvant DCF therapy showed a remarkable survival advantage in surgically resectable ESCC patients, especially in patients who were 75 years old or younger. The current real-world evidence will encourage recommendations for DCF as a standard regimen in neoadjuvant chemotherapy-based treatment strategy for ESCC.

Background: Overall survival is considered as one of the most important endpoints of treatment efficacy but often requires long follow-up. This study aimed to determine the validity of recurrence-free survival as a surrogate endpoint for overall survival in patients with surgically resectable advanced oesophageal squamous cell carcinoma (OSCC). Methods: Patients with OSCC who received neoadjuvant cisplatin and 5-fluorouracil, or docetaxel, cisplatin and 5-fluorouracil, at 58 Japanese oesophageal centres certified by the Japan Esophageal Society were reviewed retrospectively. The correlation between recurrence-free and overall survival was assessed using Kendall's τ. Results: The study included 3154 patients. The 5-year overall and recurrence-free survival rates were 56.6 and 47.7% respectively. The primary analysis revealed a strong correlation between recurrence-free and overall survival (Kendall's τ 0.797, 95% c.i. 0.782 to 0.812) at the individual level. Subgroup analysis showed a positive relationship between a more favourable pathological response to neoadjuvant chemotherapy and a higher τ value. In the meta-regression model, the adjusted R2 value at the institutional level was 100 (95% c.i. 40.2 to 100)%. The surrogate threshold effect was 0.703. Conclusion: There was a strong correlation between recurrence-free and overall survival in patients with surgically resectable OSCC who underwent neoadjuvant chemotherapy, and this was more pronounced in patients with a better response to neoadjuvant chemotherapy.

Objective: This study evaluated recurrence-free survival (RFS) as a surrogate endpoint for overall survival (OS) in esophageal cancer. Background: OS is regarded as the gold-standard efficacy endpoint of oncological treatments but requires long follow-up. Methods: An integrated analysis of individual patient data (IPD) from phase III trials comparing perioperative therapies for resectable esophageal and gastroesophageal junction cancer was conducted. Surrogacy between RFS and OS was assessed at the individual level using the Kendall rank correlation coefficient (τ) and at the trial level using the coefficient of determination (R2). A τ of 0.8 and an R2 of 0.65 were considered thresholds for a good surrogate. Results: Twenty-two eligible trials were identified, and IPD were available from 10 randomized trials, including 2,145 patients who underwent R0 resection. The 5-year OS and RFS rates were 53.2% and 46.2%, with median OS of 6.2 and RFS of 3.6 years. For individual-level surrogacy, Kendall's τ was 0.823 (95% confidence interval [CI]: 0.807-0.839). Subgroup analysis by treatment modality revealed τ values of 0.830 (95% CI: 0.800-0.861) for neoadjuvant chemotherapy (NAC; n=586), and 0.827 (95% CI: 0.803-0.850) for neoadjuvant chemoradiotherapy (NACRT; n=982). Trial-level surrogacy analysis across all 22 trials demonstrated an R 2 of 0.735 (95% CI: 0.512-0.939). The surrogate threshold effect was 0.929. Conclusions: This study demonstrated strong individual- and trial-level surrogacy between RFS and OS in resectable esophageal cancer across all perioperative treatments. These findings may accelerate perioperative treatment development by shortening follow-up in esophageal cancer trials.

Background: One of the limitations of the established gold standard, overall survival (OS), is that it requires an extended follow-up period. Addressing this challenge involves investigating appropriate statistically and clinically relevant surrogate endpoints. However, there is a paucity of studies using real-world data (RWD) to explore surrogacy in patients with esophageal squamous cell carcinoma (ESCC). Our study aims to investigate whether recurrence-free survival (RFS) is a valid surrogate endpoint for OS in surgically resectable advanced ESCC patients, utilizing a comprehensive nationwide database in Japan. Methods: The ESCC patients who received neoadjuvant CF (cisplatin and 5-fluorouracil) or DCF (docetaxel, cisplatin and 5-fluorouracil) at 58 Japanese esophageal centers certified by the Japan Esophageal Society were retrospectively reviewed. Kendall’s tau between RFS and OS was used at the individual level, and the coefficient of determination was used at the institutional level to assess surrogacy. Additionally, surrogacy between each short-term postoperative endpoint (pathological complete response [pCR] or pathological grade) and OS was investigated using novel statistical methods. Results: Our study encompassed 3154 ESCC patients who underwent subtotal esophagectomy from 2010 to 2015. The cStage I/II/III/IVA/IVB (due to supraclavicular lymph node metastasis) was 224 (7.1%), 1008 (32.0%), 1664 (52.8%), 117 (3.7%), and 140 (4.4%), respectively. The 5-year OS and RFS rate for the entire cohort was 56.6% and 47.7%, respectively. In the primary analysis, a strong correlation between RFS and OS was found (Kendall’s tau = 0.797, 95% confidence interval [CI]: 0.782 to 0.812) at the individual level. Subgroup analysis revealed that the better the pathological response, the higher the tau value. An adjusted R2 of 100.0% (95% CI: 40.2 to 100.0) was obtained with the meta-regression model at the institutional level. The surrogate threshold effect was 0.703. Tau between pCR or pathological grade and OS were -0.025 (95% CI: -0.335 to 0.285) and 0.062 (95% CI: -0.086 to 0.209), respectively. Conclusions: The present study was the first nationwide RWD investigation to demonstrate a strong correlation between RFS and OS in surgically resectable ESCC patients who underwent neoadjuvant chemotherapy (NAC). Notably, this correlation was more pronounced in patients who had a more effective response to NAC. These findings hold promise for expediting the development of novel neoadjuvant treatment by shortening the duration of clinical trials. Research Sponsor: None.