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Neoadjuvant therapy is the standard treatment for patients with locally advanced oesophageal squamous cell carcinoma (OSCC). However, the prognosis remains poor and more intensive neoadjuvant treatment might be needed to improve patient outcomes. We therefore aimed to compare the efficacy and safety of neoadjuvant doublet chemotherapy, triplet chemotherapy, and doublet chemotherapy plus radiotherapy in patients with previously untreated locally advanced OSCC. In this randomised, open-label, phase 3 trial, patients aged 20–75 years with previously untreated locally advanced OSCC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were recruited from 44 centres across Japan. Patients were randomly assigned (1:1:1) centrally via a web-based system to receive neoadjuvant doublet chemotherapy (two courses of fluorouracil [800 mg/m2 per day intravenously on days 1–5] and cisplatin [80 mg/m2 per day on day 1] separated by an interval of 3 weeks [NeoCF]), triplet chemotherapy (three courses of fluorouracil [750 mg/m2 per day on days 1–5], cisplatin [70 mg/m2 per day on day 1], and docetaxel [70 mg/m2 per day on day 1] repeated every 3 weeks [NeoCF+D]), or doublet chemotherapy (two courses of fluorouracil [1000 mg/m2 per day on days 1–4] and cisplatin [75 mg/m2 per day on day 1] separated by an interval of 4 weeks) plus 41·4 Gy radiotherapy [NeoCF+RT]) followed by oesophagectomy with regional lymph node dissection. Randomisation was stratified by T stage and institution. Participants, investigators, and those assessing outcomes were not masked to group assignment. The primary endpoint was overall survival, analysed by intention to treat. Analysis of safety included all patients who received at least one course of chemotherapy, and analysis of surgical complications included those who also underwent surgery. This study is registered with the Japan Registry of Clinical Trials, jRCTs031180202, and the trial is complete. A total of 601 patients (529 male individuals and 72 female individuals) were randomly assigned between Dec 5, 2012, and July 20, 2018, with 199 patients in the NeoCF group, 202 patients in the NeoCF+D group, and 200 patients in the NeoCF+RT group. Compared with the NeoCF group, during a median follow-up period of 50·7 months (IQR 23·8–70·7), the 3-year overall survival rate was significantly higher in the NeoCF+D group (72·1% [95% CI 65·4–77·8] vs 62·6% [55·5–68·9]; hazard ratio [HR] 0·68, 95% CI 0·50–0·92; p=0·006) but not in the NeoCF+RT group (68·3% [61·3–74·3]; HR 0·84, 0·63–1·12; p=0·12). Grade 3 or higher febrile neutropenia occurred in two (1%) of 193 patients in the NeoCF group, 32 (16%) of 196 patients in the NeoCF+D group, and nine (5%) of 191 patients in the NeoCF+RT group. Treatment-related adverse events leading to termination of neoadjuvant therapy were more common in the NeoCF+D group (18 [9%] of 202 participants) than in the NeoCF+RT group (12 [6%] of 200) and NeoCF group (eight [4%] of 199). There were three (2%) treatment-related deaths during neoadjuvant therapy in the NeoCF group, four (2%) deaths in the NeoCF+D group, and two (1%) deaths in the NeoCF+RT group. Grade 2 or higher postoperative pneumonia, anastomotic leak, and recurrent laryngeal nerve paralysis were reported in 19 (10%), 19 (10%), and 28 (15%) of 185 patients, respectively, in the NeoCF group; 18 (10%), 16 (9%), and 19 (10%) of 183 patients, respectively, in the NeoCF+D group; and 23 (13%), 23 (13%), and 17 (10%) of 178 patients, respectively, in the NeoCF+RT group. The in-hospital deaths following surgery included three deaths in the NeoCF group, two deaths in the NeoCF+D group, and one in the NeoCF+RT group. Neoadjuvant triplet chemotherapy followed by oesophagectomy resulted in a statistically significant overall survival benefit compared with doublet chemotherapy and might be the new standard of care for locally advanced OSCC who are in good condition in Japan. Neoadjuvant doublet chemotherapy plus radiotherapy did not show significant improvement of survival compared with doublet chemotherapy. Japan Agency for Medical Research and Development and National Cancer Center Research and Development Fund.

Recent single-arm studies involving neoadjuvant camrelizumab, a PD-1 inhibitor, plus chemotherapy for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC) have shown promising results. This multicenter, randomized, open-label phase 3 trial aimed to further assess the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy followed by adjuvant camrelizumab, compared to neoadjuvant chemotherapy alone. A total of 391 patients with resectable thoracic LA-ESCC (T1b-3N1-3M0 or T3N0M0) were stratified by clinical stage (I/II, III or IVA) and randomized in a 1:1:1 ratio to undergo two cycles of neoadjuvant therapy. Treatments included camrelizumab, albumin-bound paclitaxel and cisplatin (Cam+nab-TP group; n  = 132); camrelizumab, paclitaxel and cisplatin (Cam+TP group; n  = 130); and paclitaxel with cisplatin (TP group; n  = 129), followed by surgical resection. Both the Cam+nab-TP and Cam+TP groups also received adjuvant camrelizumab. The dual primary endpoints were the rate of pathological complete response (pCR), as evaluated by a blind independent review committee, and event-free survival (EFS), as assessed by investigators. This study reports the final analysis of pCR rates. In the intention-to-treat population, the Cam+nab-TP and Cam+TP groups exhibited significantly higher pCR rates of 28.0% and 15.4%, respectively, compared to 4.7% in the TP group (Cam+nab-TP versus TP: difference 23.5%, 95% confidence interval (CI) 15.1–32.0, P  < 0.0001; Cam+TP versus TP: difference 10.9%, 95% CI 3.7–18.1, P  = 0.0034). The study met its primary endpoint of pCR; however, EFS is not yet mature. The incidence of grade ≥3 treatment-related adverse events during neoadjuvant treatment was 34.1% for the Cam+nab-TP group, 29.2% for the Cam+TP group and 28.8% for the TP group; the postoperative complication rates were 34.2%, 38.8% and 32.0%, respectively. Neoadjuvant camrelizumab plus chemotherapy demonstrated superior pCR rates compared to chemotherapy alone for LA-ESCC, with a tolerable safety profile. Chinese Clinical Trial Registry identifier: ChiCTR2000040034 . In a randomized phase 3 trial, neoadjuvant anti-PD-1 plus either paclitaxel and cisplatin or nab-paclitaxel and cisplatin elicited a significantly superior pathological complete response rate versus neoadjuvant paclitaxel and cisplatin alone in patients with resectable locally advanced esophageal squamous cell carcinoma.

Background 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. Methods 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. Results 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). Conclusions 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. Trial registration ClinicalTrials.gov registration NCT05213312.

Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors (TKIs), possess immunomodulatory properties and have shown promising outcomes when combined with anti-PD-1 antibodies. The OASIS phase II trial (NCT04503967) is designed to determine the clinical activity and safety of nivolumab (anti-PD-1) and anlotinib hydrochloride (a multi-targets TKI) as second-line or above therapy in patients with advanced gastric adenocarcinoma (GAC) and esophageal squamous cell carcinoma (ESCC). From December 2020 to September 2022, 45 patients with GAC and 3 with ESCC were enrolled in this study. The pre-specified endpoints were reached, with the primary endpoint of overall response rate achieving 29.2%. For secondary objectives, disease control rate was 64.6%; median progression-free survival was 4.0 months; and median overall survival was 11.1 months with a manageable toxicity profile. The exploratory analyses unveiled that the balance of gut bacteria and the presence of a pre-existing immune signature characterized by a high percentage of CD68 + PD-L1 + PD-1 + macrophages and low pretreatment variant allele frequencies (VAF), as well as low expression of certain cytokines were significantly associated with improved clinical outcomes in patients with GAC. Anlotinib hydrochloride is a multi-target tyrosine kinase receptor inhibitor, previously combined with anti-PD1 as therapeutic strategy for several cancer types. Here the authors report the results of a phase II trial of nivolumab (anti-PD1) plus anlotinib hydrochloride in patients with advanced gastric adenocarcinoma and esophageal squamous cell carcinoma.

Background 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. Methods 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. Discussion 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. Trial registration ClinicalTrials.gov NCT06061146.Registered 9/10/2023.

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.

Chemotherapy for patients with advanced oesophageal squamous cell carcinoma offers poor long-term survival prospects. We report the final analysis from our study of the immune checkpoint PD-1 inhibitor nivolumab versus chemotherapy in patients with previously treated advanced oesophageal squamous cell carcinoma. We did a multicentre, randomised, open-label, phase 3 trial (ATTRACTION-3) at 90 hospitals and cancer centres in Denmark, Germany, Italy, Japan, South Korea, Taiwan, the UK, and the USA. We enrolled patients aged 20 years and older with unresectable advanced or recurrent oesophageal squamous cell carcinoma (regardless of PD-L1 expression), at least one measurable or non-measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, a baseline Eastern Cooperative Oncology Group performance status of 0–1, and who were refractory or intolerant to one previous fluoropyrimidine-based and platinum-based chemotherapy and had a life expectancy of at least 3 months. Patients were randomly assigned (1:1) to either nivolumab (240 mg for 30 min every 2 weeks) or investigator's choice of chemotherapy (paclitaxel 100 mg/m2 for at least 60 min once per week for 6 weeks then 1 week off; or docetaxel 75 mg/m2 for at least 60 min every 3 weeks), all given intravenously. Treatment continued until disease progression assessed by the investigator per RECIST version 1.1 or unacceptable toxicity. Randomisation was done using an interactive web response system with a block size of four and stratified according to geographical region (Japan vs rest of the world), number of organs with metastases, and PD-L1 expression. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival, defined as the time from randomisation until death from any cause, in the intention-to-treat population that included all randomly assigned patients. Safety was assessed in all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT02569242, and follow-up for long-term outcomes is ongoing. Between Jan 7, 2016, and May 25, 2017, we assigned 419 patients to treatment: 210 to nivolumab and 209 to chemotherapy. At the time of data cutoff on Nov 12, 2018, median follow-up for overall survival was 10·5 months (IQR 4·5–19·0) in the nivolumab group and 8·0 months (4·6–15·2) in the chemotherapy group. At a minimum follow-up time (ie, time from random assignment of the last patient to data cutoff) of 17·6 months, overall survival was significantly improved in the nivolumab group compared with the chemotherapy group (median 10·9 months, 95% CI 9·2–13·3 vs 8·4 months, 7·2–9·9; hazard ratio for death 0·77, 95% CI 0·62–0·96; p=0·019). 38 (18%) of 209 patients in the nivolumab group had grade 3 or 4 treatment-related adverse events compared with 131 (63%) of 208 patients in the chemotherapy group. The most frequent grade 3 or 4 treatment-related adverse events were anaemia (four [2%]) in the nivolumab group and decreased neutrophil count (59 [28%]) in the chemotherapy group. Five deaths were deemed treatment-related: two in the nivolumab group (one each of interstitial lung disease and pneumonitis) and three in the chemotherapy group (one each of pneumonia, spinal cord abscess, and interstitial lung disease). Nivolumab was associated with a significant improvement in overall survivaland a favourable safety profile compared with chemotherapy in previously treated patients with advanced oesophageal squamous cell carcinoma, and might represent a new standard second-line treatment option for these patients. ONO Pharmaceutical Company and Bristol-Myers Squibb.

Although antiprogrammed death 1 antibody plus chemotherapy has recently been approved for first-line esophageal squamous cell carcinoma (ESCC), antiprogrammed death-ligand 1 antibody may offer another combination option in this setting. In this multicenter, randomized, double-blinded phase 3 trial a total of 540 adults (aged 18–75 years) with unresectable, locally advanced, recurrent or metastatic ESCC and who had not received systemic treatment were enrolled. All patients were randomized at 2:1 to receive either sugemalimab (an anti-PD-L1 antibody; 1,200 mg) or placebo every 3 weeks for up to 24 months, plus chemotherapy (cisplatin 80 mg m − 2 on day 1 plus 5-fluorouracil 800 mg m − 2  day −1 on days 1–4) every 3 weeks for up to six cycles. At the prespecified interim analysis this study had met dual primary endpoints. With a median follow-up of 15.2 months, the prolongation of progression-free survival was statistically significant with sugemalimab plus chemotherapy compared with placebo plus chemotherapy (median 6.2 versus 5.4 months, hazard ratio 0.67 (95% confidence interval 0.54–0.82), P  = 0.0002) as assessed by blinded independent central review. Overall survival was also superior with sugemalimab chemotherapy (median 15.3 versus 11.5 months, hazard ratio 0.70 (95% confidence interval 0.55–0.90, P  = 0.0076). A significantly higher objective response rate (60.1 versus 45.2%) as assessed by blinded independent central review was observed with sugemalimab chemotherapy. The incidence of grade 3 or above treatment-related adverse events (51.3 versus 48.4%) was comparable between the two groups. Sugemalimab plus chemotherapy significantly prolonged progression-free survival and overall survival in treatment-naïve patients with advanced ESCC, with no unexpected safety signal. The ClinicalTrials.gov identifier is NCT04187352 . In a prespecified interim analysis of the phase 3 trial GEMSTONE-304, anti-PD-L1 with chemotherapy versus chemotherapy alone led to significantly prolonged progression-free survival and overall survival of patients with unresectable, locally advanced, recurrent or metastatic esophageal squamous cell carcinoma.

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.

There is an unmet need for additional and more efficacious therapies for patients with unresectable metastatic oesophageal cancer. We aimed to evaluate the efficacy and safety of adding tiragolumab and atezolizumab to chemotherapy as first-line treatment for unresectable or metastatic oesophageal squamous cell carcinoma. The SKYSCRAPER-08 randomised, double-blind, placebo-controlled, phase 3 trial was done at 67 centres in mainland China, South Korea, Thailand, Taiwan, and Hong Kong and enrolled adult patients (aged ≥18 years) with treatment-naive, unresectable locally advanced, unresectable recurrent, or metastatic oesophageal squamous cell carcinoma, with an Eastern Cooperative Oncology Group performance status of 0–1. Patients were randomly assigned (1:1) to receive tiragolumab (600 mg) plus atezolizumab (1200 mg) and chemotherapy (paclitaxel [175 mg/m2] and cisplatin [60–80 mg/m2]) or placebo and chemotherapy through intravenous infusion for six 21-day cycles. The primary outcomes were independent review facility-assessed progression-free survival and overall survival in the intention-to-treat population (defined as all randomly assigned patients, regardless of whether they received any study treatment). This study was registered with ClinicalTrials.gov, NCT04540211, and is ongoing. Between Oct 30, 2020, and Nov 30, 2021, 461 patients were assigned to receive tiragolumab plus atezolizumab and chemotherapy (n=229) or placebo and chemotherapy (n=232); 406 (88%) were male and 55 (12%) female, and all patients were Asian. Median survival follow-up was 12·6 months (IQR 6·8–18·0). Median independent review facility-assessed progression-free survival (cutoff June 15, 2022) in the tiragolumab plus atezolizumab and chemotherapy group was 6·2 months (95% CI 5·7–7·2) versus 5·4 months (95% CI 4·4–5·5) in the placebo and chemotherapy group (HR 0·56, 95% CI 0·45–0·70; p<0·0001). Median overall survival (cutoff Feb 13, 2023) was 15·7 months (95% CI 13·3–20·4) and 11·1 months (95% CI 9·6–13·6; HR 0·70, 95% CI 0·55–0·88; p=0·0024). The most common grade 3–4 adverse events in the tiragolumab plus atezolizumab and chemotherapy group versus the placebo and chemotherapy group were white blood cell count decrease (46 [20%] of 228 vs 35 [15%] of 227), neutrophil count decrease (78 [34%] vs 78 [34%]), and anaemia (19 [8%] vs 24 [11%]). Serious adverse events occurred in 94 (41%) of 228 patients in the tiragolumab plus atezolizumab and chemotherapy group and 89 (39%) of 227 in the placebo and chemotherapy group; the most common serious adverse event was pneumonia (17 [7%] of 228 and 13 [6%] of 227). Treatment-related deaths occurred in six patients (3%) in the tiragolumab plus atezolizumab and chemotherapy group (immune-mediated lung disease, pneumonitis, cardiac arrest, gastrointestinal haemorrhage, hepatic failure, and bacterial pneumonia) and two (1%) in the placebo and chemotherapy group (gastrointestinal infection and death of unknown cause). No new safety signals were identified. Independent review facility-assessed progression-free survival and overall survival were significantly better in the tiragolumab plus atezolizumab and chemotherapy group compared with chemotherapy alone for unresectable locally advanced, unresectable recurrent, or metastatic oesophageal squamous cell carcinoma. These data support the rationale for exploring dual checkpoint inhibition added to chemotherapy for this group of patients with a high unmet need. F Hoffmann-La Roche–Genentech.