Published papers

Immune checkpoint inhibitors (ICPI) have been reported to be effective in various carcinomas. They excessively activate the immune system, resulting in frequent immune-related adverse events (irAEs). Colitis induced by ICPI is one of the most common and is known as immune-mediated colitis (IMC). Although IMC and inflammatory bowel disease (IBD) are similar in many respects, there are very few reports of IMC in patients with preexisting IBD such as ulcerative colitis (UC) and Crohn's disease (CD). Whether preexisting IBD is concerned with the development of the colitis is not well known. Here, we reported the case who developed severe ulcerative colitis which started from IMC. It is an important case to follow the time course of the colitis developed. Our conclusion indicated that frequent colonoscopy was important for the management of IMC in a patient who has suffered chronic inflammatory disease, such as UC.

Background: Rifabutin-based regimens are used as rescue therapy for refractory Helicobacter pylori infection; however, the duration for which treatment is required and side effects are concerning. This study assessed the efficacy and safety of 7-day rifabutin, amoxicillin, and vonoprazan triple therapy as third- or later-line treatment for H. pylori infection. Materials and Methods: Patients who did not respond to second-line therapy were enrolled. After H. pylori infection was confirmed with the culture method, the patients received rifabutin-containing triple therapy (20 mg vonoprazan b.i.d., 500 mg amoxicillin q.i.d., and 150 mg rifabutin q.d.) for 7 days. Twelve weeks after the eradication therapy, successful eradication was confirmed using a 13C urea breath test or the H. pylori stool antigen test. The results obtained from our previous study that reported a 10-day or 14-day esomeprazole based rifabutin-containing triple therapy as a third- or fourth-line rescue therapy treated patients were used as historical control. We determined the minimum inhibitory concentrations of amoxicillin and rifabutin. We also evaluated whether the patients were positive for the mutation of the rpoB gene. Results: Intention-to-treat and per-protocol analyses showed that our regimen resulted in a high eradication rate (91.2%, 95% CI: 84%–99% and 92.7%, 95% CI: 86%–100%, respectively). Adverse events occurred in 31.6% of the patients, and two patients discontinued the therapy. Conclusions: This is the first study to evaluate the efficacy and safety of a 7-day low-dose rifabutin-based triple therapy with vonoprazan and amoxicillin. Our results suggest that our regimen was effective and safe as a third- or later-line H. pylori eradication regimen. To clarify what component in this regimen are critical, subsequent studies using a factorial design (comparing vonoprazan-amoxicillin dual therapy vs. vonoprazan-rifabutin triple therapy) will be needed.

Background: Trifluridine/tipiracil (FTD/TPI) prolongs survival in the third- or later-line treatment for advanced gastric cancer (GC), esophagogastric junction (EGJ) adenocarcinoma, and colorectal cancer. While single-arm phase II trials showed promising outcomes of FTD/TPI plus ramucirumab (RAM) as third- or later-line treatments for advanced GC or EGJ cancer, there have been no clinical trials to directly compare FTD/TPI plus RAM with FTD/TPI monotherapy. Therefore, we have started a randomised phase II trial to evaluate the efficacy and safety of FTD/TPI plus RAM compared with FTD/TPI monotherapy as third- or later-line treatments in patients with advanced GC and EGJ adenocarcinoma. Methods: This RETREVE trial (WJOG15822G) is a prospective, open-label, randomised, multicentre phase II trial comparing FTD/TPI plus RAM versus FTD/TPI monotherapy in a third- or later-line setting. Eligibility criteria include age of > 20 years; performance status of 0 or 1; unresectable or recurrent gastric or EGJ adenocarcinoma; confirmed HER2 status; refractory or intolerant to fluoropyrimidine, taxane or irinotecan; refractory to RAM (not intolerant); and at least a measurable lesion per RECIST 1.1. FTD/TPI (35 mg/m2 twice daily, evening of day 1 to morning of day 6 and evening of day 8 to morning of day 13) was administered orally every 4 weeks, and RAM (8 mg/kg) was administered intravenously every 2 weeks. The primary endpoint is progression-free survival (PFS), and the secondary endpoints are overall survival, objective response rate, disease control rate, and safety. The expected hazard ratio of PFS is set as 0.7, assuming 4-month PFS rate of 27% in FTD/TPI monotherapy and 40% in FTD/TPI plus RAM. The number of subjects was 110, with a one-sided alpha error of 0.10 and power of 0.70. Discussion: This study will clarify the additional effect of RAM continuation beyond disease progression on FTD/TPI in the third- or later-line setting for patients with advanced GC or EGJ cancer. Trial registration: jRCTs041220120.

Background: Neoadjuvant chemotherapy (NAC) followed by surgery is the standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC). Chemoradiotherapy (CRT) is an alternative treatment approach. However, both treatments are associated with toxicity, and the optimal treatment for older patients with ESCC is unknown. This study aimed to evaluate the treatment strategies and prognosis of older patients with locally advanced ESCC in a real-world setting. Methods: We retrospectively evaluated 381 older patients (≥ 65 years) with locally advanced ESCC (stage IB/II/III, excluding T4) who received anticancer therapy at 22 medical centers in Japan. Based on age, performance status (PS), and organ function, the patients were classified into two groups: clinical trial eligible and ineligible groups. Patients aged ≤ 75 years with adequate organ function and a PS of 0–1 were categorized into the eligible group. We compared the treatments and prognoses between the two groups. Results: The ineligible group had significantly shorter overall survival (OS) than the eligible group (hazard ratio [HR] for death, 1.65; 95% confidence interval [CI], 1.22–2.25; P = 0.001). The proportion of patients receiving NAC followed by surgery was significantly higher in the eligible group than in the ineligible group (P = 1.07 × 10–11), whereas the proportion of patients receiving CRT was higher in the ineligible group than in the eligible group (P = 3.09 × 10–3). Patients receiving NAC followed by surgery in the ineligible group had comparable OS to those receiving the same treatment in the eligible group (HR, 1.02; 95% CI, 0.57–1.82; P = 0.939). In contrast, patients receiving CRT in the ineligible group had significantly shorter OS than those receiving CRT in the eligible group (HR, 1.85; 95% CI, 1.02–3.37; P = 0.044). In the ineligible group, patients receiving radiation alone had comparable OS to those receiving CRT (HR, 1.13; 95% CI, 0.58–2.22; P = 0.717). Conclusions: NAC followed by surgery is justified for select older patients who can tolerate radical treatment, even if they are old or vulnerable to enrollment in clinical trials. CRT did not provide survival benefits over radiation alone in patients ineligible for clinical trials, suggesting the need to develop less-toxic CRT.

A series of research frauds, including data manipulation in clinical trials of pharmaceuticals represented by the hypertension drugs Diovan and Blopress and the leukemia treatment Tasigna, as well as violation of conflict of interest disclosure in relation to pharmaceutical companies, were uncovered from 2013 to 2014. In response, the Clinical Trials Act(Act No. 16 of 2017)was enacted by the ordinary Diet session on April 7, 2017(promulgated on April 14 of the same year)to ensure confidence in clinical research. In addition to requiring researchers to comply with the Standards for Conducting Clinical Research and to conclude and disclose contracts related to funding to pharmaceutical companies and other parties, the act also stipulates that the quality of reviews should be ensured by establishing an accredited certified review board, thereby promoting high-quality social and academic clinical research that is transparent, safe, and the purpose of the Act is to promote high-quality, socially and academically significant clinical research that ensures transparency and safety. The Act came into effect on April 1, 2018, but when it first came into effect, there was atrophy in clinical research, which is essential for drug development, due to a lack of understanding among researchers, delays in response by medical institutions, and complicated procedures and high implementation costs as typified by the enormous amount of paperwork. Now, several years after the enactment of the Act, the number of specified clinical research projects stipulated in the Act is on the increase, thanks to the Q and A issued by the Ministry of Health, Labour and Welfare regarding the implementation of the Clinical Trials Act and other administrative information, as well as to the ingenious implementation of the Act. In addition, various advantages of conducting research under the Clinical Trials Act have also become apparent. This article outlines the operation and points to keep in mind regarding the specified clinical research stipulated in the Clinical Trials Act.

Background: The real-world survival benefit of FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus anti-VEGF therapy (Triplet) over doublet chemotherapy (Doublet) remains controversial in patients with BRAFV600E mutant metastatic colorectal cancer (mCRC). Patients and Methods: WJOG13219G was a multicenter, retrospective, registry-based study of patients with BRAFV600E mutant mCRC who received first-line triplet or doublet chemotherapy from January 2014 to December 2019 in Japan. Inverse probability of treatment weighting (IPTW) was used to adjust for patient background. Results: The analysis included 79 and 91 patients in the Triplet and Doublet groups, respectively. The Triplet group was significantly younger and had better performance status. No statistical difference was noted in progression-free survival (PFS; HR, 0.82; 95% CI, 0.60–1.13; P = .22) and overall survival (OS; HR, 0.88; 95% CI, 0.62–1.25; P = .48) between both groups. IPTW analysis also showed no difference between the 2 groups in PFS (HR, 0.86; 95% CI, 0.69–1.08; P = .20) and OS (HR, 0.93; 95% CI, 0.73–1.20; P = .59). The Triplet and Doublet groups had an objective response rate of 53% and 41%, respectively (P = .10). At least one grade 3 or 4 adverse event was seen in 51 (65%) and 43 (47%) patients in the Triplet and Doublet groups, respectively, with the incidence of neutropenia being significantly higher in the former. Conclusion: Triplet therapy had no survival benefit versus doublet therapy in the overall and IPTW cohorts or specific subgroups for real-world patients with BRAFV600E mutant mCRC.

Purpose: Although immune checkpoint inhibitors (ICIs) and chemotherapy combinations have been approved for the treatment of gastric and gastroesophageal junction cancer (GC/ GEJC), whether immunochemotherapy (ICT) offers advantages over the simple addition of individual monotherapies remains unclear. This study aimed to investigate whether ICT has a synergistic effect in patients with advanced GC/GEJC. Materials and Methods: Reconstructed individual patient data were electronically extracted from the Kaplan-Meier curves of 3 randomized controlled trials comparing pembrolizumab (KEYNOTE-061, KEYNOTE-062, and KEYNOTE-859). The observed progression-free survival (PFS) curve for each monotherapy was used to estimate the simulated PFS curve expected under an independent drug action model. If the observed curve demonstrated significantly better PFS than the simulated curve, combined ICI and chemotherapy was determined to have a synergistic effect, implying a superior outcome compared to adding-component monotherapy. Results: In patients with programmed cell death ligand 1 combined positive scores of ≥1 (n=2,194), the 1-year and median PFS of the observed and simulated curves were 28.0% vs. 27.9% and 6.89 months vs. 6.88 months, respectively. The one-sample log-rank test revealed no significant differences between the observed and simulated curves (P=0.107). Conclusions: The observed PFS with ICT was comparable to the predicted PFS based on the data for each monotherapy. Our findings do not provide direct evidence of synergistic effects, but they suggest that combining ICI and chemotherapy does not compromise efficacy. These results may support the continued clinical use of ICT in patients with advanced GC/GEJC.

PURPOSEMicrosatellite instability-high (MSI-H) advanced gastric or esophagogastric junction cancer (AGC), accounting for 5%-6% of all AGC cases, has shown an enhanced responsiveness to immunotherapy. We performed a single-arm phase II study to evaluate the combination of nivolumab (NIVO) and low-dose (LD) ipilimumab (IPI) for first-line treatment of MSI-H AGC.PATIENTS AND METHODSPatients with MSI-H AGC received NIVO (240 mg once every 2 weeks) and IPI (1 mg/kg once every 6 weeks). The primary end point was overall response rate (ORR) assessed by blinded independent central review. Secondary end points included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and biomarker analysis. MSI-H status was confirmed with an MSI-IVD Kit (Falco).RESULTSTwenty-nine patients were enrolled. The ORR was 62.1% (95% CI, 42.3 to 79.3), with a complete response rate of 10.3%. The DCR was 79.3% (95% CI, 60.3 to 92.0). Treatment-related adverse events (TRAEs) of any grade occurred in 93.1% of patients, with those of grade ≥3 manifesting in 37.9% of patients. At the data cutoff (median follow-up of 9.0 months), treatment had been discontinued in 21 patients, with such discontinuation being due to TRAEs in 12 (41.4%) patients. However, after exclusion of one patient with progressive disease, the remaining 11 patients showed long-term antitumor efficacy after treatment discontinuation (range of response duration, 0.9+ to 15.6+ months). The median PFS was 13.8 months (95% CI, 13.7 months to not reached [NR]) and the median OS was NR (95% CI, 13.7 months to NR), with a 12-month OS rate of 79.5%.CONCLUSIONNIVO plus LD-IPI showed robust and durable antitumor efficacy as a first-line treatment for MSI-H AGC. Although TRAEs often led to treatment discontinuation, treatment efficacy was subsequently sustained in most patients.

Background: There is no consensus on prognostic factors for advanced digestive neuroendocrine carcinoma (ADNEC). JCOG1213 was a phase III randomized trial that demonstrated equivalent overall survival (OS) between cisplatin plus etoposide and cisplatin plus irinotecan as first-line chemotherapy for ADNEC. We aimed to retrospectively explore prognostic factors for OS in patients with ADNEC using data from JCOG1213. Patients and methods: The patients included in this post hoc analysis had ADNEC (2019 World Health Organization classification system) that was histologically confirmed by a central pathological review whose records included all clinical data required for multivariable analysis using a Cox proportional hazards model. Results: Among 170 patients enrolled in JCOG1213, a total of 129 patients with ADNEC were included in this analysis. Multivariable analysis identified elevated serum lactate dehydrogenase (LDH; >222 IU/l) as a significantly unfavorable prognostic factor for OS [hazard ratio (HR) 1.721, 95% confidence interval (CI) 1.144-2.589, P = 0.0092]. OS of patients with elevated serum LDH was shorter than that of patients without elevated serum LDH [median 9.5 months (95% CI 8.1-10.7 months) versus 15.6 months (95% CI 11.4-19.7 months); HR 1.799, 95% CI 1.242-2.604, P = 0.0019]. There were no distinct differences either in objective response rates or progression-free survival between patients with and without elevated serum LDH. Conclusion: Serum LDH may serve as a simple, non-invasive, and clinically informative biomarker for prognostic evaluation in patients with ADNEC undergoing first-line platinum-based chemotherapy.

Background FOLFOXIRI plus bevacizumab improved efficacies and increased some adverse events in untreated metastatic colorectal cancer (mCRC), compared with the doublet plus bevacizumab. The clinical outcomes of ramucirumab (RAM) in combination with FOLFIRI or FOLFOXIRI as a first-line treatment are unknown. In this randomized phase II study (WJOG9216G), we compared the efficacy and safety of these regimens to determine which is more promising. Methods Patients with untreated mCRC were randomly assigned to the FOLFIRI-RAM or FOLFOXIRI-RAM arms. The primary endpoint was a confirmed objective response rate (ORR), and secondary endpoints included early tumor shrinkage (ETS), progression-free survival (PFS), overall survival (OS), and safety. Results In total, 122 patients were randomized. The confirmed ORR was 59.3% and 60.3% in the FOLFIRI-RAM and FOLFOXIRI-RAM arms, respectively (odds ratio 1.04; P = 0.91). With a median follow-up period of 42.1 and 40.4 months, PFS was comparable between the FOLFIRI-RAM and FOLFOXIRI-RAM arms (median, 11.5 and 10.5 months). ETS rate (71.2% and 52.4%) and OS (median, 32.6 and 28.2 months) were significantly better in the FOLFIRI-RAM arm than in the FOLFOXIRI-RAM arm. The major grade ≥ 3 adverse events in the FOLFIRI-RAM and FOLFOXIRI-RAM arms were neutropenia (44.1% and 72.6%), anorexia (3.4% and 14.5%), and febrile neutropenia (3.4% and 11.3%). Conclusions FOLFOXIRI plus RAM was not superior to FOLFIRI plus RAM in terms of efficacy, including ORR, in patients with untreated mCRC. Instead, first-line FOLFIRI plus RAM showed clinical efficacy and safety profiles comparable to those of doublet chemotherapy plus bevacizumab.

Comprehensive genomic profiling (CGP) is crucial in precision oncology, yet its real-world utility remains unclear. Here we analyzed data from the Japanese nationwide Center for Cancer Genomics and Advanced Therapeutics database, including clinical and genetic data from 54,185 patients with advanced solid tumors (consisting of 81 common and rare tumor types) who received CGP with a targeted sequencing panel covering 324 genes as part of their clinical care. We assessed the prognostic value of CGP-guided clinical evidence-level classification, showing that alterations predicting response to Pharmaceuticals and Medical Devices Agency-approved or Food and Drug Administration-approved therapies and to therapies supported by well-powered studies with expert consensus are detected in 16.6% and 8.1% of patients, respectively, and are associated with better prognosis than those with lower clinical evidence levels. Only 8% of patients receive CGP-guided approved–experimental genomic biomarker-linked therapies, although the proportion has improved over time. Substantial differences were observed across tumor types, with the proportions exceeding 20% in thyroid and lung cancers but remaining below 2% in pancreatic and liver cancers. Tumor-agnostic biomarker analyses reveal that tumor mutational burden (TMB) ≥20 mutations per megabase predicts better outcome across tumor types, regardless of microsatellite instability status, in TMB-high patients receiving pembrolizumab. Conversely, extramammary Pagetʼs disease is exceptionally resistant to pembrolizumab. The large-scale nationwide database allows evaluating inter-tumor type differences and investigating evidence-scarce situations, delineating where CGP offers greater benefit. These real-world findings complement those from clinical trials and prospective sequencing projects regarding CGP, providing valuable information for individualized treatment.

Background: Precision medicine for esophageal squamous cell carcinoma (ESCC) has not been implemented owing to a lack of site-specific therapeutic markers and biomarkers. We hypothesized that the genomic background of each subsite of the esophagus might be different, allowing us to develop site-specific treatment strategies (cervical, upper thoracic, middle thoracic and lower thoracic). Methods: This was a single-center retrospective cohort study. Patients diagnosed with ESCC who underwent comprehensive genomic profiling (CGP) at Keio University Hospital between April 2017 and March 2024 were recruited. Genomic profiles were analyzed and compared across esophageal subsites. Results: Among the 107 patients with ESCC who underwent CGP, 6 were cervical, 16 were upper thoracic, 54 were middle thoracic, and 31 were lower thoracic. The most frequently altered genes were TP53, followed by CDKN2A and NFE2L2. The frequency of NFE2L2 mutations was significantly higher in the middle thoracic region (P = 0.041). The mutation rate increased from Stage I to IV (P = 0.0046). NFE2L2 mutations were rarely observed in early-stage cancers, suggesting that they may subsequently be acquired during growth and metastasis. Furthermore, a significant association was observed between a history of heavy alcohol consumption and NFE2L2 mutations. The overall survival of patients with unresectable or metastatic ESCC harboring NFE2L2 mutations was 12.0 months, compared to 29.7 months in patients without the mutations (HR: 2.37, P = 0.047). Conclusion: NFE2L2 mutations were more common in the middle thoracic esophagus, appeared to be associated with tumor progression, and were linked to poor prognosis.

SummaryBackgroundGastric cancer (GC) with peritoneal dissemination remains a challenge with poor prognosis and limited treatment options. We aimed to compare solvent-based paclitaxel (sb-PTX) + ramucirumab (RAM) vs. nanoparticle-albumin-bound paclitaxel (nab-PTX) + RAM as second-line therapy for unresectable or recurrent GC with peritoneal dissemination.MethodsThis prospective, randomised, open-label, multicentre phase 2 trial was conducted at 58 centres within the West Japan Oncology Group (WJOG) in Japan. Eligible participants were patients with histologically-confirmed GC with peritoneal dissemination refractory or intolerant to first-line therapy. Patients were randomised 1:1 to receive sb-PTX + RAM or nab-PTX + RAM. Primary endpoint was overall survival (OS); key secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), safety, and protocol-specified biomarker analyses including the assessment of stromal caveolin-1 (Cav-1) expression by immunohistochemistry on archival tumour specimens. The data cutoff for the analysis presented herein was January 27, 2021. This trial was registered in the Japan Registry of Clinical Trials (jRCTs031180022).FindingsBetween Oct 1, 2018, and Jan 27, 2020, 105 patients were assigned to sb-PTX + RAM (n = 53) or nab-PTX + RAM (n = 52). Median follow-up was 18.1 months. Median OS was 8.1 months with sb-PTX + RAM and 7.2 months with nab-PTX + RAM (HR [nab-PTX + RAM vs. sb-PTX + RAM], 0.960; 95% CI, 0.621–1.484; P = 0.631). Median PFS was 5.1 vs. 3.9 months (HR [nab-PTX + RAM vs. sb-PTX + RAM], 0.965; 95% CI, 0.642–1.450; P = 0.893). ORR was 20.7% vs. 20.0% (P = 0.993), and DCR was 77.4% vs. 63.5% (P = 0.150), with sb-PTX + RAM and nab-PTX + RAM. Grade≥3 neuropathy occurred in 7.5% with sb-PTX + RAM and 17.6% with nab-PTX + RAM, and febrile neutropenia in 11.3% vs. 5.9%. In biomarker analysis, OS and PFS improved stepwise with increasing Cav-1 expression in patients receiving nab-PTX + RAM (P = 0.007, P = 0.012); no such association was observed with sb-PTX + RAM. Among patients with high stromal Cav-1 expression (IHC score 3+), nab-PTX + RAM showed some evidence of improved OS compared with sb-PTX + RAM (HR [nab-PTX + RAM vs. sb-PTX + RAM], 0.371; 95% CI, 0.130–1.060; P = 0.055). The interaction between Cav-1 expression and treatment arm showed a non-significant trend (HR for interaction, 0.364; 95% CI, 0.115–1.152; P = 0.086), consistent with this finding.InterpretationTreatment with nab-PTX + RAM did not meet the prespecified threshold (HR < 0.90) for promising efficacy in patients with GC and peritoneal dissemination. High stromal Cav-1 expression was associated with improved efficacy of nab-PTX + RAM. Future studies should prospectively validate the predictive value of stromal Cav-1 in patients receiving nab-PTX + RAM.FundingTaiho Pharmaceutical Co. Ltd.

Background: Palliative care has been shown to be effective for patients with advanced cancer; however, the best approach to deliver palliative care needs to be considered. We hypothesized that a combination of palliative care via video telemedicine (TMD) and usual outpatient treatment would improve patients’ quality of life (QOL) and ameliorate depression and prognosis. Methods: Patients with advanced cancer who terminated treatment with chemotherapy were enrolled. Patients who could perform videoconferencing were assigned to the TMD group and those who could not perform were assigned to the (no TMD; control) group. The primary endpoint was QOL, which was evaluated using the difference in the Functional Assessment of Cancer Therapy-General (FACT-G) scores between baseline and one-month follow-up. Secondary endpoints included depression, measured using the Center for Epidemiological Studies Depression (CES-D) scale, overall survival, and patient satisfaction. Results: Fifty patients were included in this study (25 in each group). A comparison of measures of QOL at one month showed that the TMD group maintained a better QOL. FACT-G decreased by 0.21 and 5.96 points in the TMD and no TMD groups, respectively (p = 0.047). The TMD group maintained better QOL. There were trends suggesting improvements in depression and survival which did not reach significance. CES-D increased by 0.92 and 3.50 points in the TMD and no TMD groups, respectively (p = 0.26). Median survival time was 7.82 (3.30–14.59) and 6.37 (2.33–11.04) months in the TMD and no TMD groups, respectively. The results of the Patient Satisfaction Questionnaire suggest that video TMD could be a feasible tool in palliative care. Conclusion: Video TMD is effective in maintaining the QOL of patients with advanced cancer and is feasible based on patient satisfaction. It is desirable to further evaluate the usefulness of palliative care using video TMD and evaluate its clinical applications.

Cisplatin-based chemotherapy is the standard advanced esophageal squamous cell carcinoma (ESCC) treatment. However, the 5-fluorouracil plus L-leucovorin and oxaliplatin (FOLFOX) regimen is available in Japan as an alternative to cisplatin-based chemotherapy, but its efficacy and safety remain unclear. Hence, we aimed to evaluate patients with advanced ESCC who received FOLFOX therapy retrospectively. Patients with advanced ESCC who received FOLFOX therapy at 18 institutions between April 2019 and October 2020 were included. Fifty-two patients received first-line FOLFOX treatment, while 39 received later-line FOLFOX treatment. The median progression-free survival, median overall survival, and objective response rate were 3.8 months (95% confidence interval [CI]: 3.0–5.0), 13.9 months (95% CI: 10.3–17.9 months), and 35% in the first-line group and 2.4 months (95% CI: 2.1–3.8 months), 7.2 months (95% CI: 5.3–9.8 months), and 4% in the later-line group, respectively. The most frequent grade 3 or 4 adverse events were neutropenia (23%) and anemia (12%) in the first-line group and neutropenia (18%), anorexia (13%), anemia (10%), and nausea (10%) in the later-line group. First-line FOLFOX treatment is suitable for patients with advanced ESCC. However, FOLFOX has shown limited efficacy as a later-line treatment.