Programmed death-1 (PD-1) inhibitors combined with chemotherapy have become a standard first-line treatment for advanced oesophageal squamous cell carcinoma (ESCC). Given the high costs associated with immunotherapy, evaluating the cost-effectiveness of different PD-1 inhibitors in the Chinese healthcare setting is essential for guiding treatment decisions and policy development.

A cost-effectiveness analysis was conducted comparing six PD-1 inhibitors-sintilimab, toripalimab, tislelizumab, camrelizumab, serplulimab, and pembrolizumab-combined with chemotherapy for first-line treatment of advanced ESCC. A partitioned survival model was used to calculate incremental cost-effectiveness ratios (ICERs) from healthcare system perspective, with a willingness-to-pay (WTP) threshold set at $36,598.19 per quality-adjusted life year (QALY). Sensitivity analyses were performed to evaluate the robustness of the results.

The ICERs for toripalimab, camrelizumab, pembrolizumab, serplulimab, sintilimab, and tislelizumab were $32,356.79/QALY, $48,410.64/QALY, $312,743.54/QALY, $121,200.84/QALY, $29,663.42/QALY, and $35,304.33/QALY, respectively. Sintilimab, toripalimab, and tislelizumab were below the WTP threshold. Among all regimens, the top three in life years (LYs) gained were toripalimab, serplulimab, and tislelizumab. Sensitivity analysis showed that utility values and drug prices were key factors influencing ICERs. Probabilistic analysis indicated that toripalimab, sintilimab, and tislelizumab had the highest probabilities of being cost-effective, at 83.1%, 81.4%, and 70.0%, respectively.

Sintilimab, toripalimab, and tislelizumab are the most cost-effective PD-1 inhibitors when combined with chemotherapy for the first-line treatment of advanced ESCC in China, with ICERs below the WTP threshold. While all six PD-1 inhibitors demonstrated clinical benefits, pembrolizumab and serplulimab were less favourable from a cost-effectiveness standpoint. Sensitivity analysis confirmed that drug prices and utility values are significant determinants of cost-effectiveness.

Trial no. NCT04821778 registered in ClinicalTrials.gov.

Immune checkpoint inhibitors (ICIs) have become an important treatment option for patients with nasopharyngeal carcinoma. With the increasing use of such agents, immune-related adverse events (irAEs) have become a concern. Identifying and managing the toxicity and side effects of ICIs is crucial, since it not only has implications for their safety but also the intensity and efficacy of subsequent use by patients. The present case report documents a 40-year-old male patient with acute erosive hemorrhagic gastritis associated with sintilimab treatment. In particular, the clinical manifestations, treatment, side effects and prognosis of this case was focused upon. The patient was diagnosed with locally advanced nasopharyngeal carcinoma (cT4N3M0 stage IVa) and developed bone metastases after 1 year of standard radiotherapy and adjuvant chemotherapy. After the first- and second-line treatments, pulmonary metastases occurred and sintilimab monotherapy was used as the third-line therapy. During the course of treatment, the optimal outcome for this patient was partial response according to the Response Evaluation Criteria in Solid Tumors (version 1.1). However, after 14 cycles of sintilimab the patient developed melena and epigastric pain and was diagnosed with acute erosive hemorrhagic gastritis, which was treated with methylprednisolone therapy. Progression-free survival with the third-line treatment was 542 days. Sintilimab-associated hemorrhagic gastritis is not fully recognized as an irAE. Therefore, early identification, diagnosis and management of irAEs are critical for subsequent therapy and progression-free survival of patients.

This study aims to comprehensively evaluate the hematologic toxicity profiles, toxicity spectrum, and safety rankings of immune checkpoint inhibitors (ICIs) used for digestive system tumors. The PubMed, Cochrane Library, Web of Science, and Embase databases were systematically searched from inception to August 2024 to identify randomized controlled trials (RCTs). The primary outcome was anemia, while secondary outcomes included neutropenia, neutrophil count decreased, thrombocytopenia, platelet count decreased, leukopenia, white blood cell (WBC) count decreased, lymphocyte count decreased, and febrile neutropenia (FN). Subgroup analyses were performed based on tumor type, country category, study phase, ICI regimen, control group, chemotherapy regimen, ICI plus different chemotherapy regimens. Two reviewers independently selected the studies, extracted data according to pre-specified criteria, and assessed the risk of bias using the Cochrane Collaboration risk of bias tool. RevMan 5.4 software was utilized to visualize the risk of bias assessments. Stata 16.0 was used to conduct network meta-analysis, sensitivity analysis and meta-regression. 25 phase II and III RCTs (n = 15216) were included. The general safety of ICIs ranked from high to low for grade 1-5 anemia were as follows: avelumab, nivolumab, pembrolizumab, sintilimab, camrelizumab, and tislelizumab. For grade 3-5 anemia, the general safety profile of the ICIs were as follows, from highest to lowest: avelumab, nivolumab, pembrolizumab, sintilimab, and camrelizumab. Compared to chemotherapy, treatment-related hematologic toxicities with ICIs occurred primarily in grade 1-5 anemia, neutropenia, thrombocytopenia, leukopenia, and WBC count decreased. Taking ICI monotherapy, nivolumab plus ipilimumab were generally safer than taking chemotherapy, one ICI drug with chemotherapy, or two ICI drugs with chemotherapy. In terms of grade 1-5 hematologic toxicities, tislelizumab had the highest risk of neutropenia and leukopenia; the primary treatment-adverse events (AEs) for sintilimab was neutrophil count decreased and WBC count decreased; the primary treatment-related AE associated with nivolumab was platelet count decreased; camrelizumab posed the highest risk for lymphocyte count decreased. In terms of grade 3-5 hematologic toxicities, pembrolizumab was predominantly linked to neutropenia; sintilimab showed the greatest risk for neutrophil count decreased, platelet count decreased, and lymphocyte count decreased; avelumab was most associated with WBC count decreased. FN primarily manifested as grade 3-5, with camrelizumab having the highest risk. Among agents used in gastric or gastroesophageal junction cancer, avelumab demonstrated the most favorable safety profile for anemia. Each treatment regimen has its unique safety profile. Early identification and management of ICI-related hematologic toxicities are essential in clinical practice.Systematic Review Registration: PROSPERO CRD42024571508.

The incorporation of immunotherapy has transformed the treatment landscape for advanced, unresectable, or metastatic gastroesophageal cancers (GECs), with improved survival outcomes. These improvements in outcomes for advanced GECs have led to clinical trials evaluating the role of immunotherapy in patients with resectable early-stage GECs. However, there remains a high burden of morbidity and mortality, and ongoing trials utilizing novel immunotherapy agents and combinations are underway. This review summarizes the findings of previous and ongoing clinical trials related to immunotherapy for patients with early- and late-stage GECs.

The NEOCRTEC1601 trial aimed to evaluate the efficacy and safety of paclitaxel in combination with cisplatin and 5-fluorouracil (TPF) as an induction chemotherapy for borderline-resectable esophageal squamous cell carcinoma (BR-ESCC). This study presents an updated 5-year analysis to further elucidate the impact of TPF chemotherapy followed by surgery.

This study was conducted as a single-center, phase II clinical trial. Eligibility was extended to patients diagnosed with BR-ESCC, characterized by a primary tumor or bulky lymph nodes with potential invasion into adjacent organs. The treatment protocol commenced with TPF chemotherapy, followed by surgery, if the tumor was deemed resectable, or by concurrent chemoradiation in cases where resection was not feasible. This updated report delineates the 5-year overall survival (OS) and progression-free survival (PFS) rates.

Surgery was performed on 27 patients (57.4%), and R0 resection was observed in 26 patients (53.2%). Pathologic complete response was confirmed in four patients (8.5%). Following a minimum follow-up period exceeding 60 months for all patients, the total number of deaths was 31 (65.96%). The OS and PFS for the R0 group were significantly longer than those for the non-R0 group (median OS: 53.0 months vs. 13.9 months, HR: 0.36, 95% confidence interval [CI]: 0.17-0.76, P = 0.0032; median PFS: 50.84 months vs. 5.42 months, HR: 0.40, 95% CI 0.19-0.84, P = 0.0076). The 5-year OS rate was 50.0% (34.0%-73.4%) for the R0 group compared to 19.0% (7.9%-46.0%) for the non-R0 group (HR: 0.36, 95% CI: 0.17-0.79, P = 0.0041).

Long-term follow-up confirmed that the OS and PFS were significantly improved in patients who underwent R0 resection compared to those who did not. The 5-year OS rate for patients who achieved R0 resection was 50.0%. R0 resection might be an independent prognostic factor for OS. To further improve the R0 resection rate and prognosis, more effective induction treatment regimens need to be explored.

Advanced esophageal squamous cell carcinoma (ESCC) patients had poor prognosis and few effective drugs based on the randomized controlled trials (RCTs). In such a circumstance, recent RCTs have shown the clinical efficacy of immune checkpoint inhibitors (ICIs) as first- or second-line treatment for advanced ESCC patients. Tislelizumab is one of the anti-Programmed-Death-1 (PD-1) antibodies; at first, tislelizumab monotherapy showed clinical efficacy as a second-line treatment for advanced ESCC patients based on the results of the RATIONALE-302 trial. Since then, tislelizumab plus doublet chemotherapy has shown superiority in overall survival compared to doublet chemotherapy for untreated advanced ESCC patients in the RATIONALE-306 trial. In this review, we share the overview of the development of tislelizumab and discuss the future perspectives on ICIs for advanced ESCC patients. In our opinion, tislelizumab plus doublet chemotherapy is one of the first-line standard treatments for advanced ESCC patients regardless of Programmed cell Death ligand 1 expression. Some other ICI-containing treatments showed clinical efficacy for untreated ESCC patients; we need further investigation to select these treatments appropriately.

Esophageal cancer is a type of digestive system tumor with a high degree of malignancy. In recent years, research has been conducted on immunotherapy, chemotherapy and radiation therapy for esophageal cancer. However, there are still shortcomings in the improvement of 5-year survival rates. In order to explore more therapy options, the present study evaluated the efficacy and safety of recombinant human-endostatin (rh-endostatin) combined with sintilimab and chemotherapy for the first-line treatment of locally advanced or metastatic esophageal squamous cell carcinoma (ESCC). This retrospective study included data from 31 patients with unresectable locally advanced or metastatic esophageal cancer treated between January 2019 and December 2023, and was approved by the First Affiliated Hospital of Nanjing Medical University (Nanjing, China). All patients received first-line treatment combining rh-endostatin with sintilimab, paclitaxel liposome and platinum. Following the completion of 6 cycles, maintenance therapy with sintilimab was administered until disease progression occurred. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) time, overall survival (OS) time and adverse events (AEs) were observed. Symptomatic or supportive care was administered as needed, according to the clinical discretion of the treating physician. As of July 17, 2024, the median follow-up time was 13.07 months, with a median PFS time of 8.30 months (95% confidence interval, 3.442-13.158 months). For these 31 patients, the ORR was 67.7% (21/31), while the DCR was 93.5% (29/31). The median OS time reached 23.07 months. Furthermore, 77.4% of patients experienced at least one treatment-related AE (TRAE), and grade 3 TRAEs occurred in 8 patients (25.8%). No unexpected AEs were observed. In conclusion, rh-endostatin combined with sintilimab and chemotherapy exhibited positive efficacy and safety in patients with advanced ESCC, providing a promising treatment regimen for these patients.

Neoadjuvant immunochemotherapy is expected to become the standard treatment mode for locally advanced esophageal squamous cell carcinoma (ESCC). This study aims to analyze the clinical outcomes and long-term survival of neoadjuvant immunochemotherapy for locally advanced ESCC, and explore the feasibility of using major pathological response (MPR) as a surrogate endpoint.

This real-world retrospective study consecutively included eligible patients with stage II-IVA locally advanced ESCC who received neoadjuvant immunochemotherapy and surgery between 2019 and 2022 at the Department of Thoracic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine.

This study collected a total of 166 patients, and ultimately included 126 patients after screening. The objective response rate (ORR) was 69.8% (88/126). The incidence of grade 3-4 adverse events (AEs) was 13.5% (17/126). MPR was observed in 49 (38.9%) patients, and 24 (19.0%) patients achieved a complete pathological response (pCR). The median progression-free survival (PFS) was 31.7 months and the 3-year PFS rate was 56.3%. The median overall survival (OS) was not reached and the 3-year OS rate was 70.6%. The median PFS of the non-MPR group was 25.0 months, with the MPR group not achieved (hazard ratio [HR], 2.503; 95% CI 1.359-4.610; P = 0.0022). The median OS in the non-MPR group was 31.7 months and not reached in the MPR group (HR, 3.607; 95% CI 1.576-8.254; P = 0.0012). MPR is an independent prognostic factor affecting OS (HR, 2.522; 95% CI 1.018-6.401; P = 0.046).

Neoadjuvant immunochemotherapy is safe and effective for locally advanced ESCC, and can result in certain survival benefits. MPR can serve as a surrogate endpoint for predicting long-term OS.

Lung cancer is the cancer with the highest incidence and mortality rate worldwide. In addition to the diversified treatment and prolonged lifespan in view of the development of medical technology, the side effect of medicine should not be ignored. Drug-induced interstitial lung disease (DI-ILD) is also commonly encountered during this process, and ILD triggered by the treatment of lung cancer characterized by the inflammation and scarring of lung tissue after the antitumor treatment in lung cancer leads to a poor prognosis and high mortality. The diagnosis and treatment of ILD caused by anti-lung cancer agents remains challenging in clinical settings and requires joint efforts from multidisciplinary team (MDT). This review systematically updates the epidemiology, molecular pathogenesis, genomics/genetics study, diagnosis and treatment of ILD related to anti-lung cancer agents. By the integration of the latest evidences, the paper offers clinical work references for early diagnosis of ILD related to anti-lung cancer agents to enhance the survival and quality of life of the lung cancer patients.
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Recent advances in immunotherapy have changed the treatment landscape for cancers of the upper gastrointestinal (GI) system. Immune checkpoint inhibitors can lead to better survival and improved quality of life for affected individuals. Adopting new treatment strategies in real-world practice can be challenging, and algorithms that are easy to implement in Canadian oncology practices would benefit clinicians and patients. In this study, we present expert opinion on best practices for upper GI cancer management, including a new algorithm that integrates the latest evidence for screening, workup, diagnosis, treatment, and survivorship. The algorithm is based on a novel approach comprising a case-based, accredited educational program with asynchronous discussion among clinicians practicing across Canada, with the input of expert medical oncologists and gastroenterologists. A needs assessment was employed to determine current areas of educational need in the field of upper GI cancers, and a patient representative provided insights into patient concerns and priorities. The best practices described here include seeking patient input throughout treatment, integrating immune checkpoint inhibitors into systemic therapy for both localized and advanced disease, and providing comprehensive supportive care throughout the treatment and survivorship journey.

Numerous immune checkpoint inhibitors have been approved for clinical use in metastatic advanced esophageal cancer. While immunotherapy brings therapeutic benefits, immune-related adverse events (irAEs) should nevertheless not be overlooked. This paper reports on the first documented case of Autoimmune hemolytic anemia (AIHA) caused by anti-programmed cell death protein-1 therapy in esophageal squamous cancer.

An 84-year-old female patient with metastatic squamous esophageal cancer developed chest tightness, generalized weakness, and a yellowing of the skin after 2 cycles of sintilimab treatment.

Initial examination revealed severe anemia with elevated levels of bilirubin, reticulocytes, lactate dehydrogenase, decreased levels of haptoglobin, and a positive direct antihuman globulin test. The patient was diagnosed with immunotherapy-associated AIHA.

The patient was promptly treated with corticosteroids and human immunoglobulin, supportive transfusion with washed erythrocytes.

Her AIHA was controlled after treatment. Subsequent immunotherapy was not continued, and there was no recurrence of AIHA.

We have identified a rare case of serious adverse reaction caused by anti-PD-1 therapy. We summarize the clinical presentations, diagnosis, and treatment of this case of immunotherapy-related AIHA and discuss the pathogenesis and therapeutic advances in immunotherapy-related AIHA, as well as sintilimab-induced irAEs, in detail. These findings underscore the importance of the early detection, diagnosis, and treatment of these rare and potentially fatal irAEs.

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

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

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

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

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

Although multiple agents targeting PD-1 have been approved as second-line treatment for esophageal squamous cell carcinoma (ESCC), only a fraction of patients derive long-term survival. Hence, reliable predictive biomarkers are urgently needed.

Comprehensive tumor genomic profiling and transcriptome sequencing were performed on samples from the RATIONALE-302 study. We also conducted single-cell RNA sequencing analysis on Notch1 knockdown ESCC murine models to further explore the potential molecular mechanisms underlying anti-PD-1 benefit.

We identified NOTCH1 mutation as a potential predictive biomarker for longer overall survival (OS) with tislelizumab versus chemotherapy (18.4 months v 5.3 months; hazard ratio, 0.35 [95% CI, 0.17 to 0.71]). At the transcriptional level, type I IFN (IFN-I)/toll-like receptor expression signatures were positively associated with OS benefit of tislelizumab, whereas B-cell and neutrophil signatures predicted unfavorable OS. Exploratory analyses showed that the presence of NOTCH1 mutation correlated with enrichment of IFN-I signatures and reduced infiltration of B cells and neutrophils. In murine models, comparative single-cell transcriptome analyses further revealed that Notch1 deficiency facilitated a more immunologically activated tumor microenvironment which potentiated anti-PD-1 treatment.

Our data provide novel insights for anti-PD-1 treatment selection using NOTCH1 mutations and may provide a rationale for combination therapy in ESCC.

Cervical esophageal cancer (CEC) is an uncommon malignancy accounting for <5% of all esophageal carcinomas. Treatment of CEC varies and is adapted from established regimens used for squamous cell carcinoma (SCC) or the lower esophageal and head and neck. The present systematic review and guidelines are intended to assist treatment decision making for patients with CEC based on the available evidence.

Using the Population, Intervention, Comparator, Outcome, Timing, and Study Design (PICOTS) framework, the evidence regarding treatment outcomes was assessed using Cochrane and PRISMA 2020 methodology. Eligible studies included prospective Phase II to III trials and retrospective analyses published between January 1, 2013 and February 23, 2024 in the Ovid Medline database. These references were assessed through the American Radium Society (ARS) Appropriate Use Criteria (AUC) methodology. A systematic review PRISMA 2020 checklist confirmed the completion of essential elements. RAND-UCLA consensus methodology was used by the expert panel to rate the appropriateness of the treatment options.

ARS AUC recommendations include (1) larynx preservation using endoscopic resection (EMR or ESD) alone for the typical case with pT1a cN0 cM0 CEC, (2) definitive CRT for the typical case with cT1bN0M0 in patients who cannot undergo endoscopic resection, (3) larynx-preserving using definitive CRT (with or without induction chemotherapy) for the typical case with nonmetastatic locally advanced CEC (advanced T-stage tumors or involved lymph nodes), with surgery reserved for those patients with incomplete response or locoregional recurrence.

This ARS AUC summary provides guidelines for the management of SCC of the cervical esophagus provides based on available evidence. Topics that warrant further investigation include optimization of (1) patient selection; (2) multimodality therapies including chemotherapy, immunotherapy, and targeted agents; (3) radiation dose, schedule, and treatment volume; and (4) supportive care for patients with CEC. Ongoing trials continue to improve outcomes for patients with CEC.

Esophageal squamous cell carcinoma (ESCC) is a prevalent and highly lethal malignancy in Asia. Recent advancements in immune checkpoint inhibitors (ICIs) have markedly transformed the systemic therapy landscape for ESCC. Anti-PD-1-based combination with chemotherapy or with ipilimumab, an anti-CTLA-4 antibody, have been established as the new standard first-line treatments for patients with advanced ESCC. Moreover, anti-PD-1 monotherapy has demonstrated improved efficacy and survival compared with second-line chemotherapy in previously treated patients with ESCC. Novel ICIs targeting other immune checkpoints also show potential for enhancing anticancer therapy in advanced ESCC.The TIGIT/PVR pathway represents a new immune checkpoint. Preclinical studies have indicated that the dual blockade of TIGIT and PD-1 can enhance antitumor immune responses. Clinical trials have reported that combining anti-TIGIT with anti-PD-1/PD-L1 antibodies elicited clinical responses in patients with advanced ESCC. In the first-line systemic therapy setting, combinations of dual ICIs targeting TIGIT and PD-1/PD-L1 plus platinum-based chemotherapy have demonstrated acceptable toxicity profiles and promising antitumor activity in several phase II trials and one phase III study. However, the role of adding an anti-TIGIT antibody to the current standard of anti-PD-1/PD-L1 plus platinum-based chemotherapy in first-line therapy for advanced ESCC remains to be fully determined, necessitating further clinical trials. Ongoing studies are also investigating the role of anti-TIGIT, with or without anti-PD-1/PD-L1, in locoregional ESCC. Additional research is essential to optimize the potential of anti-TIGIT therapy in ESCC and other malignancies by identifying predictive biomarkers, determining optimal antibody types, and gaining key mechanistic insights.

This prospective, two-cohort phase 2 trial with random allocation was conducted to evaluate the safety and efficacy of neoadjuvant tislelizumab combined with nab-paclitaxel/paclitaxel and cisplatin (TP) in patients with esophageal squamous cell carcinoma (ESCC). Patients were enrolled and randomly assigned to the nab-paclitaxel or paclitaxel cohorts at a 1:1 ratio, and received intravenous tislelizumab (200 mg, day 1) combined with cisplatin (25 mg/m2, days 1-3) and either nab-paclitaxel (125 mg/m2, days 1 and 8) or paclitaxel (150 mg/m2, day 1) in a 21-day cycle for two cycles before surgery. The primary endpoint was the major pathological response (MPR) rate. From March 01, 2022 to April 10, 2023, 46 patients were enrolled (n = 23 in each cohort), with 42 patients receiving the full two-cycle treatments and undergoing surgery (n = 22 in the nab-paclitaxel cohort, n = 20 in the paclitaxel cohort). The MPR rate and the pCR rate in the total cohort were 44.2% (19/42) and 19.0% (8/42), respectively, with 59.1% (13/22) and 31.8% (7/22) in the nab-paclitaxel cohort and 30.0% (6/20) and 5.0% (1/20) in paclitaxel cohorts. The most common treatment-related adverse events (TRAEs) were anemia (89.1%) and alopecia (71.7%), and no significant difference in TRAEs was observed between the two cohorts. Up until March 28, 2024, the median follow-up time was 15.5 months (range of 6.0-24.3 months), and the survival analysis revealed that the patients in the nab-paclitaxel cohort had a higher event-free survival (p = .002). In conclusion, neoadjuvant tislelizumab combined with cisplatin and nab-paclitaxel, rather than cisplatin and paclitaxel, is a more effective neoadjuvant strategy for locally advanced thoracic ESCC.

Although combinations of immune-checkpoint inhibitors (ICI) with chemotherapy have been approved for esophageal squamous cell carcinoma (ESCC), it remains unclear whether immunochemotherapy (ICT) offers advantages over the simple addition of individual monotherapies. This study aimed to investigate whether ICT exhibits a synergistic effect in patients with advanced ESCC.

Reconstructed individual patient data of 3330 patients were electronically extracted from the Kaplan-Meier (KM) curves of eight randomized-controlled trials (ATTRACTION-3, CheckMate648, KEYNOTE-181, KEYNOTE-590, RATIONALE-302, RATIONALE-306, ESCORT, and ESCORT-1st). The observed progression-free survival (PFS) curve of each constituent monotherapies was used to estimate simulated PFS curves expected under a model of independent drug action. If the observed curve demonstrated significantly better PFS than the simulated curve, the combination of ICI and chemotherapy may have a synergistic effect, implying a superior outcome compared to simply adding the component monotherapy.

The 1-year, 2-year, and median PFS of the observed and simulated KM curves were 26.3% vs. 24.8%, 14.6% vs. 12.0%, and 6.9 vs. 6.4 months, respectively. The one-sample log-rank test showed no significant differences between the observed and simulated KM curves (p = 0.073).

The observed PFS with ICT was comparable to the simulated PFS estimated from the data for each monotherapy. Although it is unclear whether potential synergies exist for ICT, these findings suggest that the benefits of ICI and chemotherapy do not interfere with each other, thereby providing theoretical support for the efficacy of ICT.

Current evidence for the combined use of immunotherapy, low-dose chemoradiotherapy, and epidermal growth factor receptor-targeted therapy for the treatment of advanced esophageal squamous cell carcinoma is lacking. We report the case of a 73-year-old woman with squamous cell carcinoma of upper middle thoracic esophagus. After undergoing concurrent chemoradiotherapy combined with immunotherapy and anti-angiogenic targeted therapy, the patient achieved a progression-free survival of 17 months. To date, the patient has achieved 35 months of overall survival, which continues to extend, with a good quality of life. Immunotherapy combined with low-dose concurrent chemoradiotherapy is a promising option for elderly patients with advanced esophageal cancer who are intolerant to standard treatments. The addition of an epidermal growth factor receptor monoclonal antibody as a radiosensitizer improves therapeutic efficacy. The combination of sintilimab and anlotinib has the potential to treat recurrent and metastatic esophageal cancer. Tailoring treatment strategies for specific patient groups is essential in personalized medicine.

This study aims to investigate the efficacy and safety of PD-1/PD-L1 inhibitors in the first-line treatment of esophageal squamous cell carcinoma (ESCC) and identify factors influencing efficacy through a meta-analysis of multiple phase 3 randomized controlled trials (RCTs).

A systematic literature search was conducted in Cochrane, PubMed, and Embase databases. Two researchers independently extracted trial data, including efficacy-related outcomes such as overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and duration of response (DoR), along with their subgroup data and safety-related indicators. The overall hazard ratio (HR) and 95% confidence interval (CI) were calculated for OS and PFS, while the overall odds ratio (OR) and 95% CI were computed for ORR to compare the classification and predictive abilities of combined positive score (CPS) and tumor proportion score (TPS) for PD-L1 status. Additionally, survival outcomes across different subgroups were evaluated to explore the potential influencing factors for the efficacy of PD-1/PD-L1 inhibitors in ESCC.

This meta-analysis included eight phase 3 RCTs encompassing 4,479 participants. PD-1/PD-L1 inhibitors combined with chemotherapy significantly improved OS (HR: 0.68, 95% CI: 0.63-0.74) and PFS (HR: 0.62, 95% CI: 0.58-0.67) in ESCC patients compared to non-combination therapy. Patients with higher PD-L1 expression (CPS>1 or TPS>1) demonstrated superior responses to PD-1/PD-L1 inhibitions, with CPS identified as a stronger predictor of therapeutic benefit, particularly at a threshold of CPS =10. Subgroup analysis revealed that male, Asian, smoking, and liver metastasis patients exhibited a greater trend toward improved disease control with PD-1/PD-L1 inhibitors. However, there was no significant difference in treatment efficacy between immune therapy combined with TP (taxol [paclitaxel] + cisplatin) and FP (5-fluorouracil [5-FU] + cisplatin) regimens (POS =0.51, PPFS =0.11). Finally, PD-1/PD-L1 inhibition was associated with a higher incidence of grade ≥3 adverse events compared to chemotherapy alone (HR: 1.21, 95% CI: 1.07-1.37).

This study confirms that the combination of PD-1/PD-L1 inhibitors and chemotherapy provides significant clinical benefits in ESCC. CPS =10 serves as a key threshold for predicting treatment response. There is a trend suggesting that male, Asian, smoking, and liver metastasis patients may experience better survival benefits, while no significant difference was observed between TP- and FP-based regimens.

https://www.crd.york.ac.uk/prospero, identifier CRD42024536221.

Rechallenge with immune checkpoint inhibitor (ICI) seemed favorable in several tumors, but clinical experience on esophageal squamous cell carcinoma (ESCC) was scanty. This real-world study aimed to assess the feasibility and safety of anlotinib plus ICI for patients with previously ICI-treated advanced ESCC.

We retrospectively identified advanced ESCC patients who received anlotinib plus ICI in the rechallenge setting for evaluation of clinical outcomes and safety. Totally 110 ICI-pretreated patients, of which 89 (80.9%) received prior first- or second-line treatment, were included from September 9, 2019, to November 30, 2022. Most patients (63.6%) discontinued initial ICI due to disease progression.

After rechallenge, median overall survival (OS) and progression-free survival (PFS) were 11.1 (95% CI, 8.6-13.7) and 5.6 (95% CI, 4.4-6.8) months, respectively; estimated OS and PFS rates at 12 months were 47.6% (95% CI, 36.8%-57.7%) and 21.4% (95% CI, 10.9%-34.2%), respectively. No complete response was reported and 21 (19.1%) patients attained partial response; the objective response rate was 19.1%. Fifty-five (50.0%) had stable disease for a disease control rate of 69.1%. Of the 21 responders, median duration of response was 6.4 months. Tendencies for longer OS were observed in patients with Eastern Cooperative Oncology Group Performance of 0 (P = .056). The incidence of grade 3 or higher treatment-related adverse events was 10.0%.

Anlotinib plus ICI in the rechallenge setting was promising and resulted in encouraging benefits for patients with previously ICI-treated advanced ESCC. Our findings provided preliminary but unique evidence to help select ESCC patients benefiting from this strategy.

chictr.org.cn; number ChiCTR2300070777.

This individual patient data pooled analysis aimed to evaluate the effectiveness, safety, and patterns of use of camrelizumab in a large cohort of advanced esophageal cancer (AEC) patients.

Adult patients (≥ 18 years) who had received camrelizumab as part of AEC treatment were pooled from three independent, prospective observational cohort studies (NCT04616040, ChiCTR1900027275, and ChiCTR2000039499). The main outcomes were patterns of camrelizumab use, progression-free survival (PFS), overall survival (OS), and safety in the overall population and specific subgroups of underrepresented patients. Among 987 patients, 450 (45.6%) received camrelizumab in the first line, 398 (40.3%) in the second line, and 139 (14.1%) in the third line or later. Most (69.7%) patients received camrelizumab plus chemotherapy regardless of treatment lines. The median PFS was 9.9 (95% CI 7.4, 14.4), 6.6 (95% CI 5.1, 8.8), and 5.7 (95% CI 3.1, 9.6) months in the first line, second line, and third line or later, respectively. The corresponding median OS was 15.5 (95% CI 12.6, 18.4), 12.1 (95% CI 10.0, 14.7), and 10.9 (95% CI 8.1, 14.5) months. Patients with poor performance status (ECOG PS ≥ 2) and with camrelizumab in the second line or later, but not patients with older age (≥ 75 years), were associated with poor survival. Adverse events occurred in 721 (73.0%) patients, with no new safety signals.

This study provides an overview of camrelizumab use in unselected AEC patients. The real-world effectiveness and safety of camrelizumab are generally consistent with those observed in pivotal trials.

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.

Esophageal squamous cell carcinoma (ESCC) is a predominant and highly lethal form of esophageal cancer, with a five-year survival rate below 20%. Despite advancements, most patients are diagnosed at advanced stages, limiting effective treatment options. Multi-omics integration, encompassing somatic genomic alterations, inherited genetic mutations, transcriptomics, proteomics, metabolomics, and single-cell sequencing, has enabled the identification of distinct molecular subtypes of ESCC.

This article systematically reviewed the current status of molecular subtyping of ESCC based on big data, summarized unique subtypes with differing treatment responses and prognostic outcomes.

Key findings included subtype-specific genetic mutations, signaling pathway alterations, and metabolomic profiles, which offer novel biomarkers and therapeutic targets. Furthermore, this review discusses the link between molecular subtypes and immunotherapy efficacy, chemotherapy response, and drug development.

These insights highlight the potential of omics-based molecular typing to transform ESCC management and facilitate personalized treatment strategies.

Esophageal cancer is one of the most common and deadliest cancers worldwide. Rates of esophageal cancer worldwide have been steadily rising over the past decade due to higher incidence of gastroesophageal reflux disease (GERD). Current therapies include surgical resection, chemotherapy, and limited targeted therapies. One obstacle to care is tumor cells' ability to evade immune surveillance, which can render certain therapeutics ineffective. Immunotherapy provides a new paradigm to cancer treatment, which has proven to be effective in evasive tumors. In recent years, PD-1/PD-L1 and CLTA-4 inhibitors have been used as frontline treatment and have shown to be extremely effective in the treatment of hard-to-treat tumors. Here, we aim to analyze the current literature regarding current therapeutics along with emerging techniques and future receptor targets for immunotherapy.

Immune checkpoint inhibitors (ICIs) have been extensively utilized in the treatment of esophageal squamous cell carcinoma (ESCC); however, patient responses to these therapies exhibit significant variability. This study aimed to investigate the prognostic value of Geriatric Nutritional Risk Index (GNRI) in patients with ESCC undergoing immunotherapy.

A retrospective study was conducted on 677 patients with metastatic/recurrent or unresectable ESCC who received immunotherapy. Kaplan-Meier analysis and Log-rank test compared survival differences between high and low GNRI groups, while Cox proportional hazards models analyzed the impact of GNRI on survival in various subgroups and identified independent prognostic factors. Furthermore, immunohistochemistry (IHC) was performed on endoscopic biopsy tissues from 45 patients with unresectable disease who received immune ICIs as first-line treatments to investigate the predictive performance of GNRI combined with programmed cell death ligand 1 (PD-L1) for tumor response and overall survival (OS).

Regardless of metastatic/recurrent disease or unresectable status, patients with high GNRI levels had significantly longer OS time (P<0.001). Moreover, the protective role of GNRI was observed in various subgroups. Eastern Cooperative Oncology Group performance status (ECOG PS) score, distant organ metastasis, previous treatments, ICI modalities and GNRI were identified as independent prognostic factors for OS. Furthermore, the predictive performance of GNRI for OS may surpass that of PD-L1 expression (P=0.009 vs. P=0.38), while PD-L1 expression excelled in predicting tumor response (P=0.007 vs. P=0.08). The combination of these two indicators effectively predicted both tumor response (P=0.04) and OS (P=0.03) in immunotherapy.

The GNRI serves as a robust prognostic indicator in patients with ESCC who are treated with ICIs. The integration of PD-L1 expression and GNRI demonstrates significant predictive value for tumor response and OS.

This study evaluated the efficacy and safety of camrelizumab combined with platinum-based chemotherapy (taxanes [T] or fluorouracil agents [F] plus platinum [P] drugs) as the first-line treatment in advanced esophageal squamous cell carcinoma (ESCC), using immune repertoire sequencing (IRS) to explore treatment response mechanism. In this multi-center, prospective cohort study, 88 patients received camrelizumab plus TP or FP, achieving a 1-year progression-free survival of 56.8% and overall survival of 68.2%. The objective response rate (ORR) was 64.8%, with a disease control rate of 91.1%. While most treatment-related adverse events were mild, 12.5% of patients experienced grade ≥3 toxicities. IRS showed significant differences in T-cell receptor (TCR) β-chain and immunoglobulin heavy chain between patients with (ORR group) or without ORR (non-ORR group), particularly in the distribution and expression of some genes. Specifically, we found the significant differences in the amino acid composition of complementarity determining region 3 (CDR3) polypeptide sequences in TCR and B-cell receptor (BCR) between the ORR and non-ORR groups. For TCR, we observed substantial oligoclonal enrichment and differences in the abundance of specific V and J genes. Similarly, for BCR, we detected differences in the clonotype abundance of CDR3 polypeptide segments and identified several differential V genes. Camrelizumab combined with platinum-based chemotherapy is effective and well-tolerated as the first-line treatment for ESCC, and IRS may reveal mechanism influencing treatment response.

Immune checkpoint inhibitors (ICIs) benefit only a subset of patients in advanced esophageal squamous cell carcinoma (ESCC). Our study aims to develop and validate a clinically accessible model to better identify those who may respond to ICIs.

This study enrolled advanced ESCC patients treated with ICIs at Peking University Cancer Hospital from January 14, 2016, to January 26, 2024 for the training cohort and at Harbin Medical University Cancer Hospital between January 10, 2019, and July 6, 2022 for the validation cohort. Combined positive score (CPS) was recorded to assess the predictive value of programmed cell death ligand-1 (PD-L1). Baseline clinical and laboratory characteristics were identified as predictors through Akaike information criterion (AIC) and Cox proportional hazards regression. The prediction model underwent internal validation through bootstrapping and was externally validated in the validation cohort.

The training cohort consisted of 430 patients, while the validation cohort included 184 patients. PD-L1 expression failed to discriminate survival outcomes. The prediction model incorporates 10 variables: stage, bone metastasis, line of therapy, treatment, lactate dehydrogenase, carcinoembryonic antigen, carbohydrate antigen 199, systemic immune-inflammation index, lymphocyte count and prognostic nutritional index. The model achieved a C-index of 0.725 in the training cohort, 0.722 following bootstrapping, and 0.691 in the external validation cohort. An interactive online prediction tool ( https://escc-survival.shinyapps.io/shiny_app/ ) was subsequently developed.

This is the first large-scale, real-world model for individualized survival prediction for advanced ESCC patients treated with ICIs, offering a practical tool for optimizing clinical decisions.

Thyroid dysfunction is a common immune-related adverse event (irAE) associated with immune checkpoint inhibitors (ICIs) that target PD-1, PD-L1, and CTLA-4. Nevertheless, the incidence of severe cases, defined as grade 3 or higher, remains rare. This report presents a detailed case study of severe thyroiditis in a patient with non-small cell lung cancer (NSCLC) who developed grade 3 thyroiditis following a single cycle of sintilimab monotherapy. The clinical presentation in this patient was remarkable for its early onset, occurring one week after the initiation of sintilimab therapy, and for its severe manifestations. During hospitalization, a prompt and accurate differential diagnosis was performed. Sintilimab treatment was discontinued, and the patient was promptly started on high-dose glucocorticoids, with a tapering schedule implemented as the condition improved or reached Common Terminology Criteria for Adverse Events (CTCAE) grade 1 or lower. The patient subsequently developed overt hypothyroidism, necessitating the initiation of thyroxine replacement therapy. Furthermore, we provide a comprehensive review of the mechanisms and risk factors associated with thyroid dysfunction immune-related adverse events (TD-irAEs). It is imperative for clinicians to meticulously monitor the clinical symptoms exhibited by patients. For those presenting with symptoms, prompt diagnosis and appropriate symptomatic management are essential. Additionally, regular thyroid function testing is recommended for high-risk patients, and we advocate for the assessment of baseline levels of thyroid peroxidase antibodies (TPOAb) and thyroglobulin antibodies (TGAb) prior to initiating ICI treatment.

The occurrence of multiple primary cancers has become common, and the treatment of such patients is very complex, so it is necessary to combine a variety of individualized treatment methods to achieve better treatment results.

This report describes a patient with double primary tumors of lung and esophageal cancer had more than 36 months survival with non-operation treatment. The patient diagnosed as lung adenocarcinomas (LADC) and esophageal squamous cell carcinoma (ESCC), was treated with albumin-bound paclitaxel, nedaplatin, and anti-programmed death 1 (anti-PD-1). The esophageal lesions achieved complete response (CR) after finishing two courses of induction chemotherapy combined with anti-PD-1 followed by definitive chemoradiotherapy (CRT). Radiation pneumonitis (RP) occurred one month after the completion of CRT. The pneumonia was relieved after dexamethasone and moxifloxacin treatment. Then, the lung lesion was treated with oral chemotherapy followed by stereotactic body radiation therapy (SBRT). As of July 2024, the patient has survived for more than 3 years after the above treatments, and the current efficacy evaluation is CR of esophageal lesions, PR of pulmonary lesions.

The multi-modality approach of systemic therapy combined with localized radiotherapy is an effective treatment in the patients of the double primary malignant tumors of LADC and ESCC. The safety and toxicity of radiotherapy for the thoracic double primary tumors demonstrate acceptability.

Esophageal cancer (EC) is associated with a high morbidity and mortality rate. Immunotherapy has demonstrated effective antitumor activity in patients with EC, making it imperative to investigate easily accessible prognostic factors. Consequently, we conducted a meta-analysis to explore the prognostic significance of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in EC patients treated with immunotherapy.

The literature search was conducted across three databases: PubMed, Embase, and Web of Science. The primary deadline for literature retrieval was July 2024. Hazard ratio (HR) with a 95% confidence interval (CI) was utilized to assess the association between NLR or PLR and overall survival (OS) as well as progression-free survival (PFS). Statistical analysis was performed using Review Manager version 5.4 and STATA version 15.0.

The meta-analysis included a total of 16 studies involving 1,481 patients. The results indicated a significant correlation between high pretreatment NLR and poor PFS (HR=1.76, 95%CI:1.38-2.25, p<0.001) as well as poor OS (HR=2.61,95%CI:1.86-3.67, p<0.001). Subgroup analyses based on tumor stage revealed that the association between elevated NLR and poor PFS was only observed in advanced EC patients. Regarding PLR, an increased PLR was found to be indicative of inferior PFS (HR=1.44, 95%CI: 1.20-1.72, p<0.001) and OS (HR=1.72,95%CI:1.08-2.74, p=0.020). However, the sensitivity analyses suggested that the observed increase in PLR lack robustness in terms of its impact on inferior OS.

Elevated NLR and PLR are associated with inferior PFS and OS in EC patients receiving immunotherapy. These findings suggest that NLR and PLR levels hold promise as prognostic biomarkers in clinical practice, offering valuable guidance for personalized immunotherapy strategies.

PROSPERO https://www.crd.york.ac.uk/prospero/, identifier CRD42024596737.

To evaluate the cost-effectiveness of first-line sintilimab plus chemotherapy versus chemotherapy for advanced esophageal squamous cell carcinoma (ESCC) from the perspective of the Chinese health service system.

A partitioned survival model was constructed to simulate quality-adjusted life years and incremental cost-effectiveness ratios over a patient's lifetime based on a phase III clinical trial.

Sintilimab plus chemotherapy increased by 0.316 QALY and 0.285 QALY with the additional cost of $5692 and $5269, which led to the ICER of $18000/QALY and $18519/QALY gained in the overall population and the patients with CPS ≥ 10, respectively.

Compared with chemotherapy alone, sintilimab may be a cost-effective first-line treatment choice for locally advanced or metastatic ESCC.