Treatment Of Advanced Esophageal Cancer Research Articles

Alarmin S100A8 imparts chemoresistance of esophageal cancer by reprogramming cancer-associated fibroblasts.

Chemotherapy remains the first-line treatment for advanced esophageal cancer. However, durable benefits are achieved by only a limited subset of individuals due to the elusive chemoresistance. Here, we utilize patient-derived xenografts (PDXs) from esophageal squamous-cell carcinoma to investigate chemoresistance mechanisms in preclinical settings. We observe that activated cancer-associated fibroblasts (CAFs) are enriched in the tumor microenvironment of PDXs resistant to chemotherapy. Mechanistically, we reveal that cancer-cell-derived S100A8 triggers the intracellular RhoA-ROCK-MLC2-MRTF-A pathway by binding to the CD147 receptor of CAFs, inducing CAF polarization and leading to chemoresistance. Therapeutically, we demonstrate that blocking the S100A8-CD147 pathway can improve chemotherapy efficiency. Prognostically, we found the S100A8 levels in peripheral blood can serve as an indicator of chemotherapy responsiveness. Collectively, our study offers a comprehensive understanding of the molecular mechanisms underlying chemoresistance in esophageal cancer and highlights the potential value of S100A8 in the clinical management of esophageal cancer.

A Phase II Study of Neoadjuvant Chemoradiotherapy with Docetaxel, Cisplatin and 5-FU Followed by Surgical Resection in the Treatment of Locally Advanced Esophagogastric Junction Cancer and Locally Advanced Esophageal Cancer.

We conducted a phase II study evaluating chemoradiotherapy in patients with advanced esophageal cancer, using the docetaxel, cisplatin, and 5-fluorouracil (DCF) regimen followed by surgery. The primary purposes of this clinical trial were to assess the efficacy and safety of chemoradiotherapy employing the DCF regimen in the treatment of advanced esophageal cancer. We enrolled a total of 24 newly diagnosed esophageal cancer patients between April 2015 and November 2017 in this prospective study. The radiotherapy regimen consisted of a total dose of 45 Gy in 25 fractions. The chemotherapy protocol included docetaxel 35 mg/m2 for 1 h on day 1 and day 29, cisplatin 35 mg/m2 for 1 h on day 1 and day 29, and 5-FU 400 mg/m2 for 24 h on day 1-4 and day 29-32. The patients who accepted the re-staging exam should undergo surgery in 4-8 weeks after the completion of radiotherapy. The primary endpoints of this study were disease-free survival (DFS), overall survival (OS), and the evaluation of hematologic toxicity. The study population had a median age of 55.5 years, ranging from 44 to 66, with over 90% of the patients being male. The 5-year DFS was 37.1%, and the 5-year OS was 48.7%. The pathologic complete response rate was 45.8% (11/24). The most common types of toxicity were leukopenia and thrombocytopenia. No grade 3 or greater hematologic toxicity was reported. The use of the DCF regimen in neoadjuvant chemoradiotherapy followed by surgery demonstrated tolerable toxicity and achieved acceptable DFS and OS outcomes.

Dose Evaluation in 2-Phase Method for Advanced Esophageal Cancer by Hybrid Irradiation Techniques

PurposeIn concurrent chemoradiotherapy for advanced esophageal cancer, a 2-phase method consisting of initial irradiation of a wide elective nodal region and boost irradiation of the primary lesion is commonly employed. Although dose escalation to the primary lesion may be required to achieve higher local control rates, the radiation dose to critical organs must not exceed dose constraints. To achieve an optimum balance of dose prescription and dose reduction to surrounding organs, such as the lungs and heart, we compared hybrid dose distributions and investigated the best combination of the following recent irradiation techniques: volumetric modulation arc therapy (VMAT), proton broad-beam irradiation, and intensity-modulated proton beam therapy (IMPT). Materials and MethodsForty-five patients with advanced esophageal cancer whose primary lesions were located in the middle- or lower-thoracic region were studied. Radiotherapy plans for the initial and boost irradiation in the 2-phase method were calculated using VMAT, proton broad-beam irradiation, and IMPT calculation codes, and the dose-volume histogram indices of the lungs and heart for the accumulated plans were compared. ResultsIn plans using boost proton irradiation with a prescribed dose of 60 Gy(RBE), all dose-volume histogram indices were significantly below the tolerance limits. Initial and boost irradiation with VMAT resulted in the median dose of V30 Gy(RBE)(heart) of 27.4% and an achievement rate below the tolerance limit of 57.8% (26 cases). In simulations of dose escalation up to 70 Gy(RBE), initial and boost IMPT resulted in the highest achievement rate, satisfying all dose constraints in 95.6% (43 cases). ConclusionApplying VMAT to both initial and boost irradiation is not recommended because of the increased risk of the cardiac dose exceeding the tolerance limit. IMPT may allow dose escalation of up to 70 Gy(RBE) without radiation risks to the lungs and heart in the treatment of advanced esophageal cancer.

Clinicopathological, metastatic and prognostic features of stage IV esophageal adenocarcinoma versus squamous cell carcinoma: a SEER database analysis.

It is important to note that although the current treatment for advanced esophageal cancer (EC) has made great technological advances, patients' 5-year survival rates do not appear to be encouraging. Therefore, understanding the clinicopathological features and metastasis patterns of the patients with stage IV EC, combined with the prognosis of these patients, can aid in choosing the optimal treatment plan. It is well known that esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are the two most common pathological types. The aim of this study is to examine and compare the clinicopathological features and metastatic modes of stage IV ESCC and EAC, as well as their prognosis and survival. Based on the Surveillance, Epidemiology, and End Results (SEER) database, we assessed the characteristics of ESCCs and EACs associated with prognosis using the Kaplan-Meier survival analysis, and the Cox regression model. Furthermore, the clinical data of 217 patients with stage IV ESCC and EAC in the Department of Gastroenterology of the Second Affiliated Hospital of Nantong University between 2014 and 2016 were reviewed. A total of 3,707 cases treated between 2010 and 2016 were included. The incidence of EAC in the United States is much higher than that of ESCC. Common metastasis patterns were lungs only, liver only, bones only, and lung & liver. The multivariate Cox analysis showed that treatment mode and metastasis patterns were independent risk factors affecting the overall survival (OS) time of patients (stage IV ESCC & EAC). EAC patients with only lung metastases may have a longer survival if chose treatment options that included surgery. In the external cohort, a total of 217 cases were included. The prevalence of ESCC is much higher than that of EAC, and the common metastasis patterns are liver only, lung only, and liver & lung. The multivariate Cox analysis showed that treatment mode was independent risk factor affecting the OS time of patients (stage IV ESCC & EAC). EAC patients treated with surgery combined with chemoradiotherapy may have a better prognosis. In general, the prognosis of patients with stage IV ESCC and EAC are poor. However, surgery was found to significantly improve the OS time of patients with stage IV EAC in this study.

Novel Advances in Qualitative Diagnostic Imaging for Decision Making in Multidisciplinary Treatment for Advanced Esophageal Cancer.

Background: Recently, neoadjuvant therapy and the succeeding surgery for advanced esophageal cancer have been evaluated. In particular, the response to the therapy has been found to affect surgical outcomes, and thus a precise evaluation of treatment effect is important for this strategy. In this study, articles on qualitative diagnostic modalities to evaluate tumor activities were reviewed, and the diagnostic indices were examined. Methods: For prediction of the effect, perfusion CT and diffusion MRI were estimated. For the histological response evaluation, perfusion CT, diffusion-MRI, and FDG-PET were estimated. For downstaging evaluation of T4, tissue-selective image reconstruction using enhanced CT was estimated and diagnostic indices were reviewed. Results: The prediction of the effect using perfusion CT with 'pre CRT blood flow' and diffusion MRI with 'pre CRT ADC value'; the estimation of the histological response using perfusion CT with 'post CRT blood flow reduction, using diffusion MRI with 'post CRT ADC increasing', and using FDG-PET with 'post CRT SUV reduction'; and the downstaging evaluation of T4 using CT image reconstruction with 'fibrous changed layer' were performed well, respectively. Conclusions: Qualitative imaging modalities for prediction or response evaluation of neoadjuvant therapy for progressive esophageal cancer were useful for the decision making of the treatment strategy of the multidisciplinary treatment.

Transarterial infusion chemotherapy for advanced esophageal cancer with airway stenosis.

This study aimed to investigate the safety and efficacy of transarterial infusion chemotherapy for the treatment of esophageal cancer with airway stenosis. Data of patients with advanced esophageal cancer complicated with airway stenosis treated with transarterial infusion chemotherapy were retrospectively analyzed. Dyspnea, clinical efficacy and adverse reactions were evaluated. Of these patients, 27 had grade II preoperative dyspnea, and 31 had grade III preoperative dyspnea, 26 had grade I postoperative dyspnea, 25 had grade II postoperative dyspnea, and 7 had grade III postoperative dyspnea. Among 3 patients with left main bronchial stenosis and atelectasis, 2 had complete remission after transarterial infusion chemotherapy, and 1 demonstrated partial remission. After treatment, complete response, partial response, and stable disease were observed in 7, 34, and 17 cases, respectively. Total objective effective rate and disease control rate were 70.6% (41/58) and 100.0%, respectively. During follow up, 24 patients died of organ failure, and 17 patients died of tumor-related respiratory failure. Seven patients died of gastrointestinal bleeding, 1 patient died of myocardial infarction, and 9 patients survived. Transarterial infusion chemotherapy is safe and effective for the treatment of advanced esophageal cancer with airway stenosis.

Precise patient stratification in esophageal cancer: Biomarkers for immunochemotherapy.

Studies have established immunochemotherapy as the first-line treatment for advanced esophageal cancer. Chen etal. and Carrol etal. performed exploratory analysis of the JUPITER-06 and LUD2015-005 trials, respectively and identified biomarkers to predict therapy response based on immunogenomic analysis. These findings may optimize precise patient stratification in advanced esophageal cancer.

Expression molecular subtype as a predictor of outcomes of chemoradiotherapy for esophageal cancer.

4030 Background: The standard treatment for advanced esophageal cancer is preoperative chemoradiotherapy (CRT) followed by surgery or definitive CRT (NCCN Guideline 2022 ver5). CRT has the advantage of preserving organs and functions and the prognosis for patients achieved complete response by CRT is good. However, it is currently impossible to predict the outcomes of CRT before treatment. We have performed RNA expression analysis of pre-treatment biopsy specimens of esophageal cancer and identified several intrinsic molecular subtypes, as well as E-type (high expression of squamous markers) with good prognosis for CRT and M2-type (high expression of stromal markers) with poor prognosis for CRT (US patent No 10,969,390 B2). Herein, we performed an integrated analysis to confirm the relationship between intrinsic expression molecular subtype classification and prognosis in the pooled population from two prospective cohort studies (UMIN000043637). Methods: Two cohort studies were as follows; 1) single institute prospective cohort study conducted at National Cancer Center Hospital East (n=157, UMIN-C000000459), 2) multicenter prospective cohort study conducted at 10 institutions (n=226, UMIN000016141). A total 383 cases met inclusion criteria and the Affymetrix U331Plus 2 panel (47,104 transcripts, 38,572 genes) was used to identify E-type and M2-type. The clinical course and outcome were blinded for subtype classification. Treatment was performed as usual at each institution, and treatment details and outcomes were examined by subtype. Results: Among 383 patients, 181 and 164 patients were treated by CRT and surgery, respectively. Ninety-nine percent (n=342) were squamous cell carcinoma. Stage I/II/III/IV were 13/61/86/21 and 17/63/81/3 in CRT group and surgery group, respectively. Among them, 76 (22%), 100 (29%), 169 (49%) patients were classified as E, M2 and others, respectively. Among the patients treated by CRT, CR rate of E-type and M2-type were 62.8% (95% CI, 47.8-75.7) and 33.3% (95% CI, 21.9-47.1) (p=0.006). The 5-year progression free survival (PFS) and overall survival (OS) rates of CRT group was 50.5% (95% CI, 34.7-64.4) and 59.8% (95% CI, 42.6-73.3) for E-type vs. 23.0% (95% CI, 12.0-36.2) and 29.0% (95%CI, 16.8-42.4) for M2-type, with statistically significant difference (p=0.011, p=0.003). Cox regression analysis showed that crude HR for PFS and OS of E vs M2 were 0.50 (95% CI, 0.296-0.859, p=0.012) and 0.41 (95% CI, 0.226-0750, p=0.004), respectively. In contrast, E and M2-type did not show the survival difference in surgery group. Conclusions: For the first time in the world, we confirmed that expression molecular subtype of esophageal cancer has the potential to predict the outcomes of CRT. The results may provide precision medicine in the selection of treatment for esophageal cancer.

Immunotherapy with or without radiotherapy in late-line treatment for metastatic esophageal cancer: A real-world study.

e16054 Background: Single-agent immunotherapy is the standard second-line treatment of advanced esophageal cancer, however, the efficiency of single-agent immunotherapy is low, about 10-30%. Synergistic effects of radiation and immunotherapy have been demonstrated. This study evaluated the efficacy and safety of late-line immunotherapy combined with radiotherapy in patients with advanced esophageal cancer. Methods: We conducted a retrospective analysis of 85 patients treated at West China Hospital of Sichuan University between 2019 and 2022, all of whom had stage IV esophageal cancer and were treated with immunotherapy as a late-line therapy. We used Kaplan-Meier analysis to calculate progression-free survival (PFS), overall survival (OS). Results: After analysis, there were no differences in the baseline clinical characteristics such as age, gender, ECOG score, tumor location, and TNM stage. However, the proportion of received chemotherapy or targeted therapy may be greater in the non-radiotherapy group.38 were in the radiotherapy (RT) group and received radiotherapy to 41 lesion sites, and 47 were in the non-radiotherapy(non-RT) group. The most frequent radiotherapy organ sites were lymph nodes (14/41), esophagus (11/41), lung (9/41), bone (5/41), and brain (2/41) (three patients had irradiated metastases in two locations). The most common type of RT is conventional radiation therapy (31/41), including 12 radiotherapy courses of radical dose (50-60Gy, 28-30 fractions) and 18 radiotherapy courses of palliative dose (9-45Gy, 3-23 fractions). Then stereotactic body radiotherapy (10/41), (24-45Gy, 3-5 fractions). K-M analysis showed a median PFS in the RT group (16.7 months [95% CI 11.70-21.71 months]) vs. (6.97 months [95% CI 3.81-10.12 months], P = 0.014) in the non-RT group. And the median OS for the RT group was 24.4 months [95% CI 16.28-32.52 months] compared with 17.47 months [95% CI 15.11-19.83 months] (P = 0.039) for the non-RT group. The ORR of the RT group was 29.7% [95% CI, 14.3–45.2%] and 8.3% [95% CI, 2–16.4%] in the non-RT group(p=0.01). Univariate and multivariate analyses show that RT was an independent prognostic factor for OS. Overall, 33.3% and 32.5% of patients in the RT and non-RT groups, respectively, experienced at least one grade 3-4 treatment-related adverse event, with the most common treatment-related adverse reaction being myelosuppression, no differences in adverse effects between groups. Conclusions: In this study, late-line immunotherapy combined with radiotherapy for advanced esophageal cancer can improve the objective response rate and survival with manageable side effects. Although the limitations of retrospective studies should be taken into account, the findings still suggest that patients benefit from immunotherapy combined with radiotherapy, and more data are needed to assess the impact of radiation therapy on these patients.

A phase II study of paclitaxel and carboplatin plus PD-1 inhibitors combined with anlotinib as first-line treatment for advanced esophageal cancer.

395 Background: The combination of anti-PD-1 mAb with chemotherapy is one of the standard first-line therapies for advanced esophageal cancer. Recent studies have shown that anti-PD-1 mAb combined with chemotherapy or targeted treatment can improve the efficacy of immunotherapy. The purpose of this study was to evaluate the efficacy and safety of paclitaxel and carboplatin (TC) combined with anlotinib, an anti-angiogenic TKI, and anti-PD-1 mAb, in the treatment of advanced esophageal cancer. Methods: This study was a parallel, single-center, open-label, phase II trial. A total of 90 patients (pts) with previously untreated, advanced or metastatic ESCC, with an age ranging from 18-75 years old, and an ECOG performance status ≤ 1 were planned to be enrolled into three arms with an allocation ratio of 1:1:1. Arm A received paclitaxel (175 mg/m2, IV, d1, q3w) /nab-paclitaxel (260mg/m2, IV, d1, q3w) + carboplatin (AUC 4-6, IV, d2, q3w) + anti-PD-1 mAb + anlotinib (8mg, PO, d1-14, q3w); Arm B received TC with anti-PD-1 mAb; Arm C received TC only. After 4-6 cycles of induction therapy, arm A and arm B would receive anti-PD-1 mAb plus anlotinib or anti-PD-1 mAb as maintenance therapy until disease progression or intolerable adverse events, respectively. The primary endpoint was ORR. Secondary endpoints included PFS, OS and safety. Results: At data cut-off date (Sep. 20, 2022), a total of 90 pts were enrolled and 88 pts were available for efficacy assessment. 25 of 28 pts achieved partial response (PR) in arm A, 13 of 30 pts PR in arm B, and 7 of 30 pts PR in arm C. The ORR (95% CI) were 89.3% (71.8-97.7) in arm A, 43.3% (25.5-62.6) in arm B, and 23.3% (9.9-42.3) in arm C. The DCR (95% CI) were 100% (87.7-100.0) in arm A, 96.7% (82.8-99.9) in arm B, and 83.3% (65.3-94.4) in arm C. The median PFS was not reached. The rate of treatment related adverse events (TRAEs) of any grade was 100% in all three groups, and grade 3 TRAEs were 23.3%, 16.7% and 13.3%, respectively. The most common grade 3 TRAEs were thrombocytopenia (6.7%), leukopenia (5.6%), neutropenia (5.6%). No grade 4 or 5 TRAEs occurred. Conclusions: The addition of anlotinib to immunotherapy plus chemotherapy as first-line therapy for ESCC demonstrated a high ORR (89.3%), and a manageable safety profile. Clinical trial information: NCT04471480 .

Cost-Effectiveness Analysis of Sintilimab Combined with Chemotherapy Versus Chemotherapy Alone as the First-Line Treatment for Advanced Esophageal Cancer.

Background: Esophageal cancer has a poor prognosis and currently ranks sixth in global cancer mortality rates. The ORIENT-15 trial showed sintilimab plus chemotherapy significantly improved survival when compared to chemotherapy alone. This study aimed to evaluate the cost-effectiveness of sintilimab, a programmed death-ligand 1 (PD-L1) inhibitor, plus chemotherapy in treating patients with esophageal cancer compared with chemotherapy alone. Methods: A Markov model with a 10-year horizon was developed based on the perspective of the Chinese healthcare payers. We conducted a cost-effectiveness analysis for sintilimab combined with chemotherapy based on a questionnaire. Patients were grouped into the sintilimab group based on a positive score of 10 or more (combined positive score (CPS) 10 groups), and those with any other PD-L1 expression were randomized into patient groups. We estimated the cost and the effectiveness of sintilimab on the quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) was computed. One-way and probabilistic sensitivity analyses were conducted to explore the impact of uncertainties on the cost-effectiveness results. Results: In the base-case analysis, compared with chemotherapy alone, the ICER of sintilimab plus chemotherapy for all patients was $21024.05 per QALY, and in the CPS≥10 group, it was $20974.23 per QALY. This was lower than $37653 per QALY. One-way sensitivity analysis demonstrated that ICERs were most sensitive to the price of sintilimab. Conclusion: The study demonstrated that sintilimab plus chemotherapy for advanced esophageal cancer as its first-line treatment would be more cost-effective than chemotherapy alone in Chinese patients.

Cost-effectiveness analysis of pembrolizumab plus chemotherapy versus chemotherapy as the first-line treatment for advanced esophageal cancer.

The KEYNOTE-590 trial showed that individuals with advanced esophageal cancer who received Pembrolizumab in combination with chemotherapy as a first-line regimen achieved a significant extension of survival. However, this treatment option increases the financial burden on patients and the economic benefits remain to be further evaluated. A Markov model was used to simulate 10-year survival of patients with esophageal cancer from the perspective of United States (US) Medicare payers. We evaluated the economics of Pembrolizumab plus chemotherapy in the PD-L1 positive score (CPS ≥10) and any PD-L1 expression groups, respectively. We estimated total costs, quality-adjusted life years (QALYs), and calculated incremental cost effectiveness ratios (ICERs). Sensitivity analyses were conducted to explore the impact of uncertainties on the results. Subgroup analysis was also performed. The analysis results showed that the ICER for pembrolizumab plus chemotherapy versus chemotherapy alone was $293,513.17/QALYs in the any PD-L1 expression group. This exceeded the threshold of willingness to pay ($150,000/QALYs). ICERs were most sensitive to the cost of pembrolizumab and the ICERs exceeded $150,000/QALYs in all subgroups. Evidence suggests that first-line pembrolizumab in combination with chemotherapy is not a cost-effective option for advanced esophageal cancer in the US, regardless of PD-L1 expression status.

Pembrolizumab: first anti-PD-1/L1-based regimen for first-line treatment of advanced esophageal cancer in Japan

ABSTRACT Introduction Esophageal cancer (EC) is the ninth most common cancer in Japanese men. Esophageal squamous cell carcinoma (ESCC) is the major histological type and accounts for 90% of EC cases in Japan. The prognosis of advanced ESCC remains poor. The standard treatment for advanced ESCC was palliative chemotherapy with 5-fluorouracil plus cisplatin as first-line chemotherapy. After failure of first-line chemotherapy, taxanes were used as second-line chemotherapy. Recently, pembrolizumab monotherapy has demonstrated benefits as a second-line treatment in patients with advanced ESCC and a combined positive score of ≥10. Survival was found to be improved in patients with advanced EC who received first-line treatment with pembrolizumab plus doublet chemotherapy than in those who received doublet chemotherapy alone. Areas covered This overview of immune checkpoint inhibitors focuses on pembrolizumab in combination with chemotherapy and shares key clinical data relevant to the treatment of patients with EC in Japan. Expert opinion Pembrolizumab plus doublet chemotherapy is now an established first-line treatment for advanced EC in Japan. Recently, nivolumab plus doublet chemotherapy and nivolumab plus ipilimumab have also become first-line treatment options for patients with advanced ESCC. Further investigations are needed to identify biomarkers that would be useful for selecting candidates for these treatments.

Cost Effectiveness of Adding Pembrolizumab to Platinum and Fluoropyrimidine-Based Chemotherapy as First-Line Treatment for Advanced Esophageal Cancer: A US Healthcare Payer's Perspective.

Pembrolizumab plus cisplatin and fluorouracil demonstrated superior efficacy and comparable safety compared with fluorouracil and cisplatin (FP) as first-line treatment for locally advanced unresectable or metastatic carcinoma of the esophagus and gastroesophageal junction adenocarcinoma in a phase III trial (KEYNOTE-590). This study evaluated the cost effectiveness of pembrolizumab plus FP versus FP and versus a blended chemotherapy comparator including FP, carboplatin plus paclitaxel, FOLFOX, FOLFIRI, docetaxel plus FP, trastuzumab plus FP, and trastuzumab plus FOLFOX from a US healthcare payer's perspective. A partitioned survival model was developed with three health states (progression-free, progressive disease, and death). Overall survival, progression-free survival, time on treatment, and adverse events were informed by patient-level data from KEYNOTE-590. The blended chemotherapy comparator reflected the current US treatment landscape and was assumed to have similar efficacy and safety as FP. Health utilities were estimated using linear mixed-effects models based on EQ-5D-5L data from the trial. Resource use and cost inputs (2020 US dollars) were based on US standard sources and literature. Costs, life-years, and quality-adjusted life-years (QALYs) discounted at 3.0% per year and incremental cost-effectiveness ratio were outcomes in the model. Sensitivity and scenario analyses were conducted to assess the robustness of base-case results. Compared with FP, pembrolizumab plus FP produced a mean gain of 0.86 life-year and 0.77 QALY with additional costs of $112,630 over 37.6 years, yielding an incremental cost-effectiveness ratio of $147,097 per QALY. Results were similar when the intervention was pembrolizumab plus alternative chemotherapies or when blended chemotherapy became the comparator. Results were most sensitive to different overall survival extrapolation approaches. Our analysis suggests that pembrolizumab plus chemotherapy extended life-years and QALYs and is cost effective compared with chemotherapy alone as a first-line treatment for advanced esophageal cancer in the USA given a willingness-to-pay threshold of $150,000 per QALY.

461. SURGICAL TREATMENT OF STAGE IV ESOPHAGEAL CANCER AFTER CCRT IMPROVES SURVIVAL

Abstract Treatment of stage IV esophageal cancer is traditionally palliative, but treatment response is usually poor. The role of surgery in the treatment of advanced esophageal cancer remains controversial. We sought to determine whether surgical treatment followed by neoadjuvant chemoradiation therapy might provide survival benefits for these patients. A retrospective review of 163 esophageal cancer patients with M1 disease (distant organ metastasis) treated at a tertiary medical center hospital was performed from April 2002 to June 2021. Patient demographics and cancer staging, treatment, and disease recurrence, and time of follow up were included for analysis. Univariate and multivariate analysis was performed for overall survival and progression-free survival analysis. Propensity score matching based on patient age and tumor staging characteristics was also performed for analysis. 124 patients were treated by CCRT alone and 39 treated by CCRT plus surgery. 3-year and 5-year progression free survival was 17.7% and 8.9% for CCRT+surgery group vs 0.8% and 0.0% in CCRT only group. (p = 0.019) 3- and 5-year survival was 24.0% and 12.0% in CCRT plus surgery group compared to 2.8% and 1.4% for CCRT only group (p = 0.009). Propensity matching of 39 CCRT plus surgery patients and 78 CCRT-only patients showed similar results (17.5% & 8.5% PFS vs 1.3% & 0.0% for PFS, 24.0% and 12.0% vs 3.9% and 1.9% OS). Surgical resection following CCRT treatment may improve progression-free survival and overall survival for selected patients of esophageal cancer with M1 disease. Surgical indication should be judicious, and further follow up studies should be performed.

GPX2 stabilized by PCBP2 induces autophagy to protect Het-1A esophageal cells from apoptosis and inflammation

The implantation of esophageal stent loaded with iodine-125 (125I) is one of the critical approaches for the treatment of advanced esophageal cancer, but one common complication after stent implantation is benign hyperplasia associated restenosis. The aim of the current study is to understand the role of glutathione peroxidase 2 (GPX2), a key member of the GPX family of antioxidant enzymes. Initially, we detected the increased levels of GPX2 and GPX1 in esophageal benign hyperplasia tissues. Further, we evaluated the effects of GPX2 in response to H2O2 induced apoptosis and LPS induced inflammation. We observed that GPX2 expression was also significantly increased in Het-1A. Silencing of GPX2 significantly increased H2O2-induced apoptosis and LPS-induced inflammation, but GPX2 overexpression did the opposite, suggesting a protective effect by GPX2. In addition, we identified that the protective effect of GPX2 is through the activation of autophagy, and PCBP2, a poly (rC) binding protein, binds to and stabilizes GPX2 mRNA. These findings reveal a role of GPX2 in esophageal hyperplasia, allowing for a better understanding of the underlying molecular mechanism, which could lead to identification of potential treatment for clinical benign restenosis following stent implantation with 125I.

Addition of anti-PD1 antibodies to chemotherapy (CT) in first-line treatment of advanced esophageal cancer (EC): A systematic review and meta-analysis.

e16055 Background: The addition of anti-PD-1 antibodies to first-line CT is the new standard of care for pts with advanced EC. However, available data on the efficacy of such therapy in different clinical subgroups is still lacking. Therefore, we performed a meta-analysis to determine the efficacy of combination anti-PD1 and systemic CT in terms of overall survival (OS) in pts with advanced EC. Methods: We searched PubMed, proceedings of ASCO, and ESMO conferences up to February 2022. We included prospective randomized phase III trials comparing the combination of anti-PD1 and CT with CT alone as the first-line treatment option for pts with advanced EC. The primary outcome was OS. Meta-analysis was conducted by Review Manager (Ver. 5.3) software. Results: Five trials with a total of 3163 pts were included, of which 1576 received anti-PD1+CT and 1587 received CT alone. There was a significant improvement in PFS (HR, 0.62; 95% CI, 0.56-0.67; p < 0.00001; I2 = 45%, p for heterogeneity 0.12), OS (HR, 0.69; 95% CI, 0.63-0.76; p < 0.00001; I2 = 0%) and ORR (OR, 2.07; 95% CI, 1.76-2.43; p < 0.00001; I2 = 21%) in pts received anti-PD1+CT. OS was improved in pts regardless of age, race, CT regimen, presence of liver metastases, ECOG PS, or histology. Subgroup analysis suggested that the addition of anti-PD1 have a better effect in pts with PDL expression on tumor cells > 1, ≥ 10, and < 10 and in pts with CPS ≥ 10, but not in pts with PDL < 1. We found a tendency towards survival advantage in pts with CPS < 10. No survival benefit was observed in women (tab). Conclusions: Improved OS was found to be associated with addition of anti-PD1 antibodies to systemic CT in different patient subgroups with advanced EC, except for female and in pts with low PDL expression. Despite of meta-analysis results we need prospective randomized trial for pts with CPS < 10.[Table: see text]

PD-1 Inhibitor Plus Chemotherapy Versus Chemotherapy as First-line Treatment for Advanced Esophageal Cancer: A Systematic Review and Meta-Analysis.

Immunotherapy combined with chemotherapy has recently changed the first-line treatment of several cancers. We performed a systematic review and meta-analysis to assess the efficacy and safety of programmed cell death 1 (PD-1) inhibitor plus chemotherapy as a first-line treatment for advanced esophageal cancer. Data were collected from eligible studies searched from PubMed, Web of Science, Cochrane Library, Embase, and meeting abstracts. The pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and the pooled odds ratios (ORs) for objective response rate and treatment-related adverse events (TRAEs) were estimated to assess the efficacy and safety of PD-1 inhibitor plus chemotherapy versus chemotherapy. We performed several subgroup analyses to explore the variables affecting immunotherapy efficacy in esophageal cancer. The 5-point Jadad scoring system, the bias risk assessment and sensitivity analyses were used to evaluate the quality of the meta-analysis. Compared with the chemotherapy group, the OS (HR=0.70; P<0.01) and PFS (HR=0.62; P<0.01) were significantly longer and the objective response rate (OR=2.07; P<0.01) was significantly higher in the PD-1 inhibitor plus chemotherapy group. An OS benefit was observed in patients regardless of histology or programmed cell death 1 ligand 1 combined positive score. OS and PFS were generally consistent across subgroups by clinical features. In safety analyses, PD-1 inhibitor plus chemotherapy had a significantly higher incidence of TRAEs (OR=1.85; P<0.01), but there was no significant difference in grade 3 or higher TRAEs (OR=1.24; P=0.05). Compared with chemotherapy, PD-1 inhibitor plus chemotherapy improves antitumor activity and controllable adverse events in the first-line treatment of advanced esophageal cancer.

Pembrolizumab for the treatment of advanced esophageal cancer.

The prognosis of patients with advanced esophageal cancer (EC) remains poor and there are limited effective therapeutic agents for EC. Pembrolizumab monotherapy exerts clinically meaningful benefits for advanced esophageal squamous cell carcinoma patients with a combined positive score of ≥10. Additionally, pembrolizumab plus doublet chemotherapy results in a significant survival benefit for patients with advanced EC as first-line treatment compared with chemotherapy alone. We provide an overview of immune checkpoint inhibitors and present important clinical data related to treatment for EC patients. In our opinion, pembrolizumab plus chemotherapy should be the standard first-line treatment for patients with advanced EC, regardless of histology and combined positive score. Biomarker studies to identify patient populations in which immune checkpoint inhibitors are expected to show efficacy are needed.

Pembrolizumab Plus Chemotherapy as First-Line Treatment for Advanced Esophageal Cancer: A Cost-Effectiveness Analysis.

In 2021, KEYNOTE-590 (NCT03189719) showed that pembrolizumab plus 5-fluorouracil and cisplatin (PPF) has more benefits than 5-fluorouracil and cisplatin (PF) as a first-line regimen to treat individuals with advanced esophageal cancer. However, given that it is expensive, controversies over the value of using this compared to competitive strategies remain. Hence, we conducted a cost-effectiveness evaluation of pembrolizumab plus chemotherapy. A Markov model was applied in evaluating the efficacy and cost of PPF and PF over a 7-year horizon and measured the health outcomes in life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). The economic data included were relevant to patients in the USA and China. We also performed one-way and probabilistic sensitivity analyses to determine the uncertainties relevant to the model. Willingness to pay thresholds (WTP) of $150,000/QALY (USA) and $35,673/QALY (China) were used to calculate a probability for the cost-effectiveness of PPF. PPF yielded 0.386-0.607QALYs (0.781-1.195LYs) compared with PF. In our analysis, compared with receiving PF, patients with advanced esophageal cancer receiving PPF had an ICER of $577,461/QALY in the USA and $258,261/QALY in China, those for esophageal squamous cell carcinoma were $550,211/QALY in the USA and $244,580/QALY in China, and a programmed cell death ligand1 combined positive score (PD-L1 CPS) ≥ 10 was associated with a cost of $479,119/QALY in the USA and $201,355/QALY in China. Sensitivity analysis found the price of pembrolizumab to be the biggest influence. From the economic perspectives of the USA and China, a first-line regimen of PPF for esophageal cancer therapy may not be as cost-effective as PF. However, patients with esophageal cancer and PD-L1 CPS ≥ 10 may gain the most LYs from initial PPF treatment.