Treatment Of Advanced Esophageal Cancer Research Articles

575. PATHOLOGIC RESPONSE AND RESIDUAL LYMPH NODE PATTERNS IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA PATIENTS UNDERGOING NEOADJUVANT IMMUNOCHEMOTHERAPY COMPARED TO NEOADJUVANT CHEMORADIOTHERAPY

Abstract Background Concurrent chemoradiotherapy is the cornerstone treatment for locally advanced esophageal cancer. Immunochemotherapy, established as the standard treatment for advanced esophageal cancer, concurrently exhibits excellent short-term efficacy in the neoadjuvant stage. Combining concurrent chemoradiotherapy with immunochemotherapy may enhance control over primary tumor and metastatic lymph nodes, potentially improving patients’ outcomes and survival. Therefore, comparing the pros and cons of these two treatment modalities in controlling primary lesions and lymph node metastasis is crucial for guiding clinical treatment. Methods Our study enrolled a total of 137 patients with esophageal squamous cell carcinoma (ESCC) who underwent neoadjuvant immunochemotherapy (NICT) and 151 ESCC patients who underwent neoadjuvant chemoradiotherapy (NCRT) between January 2019 and March 2022. We documented baseline patient characteristics, including clinical TNM stage, tumor location, and clinical metastatic lymph nodes, as well as pathologic outcomes such as pathological stage, pathologic complete response (pCR), tumor regression grade (TRG), and pathological metastatic lymph nodes. To balance baseline patient characteristics, we employed inverse probability of treatment weighting (IPTW) to adjust for confounding in different neoadjuvant treatment groups. Results After balancing baseline characteristics, there was no statistically significant difference in pathologic outcomes, including pCR rate, major pathologic response rate, TRG, yp-TNM stage, and R0 resection rate between NCRT and NICT. However, patients with clinical N2-3 stage (OR 2.66; 95% CI 1.05 to 6.79) or lower thoracic esophageal tumors (OR 2.31; 95% CI 1.05 to 5.04) had a higher chance of achieving pCR after NICT compared to NCRT. For patients undergoing NICT, the ypN0 rates for clinically N0 patients were 100.0% (5/5), while only 65.0% (13/20) of clinical N0 patients achieved ypN0 in the NCRT group. Even after adjusting for differences in clinical stage, tumor location, and baseline lymph node metastasis rates in various locations, the NICT group still demonstrated a lower rate of abdominal lymph node metastasis during surgery (p=0.030). Conclusion In comparison to concurrent chemoradiotherapy, immunochemotherapy exhibits comparable overall disease control for primary lesions and lymph node metastasis. Notably, patients with clinical N2-3 and lower thoracic esophageal cancer may derive greater benefits from NICT. The potential of immunochemotherapy in enhancing the effectiveness of chemoradiotherapy is evident in its ability to improve the control of occult metastatic lymph nodes and reduce abdominal lymph node metastasis.

571. A PHASE I/II MULTICENTER STUDY EVALUATING THE EFFICACY AND SAFETY OF INDUCTION IMMUNOCHEMOTHERAPY FOLLOWED BY CONCURRENT IMMUNO-CHEMORADIOTHERAPY IN UNRESECTABLE LA-ESCC

Abstract Background Despite advances in radiotherapy techniques, the prognosis for patients undergoing definite chemoradiotherapy remains suboptimal. There exists an urgent and unmet need to enhance the efficacy of concurrent chemoradiotherapy for patients with unresectable Locally Advanced Esophageal Squamous Cell Carcinoma (LA-ESCC). Immunotherapy, when combined with chemotherapy, has emerged as the established first-line treatment for advanced esophageal cancer. Significant tumor shrinkage and reduced tumor residual observed after induction immunotherapy might provide the potential to enhance locoregional control of radiotherapy as well as better protection of critical organs and circulating lymphocytes. Methods We conducted a multicenter, phase I/II study aiming to assess the efficacy and safety of induction immunochemotherapy followed by immuno-chemoradiotherapy (ICRT) for unresectable LA-ESCC (SCR-ESCC-002, NCT06173986) (Figure 1). Eligible patients will initiate treatment with 2-3 cycles of immunochemotherapy. Within 4 weeks after completing the induction treatment, patients without disease progression will proceed to receive concurrent radiotherapy (45-50Gy in 25 fractions), weekly chemotherapy, and PD-1 inhibitor on day1,22. Following immuno-chemoradiotherapy, patients will continue with immunotherapy maintenance until disease progression or unacceptable toxicity, for a maximum duration of one year. The study's dual primary endpoints are progression-free survival and treatment completion rate. Results As of January 2024, 13 eligible patients were enrolled in our trial, with median follow-up of 7.8 months. Due to tumor shrinkage of induction immunochemotherapy, radiation doses to normal tissues were significantly reduced, particularly for the lungs, heart, and vertebrae. All 13 patients completed the planned induction treatment and radiotherapy, with 8 completing more than 4 weekly chemotherapies. During ICRT, 10 of 13 patients experienced grade 3-4 adverse events. These included lymphopenia (69.23%), myelosuppression (46.15%), hepatitis (7.69%), esophagitis (7.69%), and pneumonitis (7.69%). Nine patients achieved a complete response, and 3 partial response 4 weeks after ICRT according to RECIST v1.1. Conclusion Decreased radiation volumes due to tumor regression brought by induction immunochemotherapy diminish the occurrence of non-hematological adverse events during ICRT. Preliminary analysis suggests that this therapeutic modality exhibits favorable safety profiles and yields a superior clinical complete response rate compared to definitive chemoradiotherapy alone. The trial is presently enrolling participants, and the confirmation of efficacy and survival outcomes necessitates larger sample sizes and extended follow-up durations.

Safety and efficacy of radiotherapy in combination with immunochemotherapy for advanced esophageal cancer: A retrospective analysis.

e16032 Background: Combining immune checkpoint inhibitors with chemotherapy has emerged as the standard treatment for advanced esophageal cancer. Radiotherapy could alleviate symptoms related to dysphagia. Additionally, it holds the potential to enhance the efficacy of immunotherapy, albeit with an associated risk of increased immunotoxicity. The combination of radiotherapy and immunochemotherapy for advanced esophageal cancer necessitates further investigation into its safety and efficacy. Methods: The medical records of consecutively treated patients with advanced esophageal cancer who underwent immunochemotherapy were retrospectively reviewed. The primary inclusion criteria were as follows: 1. Newly treated, imaging-confirmed stage IV esophageal carcinoma; 2. Radiotherapy administered within 6 cycles of immunochemotherapy; 3. Irradiation dose ≥ 30 Gy; 4. Target area must encompass esophageal neoplasms. The primary endpoints were overall survival (OS) and safety (RECIST 1.1). OS was defined as the time from initial treatment to the date of death. The secondary endpoint was progression-free survival (PFS), defined as the time from initial treatment to cancer progression or death. Median overall survival (mOS) time and median progression-free survival (mPFS) time were used to evaluate efficacy, while the incidence of adverse events (AEs) (CTCAE 5.0) was used to evaluate safety and feasibility. Kaplan-Meier survival analysis was conducted using SPSS25 software. Results: 122 patients were screened and 40 patients were finally included. The median age was 69. A total of 30 male patients were included. Three cases were stage IVa and 37 cases were stage IVb. Distant metastatic sites in these patients were lung (50%), liver (30%), bone (17.5%) and others. All cases were treated with immunochemotherapy as first-line treatment with median 4 cycles. Immunochemotherapy regimens are based on platinum and all treated with programmed death-1 inhibitors. Twenty-three cases were concurrent radiotherapy in combined with chemoimmunotherapy and 17 cases were sequential. For radiation therapy, the median dose was 50Gy in 25 fractions. The incidence of grade 3 and above AEs was shown in 20(50%) cases. Four (10%) patients showed treatment-related grade 5 toxicity (immune pneumonia, myocarditis, hepatitis and myocarditis complicated with hepatitis) which all occurred within 1-4 months after radiotherapy. With a median follow-up of 22.0 months, 26 (65%) cases experienced tumor progression (loco-regional progression only in 3, systemic progression only in 18, and both loco-regional and systemic progression in 5 patients), while 27 patients (67.5%) died. mOS and mPFS were 18.0 months and 6.2 months, respectively. Conclusions: Radiotherapy combined with immunochemotherapy for advanced esophageal cancer showed potential efficacy but relatively high toxicities.

401P Vibostolimab coformulated with pembrolizumab (vibo/pembro) + chemotherapy (chemo) as first-line treatment for advanced esophageal cancer (ec): Results from cohort E of the phase II KEYVIBE-005 study

401P Vibostolimab coformulated with pembrolizumab (vibo/pembro) + chemotherapy (chemo) as first-line treatment for advanced esophageal cancer (ec): Results from cohort E of the phase II KEYVIBE-005 study

Immune checkpoint inhibitor retreatment in second-line treatment of esophageal cancer: A real-world study.

e16034 Background: Immunotherapy combined with chemotherapy has been recommended in several guidelines and consensus for the first-line treatment of advanced esophageal cancer(EC), but it is controversial whether to continue immune checkpoint inhibitors (ICIs) after the progress of first-line immunotherapy. Methods: This was a single-center, retrospective, observational, real-world study to collect general conditions and clinical data of EC patients hospitalized in the First Affiliated Hospital of Henan University of Science and Technology between February 2020 and December 2023. All patients received programmed cell death protein 1 (PD-1) or its ligand (PD-L1) inhibitor combination therapy in the first-line and received at least two cycles of PD-1/PD-L1 inhibitor-based therapy in the second-line setting after progression. We evaluated the efficacy and safety including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), grade 3-5 treatment-related adverse effects (TRAE) and immune-related adverse events (irAEs). We also evaluated the relationship between clinical features and outcomes using univariate and multivariate analyses. Results: We enrolled 214 patients, with a median age 67.9 (47 – 87) years, male sex 66.8%, 201(93.9%) ESCC and 11(5.1%) EAC. In all patients, the mOS and mPFS were 9.6 (95%CI 9.1-10.1) months and 4.4 (95%CI 4.1-4.7) months; The ORR was 33.2%, DCR was 65.9%. 162 (75.7%) patients treated with immunochemotherapy(I+C), 37 (17.3%) patients received immunotherapy combined with anti-angiogenic drugs(I+A) and 15 (7.0%) patients treated with immunotherapy combined with chemotherapy and anti-angiogenic drugs(I+C+A). The mOS were 9.1 (95% CI 8.4 – 9.8) months, 10.0 (95% CI 8.7 – 11.3) months and 11.5 (95% CI 10.7 – 12.3) months, respectively. The mPFS were 4.3m (95%CI 4.0-4.6) months, 4.3 (95%CI 4.0-14.6) months and 6.0 (95%CI 4.2-6.4) months. mPFS and mOS did not have significant difference between these groups. Univariate and multivariate analyses showed that PFS more than 6 months on first-line therapy was an independent prognostic factor for PFS and OS in second-line therapy. The incidence of grade ≥ 3 TRAEs and irAEs were 25.7% and 5.6%. No treatment-related deaths occurred. Conclusions: This real-world data showed PD-1 or PD-L1 inhibitors retreatment might have good efficacy and manageable safety in EC patients who progress after first-line immunochemotherapy. [Table: see text]

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.

Diabetes Mellitus Induced by Nivolumab plus Regorafenib in a Patient with Esophageal Cancer

Abstract Nivolumab is now preferred as first-line and second-line treatment for advanced esophageal cancer, while regorafenib improves survival in refractory gastroesophageal cancer. The combined use of nivolumab and regorafenib has shown promising results. Nivolumab-induced thyroid dysfunction is a common immune-related adverse event (irAE), while type 1 diabetes mellitus induced by immune checkpoint inhibitors is rare and usually permanent. It is unclear whether the combination of regorafenib and nivolumab increases the risk of irAEs. We report a patient with recurrent esophageal squamous cell carcinoma who was treated with nivolumab plus regorafenib and developed thyroiditis and diabetic ketoacidosis. The rechallenge was successful, and the patient achieved a good treatment response.

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.

Macrophage reprogramming combined with enhanced photodynamic therapy increases the patency of malignant esophageal obstruction after stenting.

Esophageal cancer (EC) is a disease characterized by progressive malignant obstruction. Stent implantation restores lumen patency, but tumor progression is likely to cause re-occlusion shortly. An esophageal stent loaded with Ce6-SiO2@MnO2 nanoparticles was designed, for which a dense δ-MnO2 coating was synthesized using a novel one-step REDOX reaction. This stent reverses the hypoxic tumor microenvironment (TME) via explosive oxygen generation, thereby increasing the efficacy of photodynamic therapy (PDT). Furthermore, Mn2+ reprograms the polarity of tumor associated macrophages (TAMs) in the immunosuppressed TME to effectively activate innate anti-tumor immunity in combination with PDT. Mn2+ downregulates the high mobility group box 1 protein (HMGB1), upregulates the signal transducer and activator of transcription 1 (STAT1) mRNA, and ultimately expresses the tumor inhibition effect of TAMs. Additionally, Ce6-SiO2@MnO2 effectively suppresses the apoptosis of TAMs to enhance their anti-tumor effect. The proposed strategy highlights the multifaceted role of Ce6-SiO2@MnO2 in the treatment of advanced esophageal cancer.

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.