Esophageal Squamous Cell Carcinoma In China Research Articles

1252P Update results of anlotinib combined with nab-paclitaxel and cisplatin as neoadjuvant treatment for esophageal squamous cell carcinoma (ESCC): A single-arm, open-label phase Ⅱ clinical trial

Due to the intolerability of concurrent chemoradiotherapy, novel neoadjuvant treatments are being explored. Anlotinib was an effective second-line monotherapy for ESCC in China and the combination therapy might be a promising strategy. The preliminary results of nab-paclitaxel and cisplatin combined with anlotinib as neoadjuvant treatment for ESCC had been reported in 2022 ASCO (e16015). Here, the update results were reported. ESCC patients (pts) with preoperative clinical stage II-III and radical potential were recruited. Eligible pts received anlotinib (12mg, po, d1∼14, q3w), nab-paclitaxel (175mg/m2, iv, q3w) and cisplatin (20mg/m2, iv, d1∼3, q3w) for 2 cycles during neoadjuvant therapy. 4 weeks later, pts underwent radical surgery after exclusion of contraindications. Tumor response was assessed by investigator per RECIST 1.1. The calculated sample size was 62. The primary endpoint was ORR, secondary endpoints were R0 resection rate, DFS, OS, DCR and safety. From Apr 2021 to Apr 2022, 33 eligible pts were enrolled. Among them, 22 pts underwent surgery after 2 cycles of neoadjuvant therapy, 4 pts chose other treatment options, and 7 pts are still receiving neoadjuvant therapy. Pts who had received surgery (n=22) were included in this analysis. In best overall response assessment, ORR was 86.4% (95%CI: 65.1∼98.5%) and DCR was 100.0% (95%CI: 84.6∼100.0%). At the data cut-off date (April 10, 2022), 22 pts (100.0%) had underwent R0 resection. Among them, 4 pts (18.2%) were confirmed to be pCR. And the median DFS was not yet available. The safety profile suggested that the most common treatment-emergent adverse events were gastrointestinal reactions (81.8%), liver damage (18.2%), hypokalemia (15.2%), nausea (15.2%) and myelosuppression (12.1%). One patient experienced grade 3 neutropenia (3.0%). Preliminary results suggested that anlotinib combined with nab-paclitaxel and cisplatin in neoadjuvant treatment of ESCC exhibited encouraging efficacy and manageable adverse events. The conclusion should be validated in more patients included subsequently.

Anlotinib combined with nab-paclitaxel and cisplatin as neoadjuvant treatment for esophageal squamous cell carcinoma (ESCC): A single-arm, open-label phase II clinical trial.

e16015 Background: Neoadjuvant therapy could significantly improve survival for patients with locally advanced esophageal cancer. However, postoperative complications and recurrence are still urgent problems to be solved. Anlotinib was an effective second-line monotherapy for ESCC in China and the combination therapy might be a promising strategy. Nab-paclitaxel plus cisplatin as first-line therapy exhibited moderate efficacy in ESCC patients. This study was to investigate the efficacy and safety of nab-paclitaxel and cisplatin combined with anlotinib as neoadjuvant treatment for ESCC. Methods: ESCC patients with preoperative clinical stage II-III and all patients who can receive radical surgery were recruited in this study. Eligible patients received anlotinib (12mg, po, d1̃14, q3w) combined with nab-paclitaxel (175mg/m2, iv, q3w) and cisplatin (20mg/m2, iv, d1̃3, q3w) for 2 cycles during neoadjuvant therapy. 4 weeks after the end of neoadjuvant therapy, the patients underwent radical surgery after exclusion of contraindications to surgery. Tumor response was assessed by investigator according to RECIST version 1.1 using CT scans at baseline and within 2 weeks before surgery. The calculated sample size was 62. The primary endpoint was ORR, secondary endpoints were R0 resection rate, DFS, OS, DCR and safety. Results: From Apr 2021 to Dec 2021, a total of 26 eligible patients were enrolled. Among them, 17 patients underwent surgery after completing 2 cycles of neoadjuvant therapy, 3 patients chose other treatment options, and 6 patients are still receiving neoadjuvant therapy. patients who had received surgery (n = 17) were included in this analysis. In best overall response assessment, there were 4 CR (23.5%), 11 PR (64.7%) and 2 SD (11.8%). Consequently, ORR was 88.2% (95%CI: 63.6̃98.5%) and DCR was 100.0% (95%CI: 80.5̃100.0%). At the data cut-off date, 17 patients (100.0%) had underwent R0 resection. Among them, 4 patients (23.5%) were confirmed to be pCR. And the median DFS was not yet available. The safety profile suggested that the most common treatment-emergent adverse events with the incidence > 10% were gastrointestinal reactions (65.4%), hypokalemia (19.2%), nausea (15.4%), liver damage (15.4%), myelosuppression (11.5%) and vomit (11.5%). No grade ≥3 adverse events were noted. Conclusions: Preliminary results suggested that anlotinib combined with nab-paclitaxel and cisplatin in neoadjuvant treatment of ESCC exhibited encouraging efficacy and manageable adverse events. The conclusion should be validated in more patients included subsequently.

Environmental Cadmium Exposure Promotes the Development, Progression and Chemoradioresistance of Esophageal Squamous Cell Carcinoma.

Cadmium (Cd) exposure has been implicated in the etiology of esophageal squamous cell carcinoma (ESCC), albeit with inconsistent results from epidemiologic studies and without causal evidence. In this study, we explore the relationship of Cd exposure and the development, progression and therapeutic resistance of ESCC. A total of 150 ESCC patients and 177 matched controls from a coastal region with a high incidence of ESCC in China were included in the study. It was found that the median blood Cd level (BCL) was significantly higher in ESCC patients than that in the controls. Odds ratios for ESCC risk were 3.12 (95% CI 1.54-6.30) and 3.71 (95% CI 1.84-7.48) in the third and fourth quartiles of Cd distribution, respectively. Notably, BCL above 4.71 μg/L was strongly associated with shorter progression-free survival time compared to that below 1.60 μg/L (p < 0.001). The chronic Cd-treated ESCC cells (CCT-ESCC) CCT-EC109 and CCT-EC9706 exhibited increased cell proliferation and tumorigenesis, enhanced migration and invasion, and upregulated EMT biomarkers following 12 weeks of exposure to 5 μM cadmium chloride. Furthermore, Cd treatment attenuated the efficacy of 5-fluorouracil, cisplatin and irradiation treatment in CCT-ESCC cells both in vitro and in vivo. Moreover, we revealed that Cd stimulated the cancer cell stemness and Wnt/β-catenin signaling pathway in the CCT-ESCC cells. Additionally, 5-aza-2-deoxy-cytidine treatment resulted in suppression of the Wnt/β-catenin signaling pathway and rescue of the Cd-induced cell radioresistance. These results offer new insights into the role of environmental Cd exposure in the development, progression and chemoradioresistance of ESCC.

Combined Mean Corpuscular Hemoglobin, Fibrinogen, and Albumin (MF-A) Is a Novel Prognostic Marker in Patients with Resectable Esophageal Squamous Cell Carcinoma.

The aim was to systematically select blood markers routinely tested in clinical settings, which are independently associated with overall survival (OS) and are able to stratify prognosis of esophageal squamous cell carcinoma (ESCC) patients undergoing esophagectomy. We selected optimal blood markers for prognostic stratification from 60 candidates in a clinical cohort of 1819 consecutive patients with resectable ESCC in China. Selection was carried out using two-step multivariable Cox proportional hazards regression adjusted for multifaceted confounders. A composite index was developed by multiplying risk factors and dividing them by protective factors. With a median follow-up of 48.07 months, 641 deaths occurred in the 1819 patients and the 5-year OS was 56.30%. Two risk factors (mean corpuscular hemoglobin, fibrinogen) and a protective factor (albumin), all dichotomized and assigned values 1 and 2, were used to construct the composite index marker "MF-A". Three risk groups were created based on the MF-A score including low- (0.5), moderate- (1), and high-risk groups (2 and 4). Compared with patients in the low-risk group (1184/1778, 66.59%), those in the moderate- (488, 27.45%), and high-risk (106, 5.96%) groups were at elevated risk of death (adjusted HR: 1.32, 95% CI: 1.11-1.57; adjusted HR: 2.08, 95% CI: 1.56-2.75; Ptrend < 10-7). Within each TNM stage grouping, OS also trended to be significantly worse as the MF-A score increased. "MF-A" is a novel independent predictor which may be used to estimate and stratify prognosis for ESCC patients undergoing esophagectomy.

Cost-effectiveness of camrelizumab versus chemotherapy for the treatment of advanced or metastatic esophageal squamous cell carcinoma.

To evaluate the cost-effectiveness of camrelizumab versus chemotherapy for patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) from the perspective of health system and to provide a basis for health decisions in China. A Markov model of 3 health states throughout the lifetime was established based on data from the ESCORT trial. Life-years, quality-adjusted life-years (QALYs), and lifetime costs were estimated. The time horizon of lifetime was 5 years and each model cycle represented 2 months. The cost and utility value adopted a 5% discount rate per year. One-way sensitivity analysis and probability sensitivity analysis were used to test the robustness of the results. The results of the cost-effectiveness analysis revealed that the camrelizumab group produced a gain of 2.93 QALY, at a cost of $37,809.12 USD, and the chemotherapy group gained 2.85 QALY, at a cost of $3,7071.52 USD. Camrelizumab was more cost-effective than chemotherapy for patients with advanced or metastatic ESCC. The results of one-way sensitivity analyses showed that the cost of camrelizumab, cost of chemotherapy and utility of progression-free survival (PFS) state were the top three parameters influencing the model. The probability sensitivity analysis results showed that the results of the basic case analysis were stable. Under the willingness to pay threshold of three times per capita GDP of China, camrelizumab as second-line treatment could provide more health benefits for advanced or metastatic ESCC in China.

Update results of paclitaxel and cisplatin in combination with anlotinib as first-line regimen for patients with advanced ESCC: A multicenter, single-arm, open-label phase Ⅱ clinical trial.

315 Background: Chemotherapy is the standard first-line therapy for advanced Esophageal Squamous Cell Carcinoma (ESCC). However, the poorly 5-year survival rate (4.8%) was unsatisfied. Anlotinib was an effective second-line monotherapy for ESCC in China and the combination therapy might be a promising strategy. Here we reported the update results and futhur evaluated the efficacy and safety of paclitaxel and cisplatin combined with anlotinib as first-line therapy in advanced ESCC. Methods: Pts with previously untreated metastatic or unresectable, locally advanced ESCC, who had not received (neo) adjuvant therapy/radical surgery within 6 months were recruited. Eligible patients were given paclitaxel (135mg/m2, iv, q3w) and cisplatin (60̃75mg/m2, iv, d1̃3, q3w) plus anlotinib (10mg, po, d1̃14, q3w) for 4̃6 cycles as initial therapy. Maintenance treatment was administered to those without disease progression with anlotinib monotherapy (10mg, po, d1̃14, q3w) until progression or unacceptable toxicity. The primary endpoint was PFS and secondary endpoints included safety, ORR, DCR and DOR. The predefined sample size was 47. Tumor response was assessed by investigators according to RECIST version 1.1 criteria using CT scans every two cycles. Results: From Oct 2019 to Mar 2021, a total of 47 pts with ESCC were included and 46 pts were included in intention-to treat analysis, among whom 4 CR (8.7%), 31 PR (67.4%) and 7 SD (15.2%) were observed and 4 patients (8.7%) were not available for efficacy assessment. Consequently, ORR was 76.1% (95%CI: 61.2%-87.4%) and DCR was 91.3% (95%CI: 79.2%-97.6%). At the cut-off date on July 15, 2021, 23 pts discontinued treatment due to PD, the preliminary median PFS of ITT patients was 8.38 months (95%CI: 6.44-10.32). And the median OS was not yet available. Additionally, safety profile exhibited that the common drug-related adverse events were myelosuppression, gastrointestinal reaction, fatigue, hypertension, constipation, hypokalemia. And the common grade ≥3 adverse events were myelosuppression (29.8%), gastrointestinal reaction (10.6%), hypertension (6.3%), fatigue (4.3%) and hypokalemia (4.3%). Conclusions: The update results suggested that paclitaxel and cisplatin combined with anlotinib as first-line therapy for advanced ESCC exhibited encouraging efficacy and tolerable safety profile. And the conclusion should be validated in more pts with ESCC subsequently. Clinical trial information: NCT04063683.

Genomic analyses reveal SCN7A is associated with the prognosis of esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) has a poor prognosis and occurs with high frequency in China. In particular, Fujian is one of the high-incidence areas of ESCC in China and the somatic mutation profile of ESCC there remains unclear. Whole-exome sequencing (WES) was performed in 49 matched ESCC tumor-normal specimens to examine the somatic mutation profiles. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between mutational profile and survival were derived from Cox regression model. We constructed a preliminary somatic mutation profiling of ESCC in Fujian. Exome sequencing data showed that the main base substitutions in ESCC were C > T transformation (close to 50%), C > A and T > C transversion. The study identified 21 significantly mutated genes, including 8 driver genes and 11 predicted driver genes. Among the 19 driver or predicted driver genes, 9 are novel (OBSCN, PKHD1L1, FSIP2, HRNR, CUBN, CELSR3, SCN7A, TULP4, SRRM2) and 10 have been previously reported. Three mutational signatures were identified to be prevalent in ESCC including Signature_15, Signature_4 and Signature_6, of which Signature_15 was related to prognosis of ESCC (HR 2.81, 95% CI 1.30-6.05; p = 0.008). Survival analysis showed that SCN7A was correlated to overall survival with an HR of 2.76 (95% CI 0.96-7.90, p = 0.058). After controlling for confounding factors such as age, gender, stage and location, the correlation between SCN7A and survival was statistically significant based on multivariate COX regression analysis (HR 4.76, 95% CI 1.20-18.85; p = 0.026, padjust = 0.053). The tumor vascular invasion was associated with SCN7A of ESCC patients (p = 0.028). In summary, this study provided comprehensive analysis of the somatic mutation profiles of ESCC, and identified SCN7A and Signature_15 for the prognosis of ESCC for the first time. The findings might serve as a conceptual basis for molecular diagnosis and prevention of ESCC.

Cost-Effectiveness Analysis of Camrelizumab vs. Placebo Added to Chemotherapy as First-Line Therapy for Advanced or Metastatic Esophageal Squamous Cell Carcinoma in China.

ObjectiveThe purpose of this cost-effectiveness analysis was to estimate the effects of adding camrelizumab to standard chemotherapy as the first-line treatment in patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) on health and economic outcomes in China.MethodsA Markov model was developed to simulate the clinical course of typical patients with advanced or metastatic ESCC in the ESCORT-1st trial. Weibull survival model was employed to fit the Kaplan-Meier progression-free survival and overall survival probabilities of the camrelizumab-chemotherapy and placebo-chemotherapy strategy, respectively. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICER) were estimated over a 5-year lifetime horizon. Meanwhile, one-way and probabilistic sensitivity analyses were conducted to test the uncertainty in the model.ResultsOn baseline analysis, the incremental effectiveness and cost of camrelizumab-chemotherapy versus placebo-chemotherapy were 0.15 QALYs and $7,110.56, resulting in an ICER of $46,671.10/QALY, higher than the willingness-to-pay (WTP) threshold of China ($31,498.70/QALY). The results were sensitive to the utility of PFS and cost of camrelizumab.ConclusionThe findings from the present analysis suggest that the addition of camrelizumab to chemotherapy might not be cost-effective in patients with advanced or metastatic ESCC in China.

557 Neoadjuvant Camrelizumab in combination with albumin paclitaxel and cisplatin for patients with locally advanced esophageal squamous cell carcinoma (ESCC)

BackgroundThe pathologic complete response (pCR) rate occurs less than 10% of patients(pts) with neoadjuvant chemotherapy agents in locally advanced ESCC, Programmed death-1 (PD-1) blockade may induce tumor regression in pts with advanced ESCC. Camrelizumab (anti-PD-1) is standard of care as second-line therapy for advanced ESCC in China. With the potential benefit of combining Camrelizumab with neoadjuvant chemotherapy, we intended to assess the efficacy and safety of Camrelizumab combined with albumin paclitaxel and cisplatin in neoadjuvant therapy of locally advanced ESCC.Methods28 pts with histologically confirmed stage II-IVA ESCC were enrolled. Eligible pts were aged 18~75 years with no prior any therapy. Pts received 2~4 cycles of Camrelizumab (200mg IV q3w) plus albumin paclitaxel (260 mg/m2 IV q3w) and cisplatin (75 mg/m2 IV q3w) followed by surgery within 4~6 weeks after completion of neoadjuvant therapy. The primary endpoint was pCR, the secondary endpoints included major pathologic response (MPR), R0 resection rate, objective response rate (ORR), disease-free survival (DFS) and safety.ResultsFrom Jul 27 2019 to Jan 29 2021, 28 eligible pts were enrolled, neoadjuvant treatment was completed in 28 pts. 12 pts (42.9%) had clinical complete response (cCR), and the ORR was 78.6% (22/28). All pts underwent surgery and surgical treatment was not delayed. The pCR was 32.1% (9/28), MPR was 53.6% (15/28). Notably, R0 resection rate was 100% (28/28). None of 28 pts progressed, the DFS was not yet achieved. The average intraoperative blood loss was 139ml (100–300ml) and the average hospitalization time after operation was 17 days (11–35 days). No patient developed anastomotic leak and other surgical treatment-related toxicity. The grade 1–2 treatment-related AEs were reactive cutaneous capillary endothelial proliferation (RCCEP) (35.7%), hepatotoxicity (21.4%), weakness (10.7%), thyroid dysfunction (10.7%). No serious AEs resulted in termination of treatment.ConclusionsCamrelizumab in combination with albumin paclitaxel and cisplatin followed by surgery for locally advanced ESCC showed promising downstaging effect and pCR with good tolerance, and further study is needed.

Camrelizumab combined with albumin paclitaxel and cisplatin as neoadjuvant therapy for locally advanced esophageal squamous cell carcinoma (ESCC).

e16021 Background: The pathologic complete response (pCR) rate is improved by neoadjuvant therapy in locally advanced ESCC, but occurs less than 10% of patients(pts) with neoadjuvant chemotherapy agents. Immunotherapy has become a new promising treatment. Camrelizumab (anti-PD-1) is standard of care as second-line therapy for advanced ESCC in China. Therefore, we intended to evaluate the efficacy and safety of Camrelizumab combined with albumin paclitaxel and cisplatin as neoadjuvant therapy for pts with locally advanced ESCC. Methods: We retrospectively analysed locally advanced ESCC pts with clinical stage Ⅱ-ⅣA. Eligible pts were aged 18–75 years with no prior any therapy. Pts received 2-4 cycles neoadjuvant therapy which including Camrelizumab (200mg IV q3w), albumin paclitaxel (260 mg/m2 IV q3w) and cisplatin (75 mg/m2 IV q3w). Surgery was performed 4-6 weeks after neoadjuvant therapy. The primary endpoint was pCR, the secondary endpoints were major pathologic response (MPR), R0 resection rate, objective response rate (ORR), disease-free survival (DFS) and safety. Results: From Jul 27 2019 to Sep 26 2020,16 pts were enrolled and available evaluated. 8 pts (50%) had clinical complete response (cCR), and the ORR was 87.5% (14/16). All pts underwent surgery and surgical treatment was not delayed. The pCR was 43.8% (7/16), MPR was 75% (12/16). Notably, R0 resection rate was 100% (16/16). None of 16 pts progressed, the DFS was not yet achieved. The average intraoperative blood loss was 131ml (100-200ml) and the average hospitalization time after operation was 14 days (11-21 days). No patient developed anastomotic leak and other surgical treatment-related toxicity. The grade 1-2 treatment-related AEs were reactive cutaneous capillary endothelial proliferation (RCCEP) (n = 3,18.8%), weakness (n = 2, 12.5%), Myelosuppression (n = 1, 6.2%) and hypothyroidism (n = 1, 6.2%). No serious AEs resulted in termination of treatment, and treatment-related death was not observed. Conclusions: The addition of camrelizumab to albumin paclitaxel and carboplatin was demonstrated encouraging clinical efficacy and acceptable safety as neoadjuvant therapy, and might be a favorable option for pts with locally advanced ESCC. Further registered clinical trials are expected.

Update results of paclitaxel and cisplatin in combination with anlotinib as first-line regimen for patients with advanced ESCC: A multicenter, single-arm, open-label phase Ⅱ clinical trial.

e16013 Background: Paclitaxel combined with cisplatin regimen has been the standard first-line therapy in advanced Esophageal Squamous Cell Carcinoma (ESCC) for almost two decades. However, the 5-year survival rate was only 4.8% in advanced ESCC. Therefore, more effective therapeutic treatments were needed to prolong the survival urgently. Anlotinib was demonstrated to be an effective second-line monotherapy for patients with advanced or recurrent ESCC in China. And the preliminary results of our trial had been reported in 2020 ESMO (Abs 1448) and 2021 ASCO-GI Symposium (Abs 181). Consequently, this study was to investigate the efficacy and safety of paclitaxel and cisplatin combined with anlotinib as first-line therapy in advanced ESCC and report the update results regularly. Methods: Pts with previously untreated metastatic or unresectable, locally advanced ESCC, who had not received (neo) adjuvant therapy/radical surgery within 6 months were recruited in this study. Eligible patients were given paclitaxel (135mg/m2, iv, q3w) and cisplatin (60̃75mg/m2, iv, d1̃3, q3w) plus anlotinib (10mg, po, d1̃14, q3w) for 4̃6 cycles as initial therapy. For those who did not have disease progression, maintenance treatment was treated with anlotinib monotherapy (10mg, po, d1̃14, q3w) until progression or unacceptable toxicity. The tumor response was assessed by investigator according to RECIST version 1.1 criteria using computed tomography scans every two cycles. The predefined sample size was 47. The primary endpoint was PFS and secondary endpoints included safety, ORR, DCR and DOR. Results: From Oct 2019 to Dec 2020, a total of 45 patients were enrolled. Among 34 pts who were available for efficacy and safety evaluation. there were 1 confirmed CR (2.9%), 26 confirmed PR (76.5%), 2 unconfirmed PR (5.9%) and 5 SD (14.7%). Consequently, ORR was 79.4% (95%CI: 62.1̃91.3) and DCR was 100.0% (95%CI: 89.7̃100.0). At the data cut-off date, 11 patients discontinued treatment due to PD, the preliminary prognostic result indicated that the median PFS of the 34 patients was 9.76 months (95%CI: 8.44-13.08). And the median OS was not yet available. Additionally, safety profile exhibited that the common drug-related adverse events were myelosuppression, gastrointestinal reaction, fatigue, hypertension, constipation, hypokalemia, hepatotoxicity and hemoptysis. And the common grade ≥3 adverse events were myelosuppression (20.6%), hypertension (8.8%), nausea and vomit (5.9%), fatigue (5.9%) and hypokalemia (5.9%). Conclusions: The update results suggested that the regimen of paclitaxel and cisplatin combined with anlotinib as first-line therapy for advanced ESCC exhibited encouraging efficacy and tolerable safety profile. And the conclusions needed to be confirmed in trials continued subsequently. Clinical trial information: NCT04063683.

Update results of paclitaxel and cisplatin in combination with anlotinib as first-line regimen for advanced esophageal squamous cell carcinoma (ESCC): A multicenter, single-arm, open-label phase Ⅱ clinical trial.

181 Background: The prognosis of pts with advanced ESCC remains dismal clinically. Paclitaxel and cisplatin were used as the standard first-line regimen in ESCC for almost two decades. As a novel multitarget tyrosine kinase inhibitor mainly targeting antiangiogenic single pathway, anlotinib was demonstrated to be an effective second-line monotherapy for pts with advanced or recurrent ESCC in China. Consequently, the aim of this study was to investigate the efficacy and toxicity of paclitaxel and cisplatin combined with anlotinib as first-line therapy for advanced ESCC. Methods: Pts with previously untreated metastatic or unresectable, locally advanced ESCC, who had not received (neo) adjuvant therapy/radical surgery within 6 months were recruited in this study. Eligible subjects were given paclitaxel (135mg/m2, iv, q3w) and cisplatin (60~75mg/m2, iv, d1~3, q3w) plus anlotinib (10mg, po, d1~14, q3w) for 4~6 cycles during initial therapy. For those without progressive disease, maintenance treatment was administrated with anlotinib monotherapy (10mg, po, d1~14, q3w) until progression or unacceptable toxicity. The tumor response was assessed by investigator according to RECIST version 1.1 using CT scans every two cycles. And the calculated sample size of this study was 47. The primary endpoint was PFS, secondary endpoints were safety, objective response rate (ORR), disease control rate (DCR) and duration of response (DOR). Results: From Oct 2019 to Aug 2020, 27 pts were available for efficacy and safety evaluation. In best overall response assessment, there were 7.4% CR (2/27), 66.7% PR (18/27) and 25.9% SD (7/27). ORR was 74.1% (95%CI: 53.7. ~ 88.9), and DCR was 100.0% (95%CI: 87.2~100.0). The median PFS of the 27 pts was not yet available. The safety profile indicated that the most common drug-related adverse events were myelosuppression, gastrointestinal reaction, fatigue, hypertension, constipation, hypokalemia and hepatotoxicity. The common grade 3-4 treatment-related adverse events were myelosuppression (18.5%), hypertension (7.4%). Conclusions: The current results indicated that paclitaxel and cisplatin combined with anlotinib as first line therapy for advanced ESCC exhibited encouraging efficacy and manageable adverse events. The conclusion should be validated in more pts consecutively. Clinical trial information: NCT04063683. [Table: see text]

Precision screening for esophageal squamous cell carcinoma in China.

Esophageal squamous cell carcinoma (ESCC) is the predominant subtype of esophageal cancer in China, and this neoplasm is associated with high morbidity and mortality as well as clear geographical heterogeneity. Since primary prevention for ESCC lacks a clear intervention target, secondary prevention, also known as screening and early diagnosis and early treatment, has become the mainstay of ESCC prevention and control in China. ESCC screening in China has been subject to decades of evaluation and practice. However, the ESCC screening strategy currently adopted in China has encountered a developmental bottleneck. In this review, we have summarized studies and significant findings for ESCC screening and proposed advancement of screening strategies as follows: 1) evidence from randomized controlled trials is needed to support the effectiveness and health economic value of endoscopic screening for ESCC; 2) the current traditional screening and surveillance strategies warrant reform, and a risk-prediction-based precision strategy should be established; and 3) a deeper understanding of the value of opportunistic screening in the prevention and control of ESCC in China is called for. Due to the low absolute prevalence of precancerous lesions, substantial investment of resources and nonnegligible risks of invasive screening techniques, precision and individualization should be the main direction of cancer screening programs for the future. We advocate cooperation on the part of Chinese scientists to solve this major China-specific health problem in the next decades.

Abstract CT211: ORIENT-15: A randomized, multicenter, double-blind, Phase III study of sintilimab + paclitaxel and cisplatin (TP) versus placebo + TP as first-line treatment in patients with unresectable locally advanced or metastatic esophageal squamous cell carcinoma

Abstract Background: China has the largest population of patients with esophageal cancer in the world. The major histopathological type is squamous cell carcinoma and it accounts for more than 90% of the cases. About 40% esophageal squamous cell carcinoma (ESCC) are PD-L1 positive, however, the prognostic and predictive value of this biomarker remains elusive for this disease. Regardless of PD-L1 status, the median overall survival of patients with advanced or metastatic ESCC is about 10 months, reflecting an unmet medical need for new treatments. Sintilimab is a fully human anti-PD-1 monoclonal antibody that blocks the PD-1/PD-L1,PD-L2 interaction and restores T-cell response thereby destroying tumor cells. Sintilimab has a safety profile consistent with other approved PD-1 antibodies and was approved for relapsed/refractory Hodgkin lymphoma in China in 2018. Recently, comparing to chemotherapy, nivolumab and pembrolizumab significantly improved overall survival in second-line esophageal cancer patients, which suggests the application of PD-1 therapy in first-line ESCC. This randomized, multicenter, double-blind, Phase III study compares the efficacy and safety of sintilimab in combination with paclitaxel and cisplatin (TP) versus placebo with TP as first-line systemic treatment in patients with unresectable, locally advanced or metastatic ESCC in China. Methods: To be eligible, patients must be between 18 and 75 years of age, not eligible for definitive therapy, have untreated locally advanced recurrent or metastatic ESCC, have at least one measurable lesion, and must provide tumor tissue for PD-L1 assessment (tumor proportion score, TPS by Dako 22 C3) within 6 months prior to entrance. Patients with prior PD-1, PD-L1 or PD-L2 antibody treatment, cisplatin cumulative exposure ≥ 300 mg/m2, or esophageal or tracheal stent placement are excluded. A total of 640 subjects will be randomized in a 1:1 ratio to receive either sintilimab plus TP Q3W or placebo plus TP Q3W until unacceptable toxicity, disease progression, death or withdrawal of consent. Stratifying factors include PD-L1 TPS ≥ 10% or &amp;lt; 10%, liver metastasis or not, and ECOG PS 0 or 1. The primary endpoint is median overall survival assessed in the experimental and control groups in both the entire population and the PD-L1 positive (TPS ≥ 10%) population. The secondary endpoints are PFS, ORR, DCR, DoR and safety. Clinical trial information: NCT03748134. Citation Format: Lin Shen, Zhihao Lu, Linxinyu Xu, Yan Wang, Hui Zhou, Ying Liu. ORIENT-15: A randomized, multicenter, double-blind, Phase III study of sintilimab + paclitaxel and cisplatin (TP) versus placebo + TP as first-line treatment in patients with unresectable locally advanced or metastatic esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT211.

Nedaplatin-based chemotherapy regimens combined with concurrent radiotherapy as first-line treatment for stage II-III esophageal squamous cell carcinoma.

Concurrent chemoradiotherapy (CCRT) is an effective first-line treatment for esophageal squamous cell carcinoma (ESCC). The present study aimed to compare clinical outcomes between three nedaplatin-based regimens for CCRT of ESCC. Patients with stage II-III thoracic ESCC in China between January 2012 and May 2016 were included. Patients received esophageal ultrasonography prior to treatment. Chemotherapy was as follows: i) 100 mg/m2 nedaplatin intravenously on day 1 and 70 mg/m2 tegafur-gimeracil-oteracil potassium (S-1) orally twice daily for 2 weeks; ii) 50 mg/m2 nedaplatin intravenously on days 1 and 2 and 35 mg/m2 docetaxel intravenously on days 1 and 8; or iii) 60 mg/m2 nedaplatin intravenously on days 1 and 2. Intensity-modulated radiotherapy was used to administer a total dose of 60-66 Gy (1.8-2.0 Gy per fraction) to the primary tumor and 45-50 Gy to the subclinical region. A total of 70 patients were enrolled (median age, 66 years; range, 50-81 years). T4 disease was identified in 45 (64.3%) patients. All patients completed radiotherapy and received ≥2 chemotherapy cycles. Estimated 1-, 2- and 3-year overall survival (OS) rates were 82.9, 53.9 and 31.4%, respectively. OS and progression-free survival were similar between the three treatment groups. Grade 3/4 hematological toxicities were observed in 35 (50%) patients. The incidence of serious treatment-associated toxicities was numerically highest for the nedaplatin/docetaxel combination. Patients with thoracic ESCC had good clinical outcomes following CCRT. With similar survival rates and disease responses yet lower hematological toxicities, nedaplatin/S-1 and single-agent nedaplatin may be preferable to nedaplatin/docetaxel. Poor control of distant metastasis may be a disadvantage of single-agent chemotherapy use in CCRT, and a further study with larger cohorts is required to confirm this.

Efficacy of endoscopic screening for esophageal cancer in China (ESECC): design and preliminary results of a population-based randomised controlled trial

ObjectiveDescription of the design and preliminary results of baseline recruitment and screening in the endoscopic screening for esophageal cancer in China (ESECC), the first randomised controlled trial (RCT) assessing efficacy...

Association of genotypes of rs671 withinALDH2 with risk for gastric cardia adenocarcinoma in the Chinese Han population in high- and low-incidence areas.

Objective: This study aimed to determine if gastric cardia adenocarcinoma (GCA) risk was associated with the lys (A or *2) allele at the rs671 (glu504lys) polymorphism within the aldehyde dehydrogenase 2 (ALDH2) gene in a Chinese Han population. We also aimed to investigateALDH2 genotypic distributions between subjects from high- and low-incidence areas for both GCA and esophageal squamous cell carcinoma (ESCC). Methods: We designed a case-control study including 2,686 patients with GCA and 3,675 control subjects from high- and low-incidence areas for both GCA and ESCC in China. TaqMan allele discrimination assay was used to genotype the rs671 polymorphism.χ2 test and binary logistic regression analysis were used to estimate the odds ratios for the development of GCA, and multivariate ordinal logistic regression was used to analyzeALDH2 genotypic distributions among different groups. Results: Compared withALDH2*1/*1 homozygotes,ALDH2*1/*2 andALDH2*2/*2 carriers did not increase the risk for GCA in the Chinese Han population (P>0.05). Interestingly, the ratio of homozygous or heterozygousALDH2 *2 carriers in high-incidence areas for both GCA and ESCC was lower than that in low-incidence areas (P<0.001). Conclusions: Genotypes of rs671 atALDH2 may not increase GCA susceptibility in Chinese Han populations. In addition, theALDH2 genotypic distribution differs between Chinese Han populations from high- and low-incidence areas for both GCA and ESCC. Our findings may shed light on the possible genetic mechanism for the dramatic geographic differences of GCA occurrence in China.

Evidence for the aetiology of human papillomavirus in oesophageal squamous cell carcinoma in the Chinese population: a meta-analysis

ObjectivesWe aimed to conduct a meta-analysis of human papillomavirus (HPV) as a risk factor for oesophageal squamous cell carcinoma (OSCC) in China, using all eligible studies published in the English...

Human Papillomavirus Infection and Esophageal Squamous Cell Carcinoma: A Case–Control Study

The risk factors for esophageal squamous cell carcinoma (ESCC) in the high-incidence areas of China remain unclear. A total of 300 patients with ESCC and 900 controls matched for age and sex were enrolled in Anyang (China), a high-risk area for ESCC in China. In tumor tissue of the cases and in esophageal biopsies of controls, the presence of human papillomavirus (HPV) DNA was assessed by an SPF1/GP6(+)-mediated PCR followed by sequencing. The presence of serum antibody against the HPV-16 E7 oncoprotein was assessed by use of the ELISA. ORs with 95% confidence intervals (CI) were calculated via unconditional logistic regression models. The presence of HPV in the esophagus (OR, 6.4; 95% CI, 4.4-9.2) was associated with increased risk of ESCC. Moreover, infection with "oncogenic" types of HPV (OR, 10.3; 95% CI, 6.3-16.8) was more strongly associated with ESCC than other types of HPV (OR, 2.4; 95% CI, 1.4-4.2). The presence of HPV-16 (OR, 12.8; 95% CI, 7.6-21.7) was particularly strongly associated with ESCC. In addition, a higher proportion of cases than controls had serum antibodies against HPV-16 E7 (OR, 6.1; 95% CI, 3.7-10.0). This study provides the strongest epidemiologic evidence to date in support of the important role of HPV in the development of ESCC in high-incidence areas of China.

Abstract 5133: Copy number variation in 13q32.1 associated with esophageal squamous cell carcinoma

Abstract Background: Esophageal squamous cell carcinoma (ESCC) is the major lethal upper gastrointestinal tract cancer in China. The highly regional and family aggregative incidence of ESCC in China suggests that genetic susceptibility contributed to pathogenesis. Copy number variation (CNV) is an important form of gene structure variations and has been associated with multiple complex diseases, such as malignant tumors. This study aimed to identify the common CNVs correlated with ESCC susceptibility and demonstrate the functional significances. Method: A genome-wide associated study was conducted on 128 discordant sibling pairs of ESCC, which were native residents in Yangquan area, Shan Xi Province of China. The genomic DNA of peripheral blood leukocytes were extracted and genotyping was detected using the Illumina HumanHap 610Q BeadChips. After stringent quality control filtering, the CNVs-penotype association analysis were performed using the paired Hidden Markov Model calling algorithm in the Partek Genomic Suite with settings of length above 1kb and minimum 10 consecutive probes. Another 223 Northern Chinese Han people (111 ESCC patients and 112 health controls) were chosen to validate the CNVs using quantitative real-time PCR assays. Then the paraffin-embedded tissue samples of 16 ESCC patients with known genotyping data were collected for immunohistochemistry. Last, the highest frequency of variation region was cloned into luciferase reporter vectors to investigate its biological significance in ESCC cells. Results: A total of 57,774 individual CNVs covering all autosomes were identified. Of them, 13q32.1 was identified as a critical enrichment region, and it mainly was involved in one candidate gene. Conditional logistic regression test showed that this region was significantly associated with ESCC with the odd ratio being 65.289 (95%CI: 11.177-381.366; P&amp;lt;0.001). Quantitative real-time PCR assays replicated CNV in this gene. The frequencies of the three genotypes in cases were 3.6% (1 copy), 74.8% (2 copies), and 21.7% (3 copies), which differed significantly from those in controls (91.1% [2 copies], and 8.9% [3 copies]). Logistic regression analysis showed that the CNV in this gene increased the risk of ESCC (odd ratio: 3.891; 95% CI: 1.53-9.91 P=0.004). Additionally, 9 out of 11 patients containing 3 copies had positive expression of the gene (2 positive and 7 strong positive), whereas only 1 out of 5 patients containing 2 copies had positive expression. Chi-Square analysis showed that there was significant difference between two groups of patients (P=0.018). The subsequently luciferase asaay further comfirmed the enhancer activity of this CNV region. Conclusion: Common CNVs at 13q32.1 was associated with ESCC susceptibility probably due to its potential enhancer activity on regulating the gene expression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5133. doi:1538-7445.AM2012-5133