Adjuvant chemoradiotherapy plus pembrolizumab for locally advanced esophageal squamous cell carcinoma with high risk of recurrence following neoadjuvant chemoradiotherapy: a single-arm phase II study.

BACKGROUND: Adjuvant nivolumab reduces recurrence in patients with locoregional esophageal cancer who had pathological residual disease after neoadjuvant chemoradiotherapy and R0 resection. However, the efficacy of adjuvant anti-PD-1 therapy in patients at higher risk of recurrence remains unclear. METHODS: This phase II trial (ClinicalTrials.gov identifier: NCT03322267) enrolled patients with locally advanced esophageal squamous cell carcinoma (ESCC) received neoadjuvant chemoradiotherapy plus esophagectomy but still had various risk factors for recurrence, such as involved or close margins (≤ 1 mm), extranodal extension of the involved lymph nodes, and the ypN2-3 stage. Patients received adjuvant therapy composed of a course of cisplatin-based chemoradiotherapy and pembrolizumab (200 mg, IV every 3 weeks) for 18 cycles. The primary endpoint was 1-year relapse-free survival (RFS) rate. RESULTS: Twenty-five patients were enrolled. The risk factors were tumor margins of ≤ 1 mm (18 patients), extranodal extension of the involved lymph nodes (9 patients), and the ypN2-3 stage (9 patients). The median follow-up duration was 21.6 months (95% CI: 18.7-33.2). The rate of 1-year RFS was 60.0%. The median duration of RFS and overall survival was 14.3 (95% CI: 9.0-19.5) and 21.6 (95% CI: 0.0-45.5) months, respectively. Treatment-emergent adverse events of any grade and those of ≥ 3 grade occurred in 56% and 8% of all patients receiving cisplatin-based chemoradiotherapy and in 79.2% and 12.5% of those receiving pembrolizumab. CONCLUSIONS: Adjuvant chemoradiotherapy followed by pembrolizumab is feasible and may be associated with improved 1-year RFS rate in patients at high risk of recurrence after trimodality therapy for locally advanced ESCC. Trial registration number ClinicalTrials.gov (No. NCT03322267).

Deleterious alterations of DNA damage response and repair genes and clinical benefit to anti-PD-1 therapy in esophageal squamous cell carcinoma.

BACKGROUND: Although DNA damage response and repair (DDR) gene alteration has been demonstrated as a biomarker for anti-PD-1 therapy in several cancer types, its role in esophageal squamous cell carcinoma (ESCC) is unknown. METHODS: Patients with advanced ESCC treated with anti-PD-1-based immunotherapy were enrolled. Tumor response was evaluated according to RECIST 1.1. Archival ESCC tissues were analyzed using FoundationOne CDx. Deleterious alterations, defined by loss of function, of DDR genes were correlated with patient survival by Cox proportional hazards model. The prognostic significance of deleterious alterations of DDR genes in The Cancer Genome Atlas (TCGA)-ESCC cohort was explored. RESULTS: Forty-three patients were enrolled. The objective response rate (ORR) was 19%. The median tumor mutational burden was 4 mutations/Mb (0-20); none of the tumors were microsatellite instable. Compared with patients with wild-type or other alterations of DDR genes (N = 35, 81%), those with deleterious alterations of DDR genes (N = 8, 19%) had a higher ORR (38 vs. 14%), longer median progression-free survival (4.1 vs. 2.0 months), and significantly longer median overall survival (OS; 27.7 vs. 6.1 months, P = 0.011). In multivariate analysis, harboring deleterious alterations of DDR genes was a favorable prognostic factor for OS (HR = 0.31 [95% CI: 0.11-0.91], P = 0.033). In the TCGA-ESCC cohort, the presence of deleterious alterations of DDR genes was not a favorable prognostic factor. CONCLUSIONS: Deleterious alterations of DDR genes may be associated with improved prognosis and efficacy of anti-PD-1 therapy in patients with advanced ESCC.

Response to Immune Checkpoint Inhibitors in Recurrent or Metastatic Esophageal Squamous Cell Carcinoma May Be Affected by Tumor Sites.

INTRODUCTION: Heterogeneous tumor response has been reported in cancer patients treated with immune checkpoint inhibitors (ICIs). This study investigated whether the tumor site is associated with the response to ICIs in patients with recurrent or metastatic esophageal squamous cell carcinoma (ESCC). METHODS: Patients with ESCC who had measurable tumors in the liver, lung, or lymph node (LN) according to the response evaluation criteria in solid tumors (RECIST) 1.1 and received ICIs at 2 medical centers in Taiwan were enrolled. In addition to RECIST 1.1, tumor responses were determined per individual organ basis according to organ-specific criteria modified from RECIST 1.1. Fisher test or χ2 test was used for statistical analysis. RESULTS: In total, 37 patients were enrolled. The overall response rate per RECIST 1.1 was 13.5%. Measurable tumors in the LN, lung, and liver were observed in 26, 17, and 13 patients, respectively. The organ-specific response rates were 26.9%, 29.4%, and 15.4% for the LN, lung, and liver tumors, respectively (p = 0.05). The organ-specific disease control rates were 69.2%, 52.9%, and 21.1% for the LN, lung, and liver tumors, respectively (p = 0.024). Five (27.8%) among 18 patients harboring at least 2 involved organs had heterogeneous tumor response. CONCLUSION: The response and disease control to ICIs may differ in ESCC tumors located at different metastatic sites, with a lesser likelihood of response and disease control in metastatic liver tumors than in tumors located at the LNs and lung.

Phase II study of metabolic response to one-cycle chemotherapy in patients with locally advanced esophageal squamous cell carcinoma.

BACKGROUND: In the treatment of esophageal squamous cell carcinoma (ESCC), the optimal use of 18fluorodeoxyglucose positron emission tomography (PET) in measuring metabolic tumor response is undetermined. We launched a phase II trial to evaluate early metabolic response to one-cycle induction chemotherapy in patients with locally advanced ESCC. METHODS: ESCC patients in stage classification T3N0, N1M0, or M1a (American Joint Committee on Cancer, 6th edition) received one-cycle chemotherapy comprising paclitaxel, cisplatin, and 24-h infusional 5-fluorouracil and leucovorin on days 1 and 8, followed by neoadjuvant chemoradiotherapy, 40 Gy, with paclitaxel/cisplatin and then esophagectomy. PET was performed at baseline and day 14 of chemotherapy. The primary endpoint was pathologic complete response (pCR). We hypothesized early metabolic responders with >35% reduction in maximum standardized uptake value (SUVmax), would have better pCR Results. RESULTS: Sixty-six patients were enrolled. The median progression-free survival (PFS) and overall survival (OS) were 16 months (95% confidence interval [CI], 9-27) and 22 months (16-40), respectively. The early metabolic response rate was 55%; and the pCR rate was 34% in the esophagectomy population. The early metabolic response was not associated with pCR or survival. In an exploratory analysis, the postchemotherapy SUVmax was an independent prognostic factor for pCR, PFS, and OS. CONCLUSION: Our study failed to validate the predefined early metabolic response for pCR to neoadjuvant chemoradiotherapy in locally advanced ESCC patients. However, postchemotherapy SUVmax may be prognostic and predictive, and warrants further study.

Systematic review and network meta-analysis: neoadjuvant chemoradiotherapy for locoregional esophageal cancer.

OBJECTIVE: Neoadjuvant chemoradiotherapy improves survival in patients with locoregional esophageal cancer. This study compares the efficacy of two common regimens, paclitaxel plus platinum and platinum plus 5-fluorouracil, based on overall survival. METHODS: We performed a systematic review and network meta-analysis of randomized trials comparing paclitaxel plus platinum-neoadjuvant chemoradiotherapy or and platinum plus 5-fluorouracil-neoadjuvant chemoradiotherapy with surgery alone. The outcome was the hazard ratios for death in the entire population and the two major histologic subgroups, squamous cell carcinoma and adenocarcinoma. RESULTS: Ten clinical trials were included. Compared with surgery alone, the hazard ratios [95% credible interval (CrI)] in the entire, squamous cell carcinoma, and adenocarcinoma population were 0.63 (0.50-0.80), 0.50 (0.36-0.71) and 0.74 (0.54-1.01) for paclitaxel plus platinum, and 0.79 (0.68-0.92), 0.82 (0.67-1.01) and 0.81 (0.63-1.05) for platinum plus 5-fluorouracil, respectively. When paclitaxel plus platinum was compared with platinum plus 5-fluorouracil, the hazard ratios (95% CrI) in the entire, squamous cell carcinoma, and adenocarcinoma population were 0.80 (0.60-1.06), 0.61 (0.41-0.91) and 0.91 (0.61-1.36), respectively. The probability of paclitaxel plus platinum being ranked the optimal treatment for the entire, squamous cell carcinoma, and adenocarcinoma population was 94.2, 99.1 and 67.6%, respectively. CONCLUSIONS: Neoadjuvant chemoradiotherapy with paclitaxel plus platinum regimen seemed to be a better treatment than platinum plus 5-fluorouracil regimen for locoregional esophageal cancer, especially for squamous cell carcinoma.

Different immune contextures underlie tumor site-specific responses to immune checkpoint blockade in esophageal cancer.

Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in advanced esophageal squamous cell carcinoma (ESCC). Heterogeneous responses to ICIs have been reported previously. Here, we describe a patient with advanced ESCC exhibiting a response to durvalumab plus tremelimumab for more than 6 months except primary resistant esophageal tumor. The esophageal tumor had higher regulatory T cells, neutrophils, and mast cells scores estimated by NanoString platform than hepatic tumor. The immunohistochemistry study confirmed higher expression levels of Foxp3, and myeloperoxidase (MPO) in the esophageal tumor. The different immune contextures may underlie the heterogeneous responses to ICI combination in this ESCC patient.

Prognostication and optimal criteria of circumferential margin involvement for esophageal cancer after chemoradiation and esophagectomy.

Purpose: Circumferential radial margin (CRM) involvement by tumor after resection for esophageal cancer has been suggested as a significant prognostic factor. However, the prognostic value of CRM involvement after surgery with neoadjuvant concurrent chemoradiotherapy (CCRT) is unclear. This study aimed to evaluate the prognostic value of and survival outcomes in CRM involvement as defined by the Royal College of Pathologists (RCP) and the College of American Pathologists (CAP) for patients with esophageal cancer undergoing neoadjuvant CCRT and esophagectomy. Methods: A total of 299 patients with esophageal cancer who underwent neoadjuvant CCRT followed by esophagectomy between 2006 and 2016 were enrolled in our study. The CRM status of the specimens obtained was determined pathologically according to both the CAP and RCP criteria. Survival analyses were performed and compared according to the two criteria. Results: Positive CRM was found in 102 (34.1%) and 40 (13.3%) patients according to RCP and CAP criteria, respectively. The overall and progression-free survival rates were significantly lower in the CRM-positive group than in the CRM-negative group according to both the RCP and CAP criteria. However, under multivariate analysis, in addition to pathological T and N staging of the tumor, only CAP-defined CRM positivity was a significant prognostic factor with adjusted hazard ratios of 2.64 (1.56-4.46) and 2.25 (1.34-3.78) for overall and progression-free survival, respectively (P < 0.001). Conclusion: In patients with esophageal cancer undergoing neoadjuvant CRT followed by esophagectomy, CAP-defined CRM positivity is an independent predictor of survival. Adjuvant therapy should be offered to patients with positive CRM.

B Cells in Tumor Microenvironment Associated With The Clinical Benefit to Programmed Cell Death Protein-1 Blockade Therapy in Patients With Advanced Esophageal Squamous Cell Carcinoma.

Background: B cells and B cell-related gene signatures in the tumor microenvironment (TME) are associated with the efficacy of anti-programmed cell death-1 (anti-PD-1) therapy in several cancer types, but not known for esophageal squamous cell carcinoma (ESCC). Patients and Methods: Patients with advanced ESCC receiving anti-PD-1/PD-L1-based therapy were retrospectively included. A targeted RNA profiling of 770 immune-related genes from archival ESCC tissues was performed. Differential immune-related pathways and the levels of infiltrating immune cells were estimated through Gene Set Enrichment Analysis and CIBERSORT, respectively. CD19 and CD138 expression were evaluated through immunohistochemistry (IHC). The markers evaluated were correlated with clinical benefit (CB; defined as either objective response or stable disease for ≥6 months) and survival. Results: A total of 64 patients were enrolled. The transcriptome analysis based on 25 patients revealed that B cell signature was significantly increased in patients with CB (P <.05) and correlated with a longer PFS (P = .032) and OS (P = .013). Multiple genes representative of B cells, B cell functions, and plasma cells were upregulated in patients with CB. On further analysis of B cell subtypes in patients with CB, increase of naïve B cells (P = .057) and plasma cells (P <.01) was found but not memory B cells (P = .27). The CD19 expression in tumor stroma, detected by IHC, was higher in patients with CB (P = .033). Conclusion: B cells in the TME were associated with CB in patients with advanced ESCC receiving anti-PD-1/PD-L1-based therapy.

Prognostic value of PD-L1 expression on immune cells or tumor cells for locally advanced esophageal squamous cell carcinoma in patients treated with neoadjuvant chemoradiotherapy.

PURPOSE: Programmed death-ligand 1 (PD-L1) expression may influence the prognosis of patients with localized esophageal cancer. The current study compared the prognostic value of PD-L1 expression between tumor cells and immune cells. METHODS: Archival esophageal tumor tissue samples were collected from patients who received paclitaxel and cisplatin-based neoadjuvant chemoradiotherapy (CRT) for locally advanced esophageal squamous cell carcinoma (ESCC) in three prospective phase II trials. PD-L1 expression on tumor and immune cells was examined immunohistochemically by using the SP142 antibody and scored by two independent pathologists. The association of PD-L1 expression with patient's outcomes was analyzed using a log-rank test and Cox regression multivariate analysis. RESULTS: A total of 100 patients were included. PD-L1 expression on tumor cells was positive (≥ 1%, TC-positive) in 55 patients; PD-L1 expression on immune cells was high (≥ 5%, IC-high) in 30 patients. TC-positive status was associated with poor overall survival (OS) (HR: 1.63, P = 0.035), whereas IC-high status was associated with improved OS (HR: 0.44, P = 0.0024). Multivariate analysis revealed that TC-positive, IC-high, and performance status were independent prognostic factors for progression-free survival and that IC-high and performance status were independent factors for OS. Furthermore, the combination of IC-high and TC-negative status was associated with the optimal OS, whereas that of TC-positive and IC-low status was associated with the worst OS. CONCLUSION: PD-L1 expression on tumor and immune cells may have different prognostic value for patients with locally advanced ESCC receiving neoadjuvant CRT. A combination of these two indexes may further improve the prognostic prediction.

Neutrophil-to-lymphocyte Ratio and Use of Antibiotics Associated With Prognosis in Esophageal Squamous Cell Carcinoma Patients Receiving Immune Checkpoint Inhibitors.

BACKGROUND/AIM: This study explored the prognostic significance of the neutrophil-to-lymphocyte ratio (NLR) and use of antibiotics in advanced esophageal squamous cell carcinoma (ESCC) patients receiving immune checkpoint inhibitors (ICIs). PATIENTS AND METHODS: Patients were enrolled from two referral centers in Taiwan. Clinical benefit was defined as complete response, partial response, or a stable disease for ≥6 months via Response Evaluation Criteria In Solid Tumors 1.1. Clinicopathological factors' impact on overall survival (OS) and progression-free survival (PFS) was analyzed via Cox proportional hazards model. RESULTS: Forty-nine patients were enrolled. The median PFS and OS were 1.8 and 6.1 months, respectively. The median NLR at baseline was 6.40, and 21 patients received antibiotics. Both high NLR and use of antibiotics were associated with inferior PFS (p=0.028 and p<0.001, respectively) and OS (p<0.001 and p<0.001, respectively) in multivariate analysis. CONCLUSION: High NLR and use of antibiotics were associated with inferior survival in advanced ESCC patients receiving ICIs.

Weekly 24-hour infusional 5-fluorouracil as initial treatment for advanced gastric cancer with acute disseminated intravascular coagulation.

BACKGROUND: Acute disseminated intravascular coagulation (DIC) occurring in patients with advanced gastric cancer (AGC) is a rare entity with a dismal prognosis. Conventional cytotoxic chemotherapy is usually not possible. Preliminary reports have suggested that non-myelosuppressive weekly 24-h infusion of high-dose 5-fluorouracil (5-FU) and leucovorin (HDFL) may be helpful. PATIENTS AND METHODS: Between 1994 and 2005, AGC patients who presented with acute DIC and were initially treated with HDFL (5-FU 2600 mg/m2 plus leucovorin 300 mg/m2, 24-h infusion weekly) were reviewed. RESULTS: Nineteen such patients were identified. After treatment with HDFL for a median of 4 weeks, 14 patients showed a response of the acute DIC. Eight of them subsequently received HDFL-based combination chemotherapy. The median survivals for the whole group, the DIC responders, and the 8 patients receiving subsequent combination chemotherapy were 3, 6, and 8 months, respectively. CONCLUSION: HDFL, as a safe initial treatment for AGC patients with acute DIC, provides the opportunity for further aggressive chemotherapy.

Number of Resected Lymph Nodes and Survival of Patients with Locally Advanced Esophageal Squamous Cell Carcinoma Receiving Preoperative Chemoradiotherapy.

BACKGROUND: The association of extended lymph node (LN) dissection with improved outcomes in patients with locally advanced esophageal squamous cell carcinoma (ESCC) who received preoperative chemoradiotherapy (CRT) followed by surgery is debatable. PATIENTS AND METHODS: We reviewed data from patients with esophageal cancer enrolled in three phase II clinical trials of preoperative paclitaxel and cisplatin-based CRT during 2000-2012. Patients with ESCC who underwent planned esophagectomy were enrolled. The number of resected LNs and other clinicopathological factors were analyzed regarding their impact on progression-free (PFS) and overall (OS) survival using Cox proportional hazards model. RESULTS: In total, 139 patients were included. The median PFS and OS were 24.4 and 31.8 months, respectively. The median number of resected and positive LNs were 19 (range=2-96) and 0 (range=0-9), respectively. The mean number of positive LNs did not differ significantly among quartile groups of total resected LNs (quartile 1: 2-12, 2: 13-19, 3: 20-29, and 4: 30-96). The resected LN number analyzed as dichotomies divided by the median or as continuous variables was not associated with PFS or OS. However, in an exploratory analysis, patients of quartiles 2 and 3 had longer PFS and OS than those with quartiles of 1 and 4 in multivariate analysis (p=0.019 and 0.005, respectively). CONCLUSION: Although extensive LN dissection was not associated with improved survival, resection of 13-29 LNs was associated with improved survival in patients with locally advanced ESCC receiving preoperative paclitaxel and cisplatin-based CRT.

Postchemoradiotherapy Pathologic Stage Classified by the American Joint Committee on the Cancer Staging System Predicts Prognosis of Patients with Locally Advanced Esophageal Squamous Cell Carcinoma.

INTRODUCTION: To determine whether the postchemoradiotherapy (post-CRT) pathologic stage predicts the outcomes of patients with locally advanced esophageal squamous cell carcinoma (ESCC) undergoing preoperative CRT followed by surgery. METHODS: From three phase II trials of preoperative CRT for locally advanced ESCC, 140 patients were included. Preoperative CRT comprised twice weekly paclitaxel and cisplatin-based regimens and 40-Gy radiotherapy in 20 fractions. The post-CRT pathologic stage was classified according to the American Joint Committee on Cancer, 7th edition staging system. The prognostic effects of clinicopathologic factors were analyzed using Cox regression. RESULTS: With a median follow-up of 61.9 months, the median progression-free survival (PFS) and overall survival (OS) of the entire cohort were 24.5 and 30.9 months, respectively. The post-CRT pathologic stage was 0 in 34.5%, I in 12.9%, II in 29.3%, III in 13.6%, and ypT0N1-2 in 6.4% of the patients. The median PFS was 47.2, 25.9, 16.0, 9.4, and 15.1 months, and the median OS was 57.4, 34.1, 26.2, 14.1, and 17.6 months for patients with post-CRT pathologic stage 0, I, II, III, and ypT0N1-2, respectively. In multivariate analysis, performance status (p < 0.001), tumor location (p = 0.016), and extranodal extension (p = 0.024) were independent prognostic factors for PFS, whereas performance status (p < 0.001) and post-CRT pathologic stage (p = 0.027) were independent prognostic factors for OS. CONCLUSIONS: The post-CRT pathologic stage classified by American Joint Committee on Cancer, 7th edition staging system predicted the survival of locally advanced ESCC patients who underwent preoperative paclitaxel and cisplatin-based CRT followed by esophagectomy.

Prognostic factors of metastatic or recurrent esophageal squamous cell carcinoma in patients receiving three-drug combination chemotherapy.

BACKGROUND: Three-drug combination therapy based on cisplatin/fluorouracil might improve treatment efficacy for metastatic esophageal squamous cell carcinoma (ESCC), but at the risk of increasing toxicity. The study sought to identify factors associated with outcomes of metastatic ESCC in patients who were treated with three-drug combinations. PATIENTS AND METHODS: One-hundred and thirteen patients with metastatic or recurrent ESCC who were treated with cisplatin/fluorouracil-based three-drug combination during 2000-2009 were studied. The prognostic impact of clinicopathological characteristics were evaluated by Cox proportional hazard regression analyses. RESULTS: The third chemotherapeutic agents comprised of paclitaxel, docetaxel, and methotrexate in 76 (67%), 13 (12%), and 24 (21%) of patients, respectively. The overall response rate was 41%. The median overall survival (OS) was 8.5 months. Results of the Cox proportional hazard regression models showed that age ≥65 years, Eastern Cooperative Oncology Group performance status of 0 and 1, lymph node-only metastasis and baseline white blood cell (WBC) count ≤10,000/mm(3) were significant prognostic factors for better OS. The OS curves were significantly separated by risk groups comprising of age, metastasis status and WBC count as risk factors. CONCLUSION: The identification of prognostic factors could facilitate for future design of randomized studies on the efficacy of three-drug combinations for metastatic ESCC.

Comparison of weekly versus every 3 weeks paclitaxel in the treatment of advanced solid tumors: a meta-analysis.

BACKGROUND: Paclitaxel is commonly given as a 3-h infusion every 3 weeks for a variety of malignancies. Several randomized clinical trials comparing weekly paclitaxel with Q3-week (Q3W) have produced mixed results in terms of efficacy and toxicity creating controversy about the ideal dose and schedule. METHODS: A literature search using PubMed, Cochrane Library, and Proceedings of the American Society of Clinical oncology from 1995 to 2011 was performed. We included all published and registered RTCs for advanced solid tumors which compared weekly paclitaxel with Q3W. Primary dependent variables--grade 3, 4 neutropenia rates and grade 3 sensory neuropathy rates--were analyzed for all cancer types. Secondary dependent variables--hazard ratios for survival and response rates--were analyzed for each cancer type. Moderators of cancer types, ethnicity, and paclitaxel dose ratio were analyzed for primary dependent variables. RESULTS: Ten trials were included. The summary effects of the meta-analysis revealed less grade 3, 4 neutropenia (odds ratio: 0.49, p=0.0023) and a trend towards less grade 3 sensory neuropathy (odds ratio: 0.54, p=0.092) with weekly paclitaxel compared with Q3W. Moderator analysis by meta-regression revealed that paclitaxel dose ratios have a significantly positive correlation with rates of G3/4 neutropenia and sensory neuropathy. In the five NSCLC (non small cell lung cancer) trials, the summary effect revealed a better response rate with weekly paclitaxel (odds ratio: 1.24, p=0.042). CONCLUSION: Weekly paclitaxel has a favorable toxicity profile compared to the current standard of Q3W paclitaxel.