Advanced Thoracic Esophageal Squamous Cell Research Articles

Propensity-matched study on locally advanced esophageal cancer: surgery versus post-operative radiotherapy

BackgroundThis study aims to delineate the long-term outcomes and recurrence patterns of locally advanced thoracic esophageal squamous cell carcinoma (TESCC) patients managed with or without postoperative radiotherapy (PORT).MethodsA retrospective cohort from two academic centers, encompassing patients who initially underwent esophagectomy and were pathologically staged T3-4, was analyzed. Survival outcomes were constructed using Kaplan–Meier method, with survival significance was evaluated using the log-rank test. Propensity score matching (PSM) was utilized to balance potential selection bias.ResultsAmong the 506 patients, 251 underwent surgery alone and 255 received radiotherapy following radical surgery. With a median follow-up of 49.1 months, PORT significantly improved 5-year overall survival (53.8% vs. 25.3%; p < 0.001) and 5-year disease-free survival rates (45.3% vs. 8.5%; p < 0.001) compared to surgery alone. These differences in survival outcomes persisted even after PSM (p < 0.001 for both). Treatment failure was significantly less frequent in the PORT group (46.7%) compared to the surgery-only group (90.0%; p < 0.001), with corresponding reductions in locoregional recurrence (9.4% vs. 54.1%; p < 0.001). This underscores the significant association between PORT and disease control.ConclusionThe absence of neoadjuvant chemoradiotherapy highlights the importance of PORT in improving survival and reducing recurrence in advanced T3-4 TESCC patients. This study underscores the importance of PORT as a salvage treatment for locally advanced TESCC patients without neoadjuvant chemoradiotherapy.

Concurrent chemoradiotherapyof different radiation doses and different irradiation fields for locally advanced thoracic esophageal squamous cell carcinoma: A randomized, multicenter, phase III clinical trial.

Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC). However, the optimal radiotherapy regimen, particularly in terms of total dose and planned range of irradiation field, remains unclear. This phase III clinical trial aimed to compare the survival benefits between different radiation doses and different target fields. This trial compared two aspects of radiation treatment, total dose and field, using a two-by-two factorial design. The high-dose (HD) group received 59.4Gy radiation, and the standard-dose (SD) group received 50.4 Gy. The involved field irradiation (IFI) group and elective nodal irradiation (ENI) group adopted different irradiation ranges. The participants were assigned to one of the four groups (HD+ENI, HD+IFI, SD+ENI and SD+IFI). The primary endpoint was overall survival (OS), and the secondary endpoints included progression-free survival (PFS). The synergy indexwas used to measure the interaction effect between dose and field. The interaction analysis did not reveal significant synergistic effects between the dose and irradiation field. In comparison to the target field, patients in IFI or ENI showed similar OS (hazard ratio [HR] = 0.99, 95% CI: 0.80-1.23, p = 0.930) and PFS (HR = 1.02, 95% CI: 0.82-1.25). The HD treatment did not show significantly prolonged OS compared with SD (HR = 0.90, 95% CI: 0.72-1.11, p = 0.318), but it suggested improved PFS (25.2 months to 18.0 months). Among the four groups, the HD+IFI group presented the best survival, while the SD+IFI group had the worst prognosis. No significant difference in the occurrence of severe adverse events was found in dose or field comparisons. IFI demonstrated similar treatment efficacy to ENI in CCRT of ESCC. The HD demonstrated improved PFS, but did not significantly improve OS. The dose escalation based on IFI (HD+IFI) showed better therapeutic efficacy than the current recommendation (SD+ENI) and is worth further validation.

Survival benefits of adjuvant chemotherapy for patients with residual pathologic disease after neoadjuvant chemotherapy and surgery for locally advanced esophageal squamous cell carcinoma

Background and purposeAlthough preoperative neoadjuvant chemotherapy (NACT) or chemoradiation is the current standard of care for esophageal cancer in China, the impact of subsequent adjuvant therapy on patient prognosis remains unknown. This study aims to analyze the effect of adjuvant chemotherapy (ACT) on the survival rates of patients who have achieved a non-pathological complete response (non-pCR) after NACT and subsequent surgery. MethodsWe reviewed the data of 2193 patients with locally advanced thoracic esophageal squamous cell carcinoma (ESCC) who underwent radical surgery between January 2006 and January 2016. Of these patients, 46 received NACT and ACT, while 109 received NACT only. Propensity score matching was used to compare 86 patients, with 43 patients in the NACT+ACT group and 43 patients in the NACT group.Univariate analysis was performed using the Kaplan-Meier method and Log-rank test, while Cox regression analysis was used for multivariate analysis. ResultsMultivariate analysis revealed that pathological lymph node status (positive vs. negative) (P<0.001) and treatment modalities (NACT+ACT vs. NACT) (P=0.005) were independent prognostic factors. There was a significant difference in long-term survival rates between the NACT+ACT and NACT groups, with 5-year survival rates of 55.8% vs. 39.5%, respectively (c2=4.270, P=0.039). In patients with ypN+ status, the 5-year survival rate was 31.8% for those who received ACT after NACT and surgery, compared to 10.0% for those who did not receive additional ACT (c2=6.101, P=0.014). The corresponding percentages in patients with ypN- were 81.0% and 65.2%, respectively (c2=1.993, P=0.158). ConclusionAdjuvant chemotherapy should be recommended for locally advanced ESCC patients with residual cancer after NACT and surgery, especially for patients with nodal metastases after NACT.

A 35-gene mutation profile predicts the therapeutic outcome of patients with esophageal squamous cell carcinoma receiving neo-adjuvant chemoradiation.

Esophageal cancer is a common malignancy worldwide with a poor prognosis without radical resection. Neoadjuvant concurrent chemoradiotherapy (NACRT) followed by esophagectomy is widely used for treating locally advanced esophageal cancer in the thorax. The study aimed to assess mutation profiles and their correlation with therapeutic outcomes in patients diagnosed with locally advanced thoracic esophageal squamous cell carcinoma (ESCC). A retrospective analysis was conducted on 62 patients with ESCC who underwent NACRT. All patients received concurrent chemoradiotherapy (CCRT) utilizing intensity-modulated radiation therapy alongside concurrent chemotherapy with a cisplatin-based regimen. A 35-gene next-generation sequencing (NGS) panel detecting 402 genetic variants was used, which has been proven predictive in ESCC patients who received definitive chemoradiation. The 35-gene mutation profiles were analyzed in pre-treatment biopsies. The results reveled there were variants correlated with pathological complete remission or partial response, overall survival, and progression-free survival. A combination of p.Pro1319Ser and p.Arg2159Gly mutations in the MUC17 gene demonstrated an adverse impact on pathological response (OR [95% CI] = 7.00 (3.07-15.94), P < 0.001). Additionally, the variants located in the MUC17, MUC4, and MYH4 genes exhibited notably effects on tumor recurrence or mortality. Patients harboring either the MUC17 p.Thr2702Val or MUC4 p.Thr3355Ser mutation displayed a more than four-fold increased risk for disease recurrence or mortality. We concluded that specific mutations correlated to the pathological complete response in ESCC receiving neoadjuvant chemoradiation can be identified through the utilization of 35-gene expression profiles. Further investigation into the pathophysiological roles of MUC17 and MUC4 mutations in ESCC is warranted.

High TLR6 Expression Status Predicts a More Favorable Prognosis after Esophagectomy for Locally Advanced Thoracic Esophageal Squamous Cell Carcinoma.

Most so-called "beneficial bacteria" in gut microbiota are Gram-positive, and TLR6 recognizes the peptidoglycan (PGN) present in their cell walls. We hypothesized that a high TLR6 expression status predicts a more favorable prognosis after esophagectomy. We used an ESCC tissue microarray (TMA) to examine TLR6 expression status in ESCC patients and to determine whether TLR6 expression status correlates with prognosis after curative esophagectomy. We also examined whether PGN influences the cell proliferation activity of ESCC lines. Clinical ESCC samples from 177 patients tested for the expression of TLR6 were categorized as 3+ (n = 17), 2+ (n = 48), 1+ (n = 68), or 0 (n = 44). High TLR6 expression (3+ and 2+) correlated with significantly more favorable 5-year overall survival (OS) and disease-specific survival (DSS) after esophagectomy than a lower TLR6 expression (1+ and 0). Univariate and multivariate analyses showed that TLR6 expression status is an independent prognostic factor that affects 5-year OS. PGN significantly inhibited the cell proliferation activity of ESCC lines. This is the first study to show that high TLR6 expression status predicts a more favorable prognosis in locally advanced thoracic ESCC patients after curative esophagectomy. PGN released from "beneficial bacteria" seems to have potential to inhibit the cell proliferation activity of ESCC.

Microscopic venous invasion is a predictor of prognosis in patients with esophageal squamous cell carcinoma undergoing ineffective neoadjuvant chemotherapy and surgery.

Neoadjuvant chemotherapy followed by surgery is Japan's most effective treatment modality for advanced thoracic esophageal squamous cell carcinoma. However, the prognosis is not as expected. This study aimed to examine prognostic factors in patients with pathologically ineffective neoadjuvant chemotherapy followed by surgery for esophageal squamous cell carcinoma. We retrospectively analyzed patients who underwent neoadjuvant chemotherapy followed by curative esophagectomy for esophageal squamous cell carcinoma between December 2008 and July 2021. The patients were divided into the neoadjuvant chemotherapy effective group and the neoadjuvant chemotherapy ineffective group according to the pathological diagnosis. Clinicopathological data, prognosis, and recurrence were analyzed. A total of 143 patients (121 males, 22 females; median age, 67years) were included in this study. Of these, 34 patients were classified into the effective group and the remaining 109 patients were assigned to the ineffective group. The ineffective group had significantly worse overall survival and recurrence-free survival than the effective group (p = 0.0192 and p = 0.0070, respectively). In the ineffective group, multivariate analysis demonstrated that microscopic venous invasion was an independent prognostic factor for overall survival (hazard ratio 2.44; 95% confidence interval 1.13-5.30) and recurrence-free survival (hazard ratio 2.43; 95% confidence interval 1.24-4.73). Microscopic venous invasion was associated with poor survival and cancer recurrence in the neoadjuvant chemotherapy ineffective group of patients who underwent esophagectomy for esophageal squamous cell carcinoma.

Multimodal Treatment Strategies to Improve the Prognosis of Locally Advanced Thoracic Esophageal Squamous Cell Carcinoma: A Narrative Review.

Esophageal cancer is the seventh most common malignancy and sixth most common cause of cancer-related death globally. Esophageal squamous cell carcinoma (ESCC) with aortic or tracheal invasion is considered unresectable, and has an extremely poor prognosis; its standard treatment is definitive chemoradiotherapy (dCRT). In recent years, induction chemotherapy (ICT) has been reported to yield high response rates for locally advanced ESCC, and the efficacy and safety of ICT followed by conversion surgery (CS) have been investigated. Multimodal treatment, combining surgery with induction chemoradiotherapy (ICRT) or ICT, is necessary to improve ESCC prognosis. CS is generally performed for locally advanced ECC after ICRT or ICT when tumor downstaging is achieved, although its prognostic benefit remains controversial. The Japan Clinical Oncology Group (JCOG) has conducted a three-arm phase III randomized controlled trial (JCOG1510) to confirm the superiority of DCF (docetaxel, cisplatin, and 5-fluorouracil) ICT, over conventional dCRT, among patients with initially unresectable ESCC. In recent years, researchers have reported favorable outcomes of induction therapy followed by CS and salvage surgery, after dCRT or systemic immunochemotherapy. In this review, we will describe the latest developments in the multimodal treatment including chemotherapy, CRT, surgery, and immunotherapy, which may improve oncological and survival outcomes for patients with cT4 ESCC.

Postoperative Concurrent Chemoradiotherapy for Locally Advanced Thoracic Esophageal Squamous Cell Carcinoma: A Phase II Clinical Trial.

BackgroundThis study aims to investigate the efficacy and safety of postoperative intensity-modulated radiotherapy (IMRT) covering partial regional lymph node areas combined with chemotherapy for locally advanced thoracic esophageal squamous cell carcinoma patients.MethodsThis was a single-center, single-arm phase II clinical trial that began in 2014. Patients who underwent radical transthoracic resection within 3 months and were histologically confirmed esophageal squamous cell carcinoma (pT3-4 or N+, M0 determined according to AJCC Guidelines, Edition 7) were recruited. Postoperative radiotherapy was performed with a total dose of 50.4Gy in 28 fractions using IMRT. Clinical target volumes (CTVs) included tumor bed, anastomosis, bilateral supraclavicular region, and superior mediastinal lymph nodes. Synchronous chemotherapy for 2 cycles (paclitaxel 150mg/m2, day1; Cisplatin 25mg/m2, day1-3; every 4 weeks), followed by 2 cycles of consolidation chemotherapy with the same regimen. The primary endpoint was the 2-year local control rate, and the secondary endpoints were overall survival (OS) and adverse events (AEs).ResultsA total of 75 eligible patients were included from 2014 to 2017. The 2-year LRFS rate, as the primary endpoint, was 73.3%. The 1-year and 3-year OS rates were 88.0% and 68.0%, respectively. Local recurrence occurred in 13/75 (17.4%) patients, of which 2.7% (2/75) were extra-target lymph nodes. Grade 4 adverse events reported in this study included 10 cases (13.3%) of neutropenia, 1 case (1.3%) of anemia, and 2 cases (2.7%) of thrombocytopenia, without toxic-related deaths. Almost all (96%) patients completed the entire postoperative radiotherapy course, and 62 (82.7%) patients completed at least 2 cycles of chemotherapy.ConclusionPostoperative IMRT (clinical target volume including tumor bed, anastomosis, bilateral supraclavicular region, and superior mediastinal lymph nodes) combined with synchronous chemotherapy in patients with locally advanced thoracic esophageal squamous cell carcinoma was well tolerated, with a high local control rate and a low probability of recurrence outside the irradiation field.Clinical Trial Registration https://clinicaltrials.gov/ChiCTR1900022689.

Phase Ib trial of camrelizumab combined with chemotherapy and apatinib for neoadjuvant treatment of locally advanced thoracic esophageal squamous cell carcinoma

This is a prospective, single-arm, phase Ib study to evaluate the safety and efficacy of camrelizumab combined with chemotherapy and apatinib as neoadjuvant therapy for locally advanced thoracic esophageal squamous cell carcinoma (ESCC). The regimen encompassed 2-4 cycles of neoadjuvant camrelizumab, nab-paclitaxel, nedaplatin, and apatinib to treatment-naive patients with resectable locally advanced ESCC. The treatment was repeated every 14 days. Initially, six patients were planned to receive two cycles of neoadjuvant therapy as safety assessment, and then 24 patients received four cycles of neoadjuvant therapy, followed by esophagectomy after 4-8 weeks. The primary endpoint was safety. The key secondary endpoints were pathologic complete response (pCR) and major pathologic response (MPR). This study enrolled 30 patients, among whom, five patients received two cycles of neoadjuvant therapy, and one patient missed the second cycle of therapy due to grade 3 elevated alanine transaminase (ALT) level. The remaining 24 patients received four planned cycles of neoadjuvant therapy. Eleven patients (36.7%) developed grade 3 neoadjuvant treatment-related adverse events (TRAEs). No patient developed grade 4 or 5 TRAEs. Neutropenia (23.3%) was the most common grade 3 TRAE. Twenty-nine patients underwent esophagectomy after neoadjuvant therapy. Among them, 15 patients (51.7%) achieved MPR, including seven patients with pCR (24.1%). Radiographic analyses established a significant correlation between maximal standardized uptake value (SUVmax) reduction and pathologic regression (P=0.00095). Neoadjuvant camrelizumab combined with chemotherapy plus apatinib demonstrated a manageable safety profile for patients with locally advanced ESCC, and an encouraging efficacy was observed in most of the treated patients. A decrease in SUVmax of the primary tumor may be a predictor of pathologic response to neoadjuvant camrelizumab combined with chemotherapy plus apatinib in ESCC.

Crosstalk between the gut microbiome and clinical response in locally advanced thoracic esophageal squamous cell carcinoma during neoadjuvant camrelizumab and chemotherapy.

BackgroundThe gut microbiome is associated with the response to immunotherapy in a variety of advanced cancers. However, the influence of the gut microbiome on locally advanced esophageal squamous cell carcinoma (ESCC) during programmed cell death protein 1 (PD-1) antibody immunotherapy plus chemotherapy is not clearly demonstrated. To explore the crosstalk between the gut microbiome and clinical response in locally advanced thoracic ESCC during neoadjuvant camrelizumab and chemotherapyMethodsPatients who were diagnosed with locally advanced thoracic ESCC and had not received treatment were enrolled. The treatment regimen was two cycles of camrelizumab combined with carboplatin and albumin paclitaxel before surgery. The research endpoints were pathological complete response (pCR) and major pathological response (MPR). Fecal samples were collected at three time points: before neoadjuvant therapy, after two cycles of neoadjuvant therapy, and after surgery. We performed 16S ribosomal ribonucleic acid (rRNA) V3–V4 sequencing of the gene amplicons of fecal samples, as well as bacterial diversity and differential abundance analyses.ResultsA total of 46 patients were recruited, and 44, 42, and 35 fecal samples were collected at the three time points, respectively. Statistically significant differences were observed in the amplicon sequence variant (ASV)-level alpha diversity indices, including Chao1, Shannon, and Good’s coverage, between the three time points. The non-pCR-enriched gut microbiota included Proteobacteria, Dialister, Aeromonadales, Pseudomonadales, Thermi, Deinococci, Moraxellaceae, Rhodocyclales, Rhodocyclaceae, and Acinetobacter. The non-MPR-enriched gut microbiota included Pseudomonadales and the mitochondria family. The MPR-enriched gut microbiota included the Barnesiellaceae, Pyramidobacter, Dethiosulfovibrionaceae, Odoribacteraceae, Butyricimonas, Prevotella, Barnesiella, and Odoribacter. Patients with ≥3 grade adverse events (AEs) exhibited enrichment in the Succiniclasticum, Nakamurella, Rhizobium, Granulicella, Phyllobacteriaceae, Pelagibacteraceae, Actinosynnemataceae, Aquirestis, Flavisolibacter, Chelativorans, Coxiellaceae Acidicapsa, Acidobacteriaceae, Lentzea, Staphylococcus, Plesiomonas, Dysgonomonas, Pseudonocardia, and Ellin6075.ConclusionsWe found that the diversity of the gut microbiome declined after neoadjuvant PD-1 antibody immunotherapy plus chemotherapy and surgery. Patients with pCR had different types and proportions of gut microbiota before treatment compared to those without pCR. We also observed the difference between patients with or without ≥ grade 3 AEs. The taxonomic features of the gut microbiome are potential biomarkers that could predict the pathological response and AEs.

The efficacy and safety of neoadjuvant camrelizumab and chemotherapy for locally advanced thoracic esophageal squamous cell carcinoma.

278 Background: To explore the efficacy and safety of neoadjuvant camrelizumab and chemotherapy for locally advanced thoracic esophageal squamous cell carcinoma (ESCC) by an open label, single-arm, phase 2 clinical trial (ClinicalTrials.gov, Identifier number: NCT04506138). Methods: The eligible patients were arranged to receive 2 cycles of camrelizumab (200mg, day 1) combined with carboplatin (AUC = 5, day 1) and albumin paclitaxel (100 mg/m2, day 1, 8). All treatments were given intravenously in 3-week cycle. Patients underwent surgery within 4-6 weeks after the completion of neoadjuvant treatment. The primary endpoint was pathologic complete response (pCR), and secondary endpoints were major pathological response (MPR), safety and feasibility. The quality of life (QoL) was assessed by the Functional Assessment of Cancer Therapy-Esophageal (FACT-E) scale and EQ-5D-3L scale. Results: A total of 46 patients were recruited, among whom the clinical stage II, III, and IVa at baseline were 11 (23.9%), 33 (71.7%), and 2 (4.3%), respectively. Forty-five patients completed 2 cycles of neoadjuvant treatment. One patient received 1 cycle of neoadjuvant treatment and then lost to be followed up. Eight patients did not receive surgery. Except 1 patient accept exploratory surgery, 37 patients (37/46, 80.4%) achieved R0 resection. Eight patients (8/37, 21.6%) had pCR in both primary tumors and lymph nodes. MPR of primary tumors and lymph nodes was observed in 18 patients (18/37, 48.6%). During neoadjuvant treatment period, all 46 patients presented with treatment-related AEs (TRAEs) of any grade. Seven patients (7/46,15.2%) experienced grade ≥ 3 TRAEs. One patient suffered grade 5 immune-associated pneumonia. The most common TRAEs were anemia (32/46, 70.0%), followed by thrombocytopenia (15, 32.6%), leukopenia (14, 30.4%), neutropenia (13, 28.3%), rash (12, 26.1%), reactive cutaneous capillary endothelial proliferation (RCCEP) (7, 15.2%). The median interval between the first cycle of neoadjuvant treatment and surgery was 64 days (range, 56-77 days). Symptom scores in FACT-E scale were improved by neoadjuvant treatment (t = -2.60, P = 0.01). PD-L1 CPS (&lt; 10 vs ≥ 10), PD-L1 TPS (&lt; 1% vs ≥ 1%) and TMB (split according to top 20% of TMB value) had no effect on the pCR rate and MPR rate. Conclusions: Neoadjuvant camrelizumab combined with chemotherapy achieved a promising pathologic response, which was effective and safe. Meanwhile, neoadjuvant treatment improved QoL of patients. Some larger multi-center trials are undergoing for further confirmation of efficacy and safety. Clinical trial information: NCT04506138.

Long-Term Treatment Outcomes of the Elder Patients with Locally Advanced Thoracic Esophageal Squamous Cell Carcinoma with Definitive Chemoradiotherapy or Radiotherapy.

Background Few randomized trials are available to guide clinical management of elderly patients with esophageal cancer. Therefore, treatment approaches for the elderly are challenging. Objective We believe that chemotherapy and radiotherapy are more effective than radiotherapy alone. We envision that chemotherapy is more effective than radiotherapy alone in elderly patients with esophageal cancer. Methods Retrospective data of patients aged 70 years and older from 2008 to 2015 at our institution were analyzed. Of 61 eligible patients, 32 received definitive CTR and 29 received RT alone. Progression-free survival (PFS) was 16 months (range, 1–67 months), and the median overall survival was 19 months. Median PFS and OS in the chemoradiotherapy group were 17 months (95% confidence interval (CI), 15.1–24.8 months) and 22 months (95% confidence interval (CI), 20.4–32.7 months), respectively. Results The median PFS and OS in the radiotherapy group were 16 months and 16 months, respectively. The OS rates at 1, 2, 3, and 5 years were 82%, 42.6%, 19.7%, and 6.6%, respectively. There was no difference in PFS between CRT and RT, but there was an advantage in OS for CRT. Positive nodules had an effect on PFS and OS. Conclusions CRT is effective in elderly patients with nodal invasion of esophageal cancer. Higher radiation doses had an effect on PFS and OS, but there was no difference in PFS and OS between CRT and RT. Therefore, treatment approaches for the elderly are challenging.

Outcomes of esophagectomy for patients with esophageal squamous cell carcinoma accompanied by recurrent laryngeal nerve palsy at diagnosis

BackgroundHoarseness is one of the classical symptoms in patients with locally advanced thoracic esophageal squamous cell carcinoma (ESCC), and it results from recurrent laryngeal nerve palsy, which is caused by nodal metastasis along the recurrent laryngeal nerve or by main tumors. We reviewed the short-term and long-term results of esophagectomy for patients with locally advanced ESCC and hoarseness at diagnosis.PatientsPatients who initially presented with hoarseness from recurrent laryngeal nerve palsy between 2009 and 2018 and underwent esophagectomy for thoracic ESCC were eligible for this study. Pharyngolaryngectomy or cervical ESCC were exclusionary.ResultsA total of 15 patients were eligible, and 14 underwent resection of the recurrent laryngeal nerves. The remaining patient had nerve-sparing surgery. Nine patients (60%) had post-operative complications ≥ Clavien–Dindo class II and, pulmonary complications were most common. Two patients (13%) died in the hospital. The 5-year overall survival rate for all patients was 16%. Age (≤ 65 years), cT1/T2 tumor, and remarkably good response to neoadjuvant treatment were likely related to longer survival; however, these relationships were not statistically significant.ConclusionsEsophagectomy for ESCC patients who are diagnosed with recurrent laryngeal nerve paralysis at initial presentation could be a treatment option if the patient is relatively young, has a cT1/T2 tumor, or shows a remarkably good response to neoadjuvant treatment. However, clinicians should be aware of the possibility of postoperative pulmonary complications, which were frequently observed with the procedure.

3D Deep Learning Model for the Pretreatment Evaluation of Treatment Response in Esophageal Carcinoma: A Prospective Study (ChiCTR2000039279)

To develop and validate a pretreatment computed tomography (CT)-based deep-learning (DL) model for predicting the treatment response to concurrent chemoradiation therapy (CCRT) among patients with locally advanced thoracic esophageal squamous cell carcinoma (TESCC). We conducted a prospective, multicenter study on the therapeutic efficacy of CCRT among TESCC patients across 9 hospitals in China (ChiCTR2000039279). A total of 306 patients with locally advanced TESCC diagnosed by histopathology from August 2015 to May 2020 were included in this study. A 3-dimensional DL radiomics model (3D-DLRM) was developed and validated based on pretreatment CT images to predict the response to CCRT. Furthermore, the prediction performance of the newly developed 3D-DLRM was analyzed according to 3 categories: radiation therapy plan, radiation field, and prescription dose used. The 3D-DLRM achieved good prediction performance, with areas under the receiver operating characteristic curve of 0.897 (95% confidence interval, 0.840-0.959) for the training cohort and 0.833 (95% confidence interval, 0.654-1.000) for the validation cohort. Specifically, the 3D-DLRM accurately predicted patients who would not respond to CCRT, with a positive predictive value (PPV) of 100% for the validation cohort. Moreover, the 3D-DLRM performed well in all 3 categories, each with areas under the receiver operating characteristic curve of >0.8 and positive predictive values of approximately 100%. The proposed pretreatment CT-based 3D-DLRM provides a potential tool for predicting the response to CCRT among patients with locally advanced TESCC. With the help of precise pretreatment prediction, we may guide the individualized treatment of patients and improve survival.

The Prognosis and Feasibility of Extensive Clinical Target Volume in Postoperative Radiotherapy for Esophageal Squamous Cell Carcinoma: A Phase II Clinical Trial

BackgroundThis trial aims to explore the feasibility and safety of postoperative radiotherapy covering all regional lymph node areas for locally advanced thoracic esophageal squamous cell carcinoma patients treated with intensity-modulated radiation therapy (IMRT).MethodsThis was a single-center single-arm, phase II clinical trial initiated in 2014. Patients who were treated with radical transthoracic resection and had negative margins within 3 months and histologically confirmed esophageal squamous cell carcinoma (pT3-4 or N+, M0 determined by the 7th edition of the AJCC guidelines) were recruited in this trial. Postoperative radiotherapy was performed with a total dose of 40 Gy in 20 fractions using IMRT. Clinical target volumes (CTVs) included the tumor bed, anastomosis, bilateral supraclavicular region, mediastinal lymph nodes, left gastric lymph nodes and celiac trunk lymph nodes. The primary endpoint was the 2-year local control rate, and the secondary endpoints were overall survival (OS) and adverse events (AEs).ResultsA total of 70 eligible patients were recruited from 2014 to 2016. The 2-year local control rate, as the primary endpoint, was 67.3%. In addition, the median OS was 57.0 months, with 1-year and 3-year OS rates of 92.8% and 60.9%, respectively. Among the patients, 28/40 (40%) developed locoregional recurrence, with 25.7% involving hematogenous recurrences. All reported AEs occurred during the course of IMRT or within 6 months thereafter. None of them suffered grade 4 hematological or nonhematological AEs. Nearly all patients completed the entire course of postoperative radiotherapy, with a completion rate of 97.1%.ConclusionFor an extensive target volume, 40 Gy is feasible and shows acceptable toxicity in patients with locally advanced thoracic esophageal squamous cell carcinoma, although the local recurrence rate is relatively high. Our findings provide a basis for further exploration of high-dose radiation with extensive CTV combined with chemotherapy.Clinical Trial Registration[http://www.clinicaltrials.gov/ct2/results?cond=&term=NCT02384811&cntry=&state=&city=&dist=], identifier [NCT02384811].

Neoadjuvant camrelizumab combined with chemotherapy and apatinib for locally advanced thoracic esophageal squamous cell carcinoma (ESCC): A single-arm, open-label, phase Ib study.

4047 Background: Neoadjuvant therapy with PD-1 blockade plus chemotherapy has been found to be effective in the first-line treatment of advanced esophageal cancer. However, evidence of PD-1 blockade combined with chemotherapy as neoadjuvant treatment is limited. This study was designed to investigate the safety and efficacy of camrelizumab, a PD-1 blockade combined with chemotherapy and apatinib as neoadjuvant therapy for locally advanced esophageal squamous cell carcinoma (ESCC). Methods: A regiment of 2–4 cycles of neoadjuvant camrelizumab (200 mg, intravenous, day 1), nab-paclitaxel (150 mg/m2, intravenous, day 1), nedaplatin (50 mg/m2, intravenous, day 1), and apatinib (250 mg, orally, day 2–4) was given to the treatment-naive patients with resectable locally advanced ESCC. The treatments were repeated every 14 days. In this study, six patients were planned to receive two cycles of neoadjuvant therapy as safety assessment, and then 24 patients received four cycles of neoadjuvant therapy, followed by esophagectomy after 4–8 weeks. The primary end points were safety and feasibility. The secondary end points were the rate of major pathologic response (MPR) and pathologic complete response rate (pCR). Results: A total of 30 patients were enrolled, among them, five patients received two planned cycles of neoadjuvant therapy, and one patient missed the second cycle of therapy due to grade 3 ALT elevations. Further, all other 24 patients received four planned cycles of neoadjuvant therapy. A total of 11 patients (11/30, 36.7%) experienced grade 3 neoadjuvant treatment-related adverse events (TRAEs). No grade 4 and grade 5 TRAEs were reported. The most frequent grade 3 TRAEs was neutropenia (7/30, 23.3%). Twenty-nine patients underwent minimally invasive esophagectomy (McKeown procedure) after neoadjuvant therapy. The reason for not undergoing surgery was due to bone metastasis. There were five treatment-related surgical delays that were caused by adverse reactions (hyperglycemia, arthritis, anemia, leukopenia, capillary endothelial proliferation in oral mucosa). Among the 29 patients undergoing esophagectomy, 15 patients (15/29, 51.7%) achieved MPR, including 7 patients with pCR (7/29, 24.1%). Among the 24 patients who received four cycles of neoadjuvant treatment, there were 7 patients with pCR (7/24, 29.2%), and 14 patients with MPR (14/24, 58.3%). No surgery related mortality was documented. Conclusions: Neoadjuvant camrelizumab combined with chemotherapy plus apatinib is a safe and tolerable treatment for patients with locally advanced ESCC, and the MPR and pCR rate are promising. Clinical trial information: ChiCTR1900023880.

Neoadjuvant Chemoradiotherapy Followed by Esophagectomy with Three-Field Lymph Node Dissection for Thoracic Esophageal Squamous Cell Carcinoma Patients with Clinical Stage III and with Supraclavicular Lymph Node Metastasis.

Simple SummaryThis study aimed to clarify the efficacy of neoadjuvant chemoradiotherapy (NACRT) followed by esophagectomy with three-field lymph node (LN) dissection for clinical Stage III patients and for clinical Stage IVB patients with supraclavicular LN metastasis as the only distant metastatic factor. We observed that NACRT followed by esophagectomy with three-field lymph node dissection is feasible and offers the potential for long-term survival of these patients. It is also suggested that supraclavicular LNs should be treated as regional LNs at least in patients with upper and middle thoracic esophageal squamous cell carcinoma (ESCC).Background: Neoadjuvant chemoradiotherapy (NACRT) followed by esophagectomy is now the standard treatment for patients with resectable advanced thoracic esophageal squamous cell carcinoma (ESCC) worldwide. However, the efficacy of NACRT followed by esophagectomy with three-field lymph node dissection for clinical Stage III patients and for clinical Stage IVB patients with supraclavicular LN metastasis has not yet been determined. Methods: Between 2008 and 2018, 94 ESCC patients diagnosed as clinical Stage III and 18 patients diagnosed as clinical Stage IVB with supraclavicular LN metastasis as the only distant metastatic factor were treated with NACRT followed by esophagectomy with extended lymph node dissection at Akita University Hospital. Long-term survival and the patterns of recurrence in these 112 patients were analyzed. Results: The median follow-up period of censored cases was 60 months. The five-year OS and DSS rates among the clinical Stage III patients were 57.6% and 66.6%, respectively. The five-year OS and DSS rates among the clinical Stage IVB patients were 41.3% and 51.6%, respectively. The most frequent recurrence pattern was distant metastasis (69.2%) in the Stage III patients and LN metastasis (75.0%) in the Stage IVB patients. Conclusion: NACRT followed by esophagectomy with three-field LN dissection is feasible and offers the potential for long-term survival of clinical Stage III ESCC patients and even clinical Stage IVB patients with supraclavicular LN metastasis as the only distant metastatic factor. At least in patients with upper and middle thoracic ESCC, treating supraclavicular LNs as regional LNs seems to be appropriate.

IGF2BP3 Expression Correlates With Poor Prognosis in Esophageal Squamous Cell Carcinoma

BackgroundInsulin-like growth factor-II mRNA binding protein 3 (IGF2BP3) is an oncofetal RNA-binding protein normally involved in cell growth and migration during the early stages of embryogenesis. However, it is also expressed in various cancers, and the relationship between IGF2BP3 and the clinicopathological features and prognosis of esophageal squamous cell carcinoma patients is not fully understood. Our aim in this study was to determine whether IGF2BP3 expression status correlates with prognosis in patients with advanced thoracic esophageal squamous cell carcinoma. MethodsThe IGF2BP3 expression statuses of 177 patients treated with esophagectomy without preoperative therapy were evaluated immunohistochemically using tissue microarray analysis. The relationships between IGF2BP3 expression status and clinicopathological features and survival were then assessed using appropriate statistics. ResultsAmong 177 esophageal tumors, 122 (68.9%) expressed high levels of IGF2BP3. In patients undergoing surgery alone, IGF2BP3-high expression was significantly associated with a poorer prognosis. By contrast, there were no significant associations between IGF2BP3 expression and clinicopathological features or outcomes in patients treated with surgery plus postoperative adjuvant chemotherapy. ConclusionsIGF2BP3 positivity in advanced thoracic esophageal squamous cell carcinoma is associated with adverse clinical outcomes in patients treated with surgery alone.

Efficacy and Safety of Large-field Postoperative Radiotherapy Using Three-dimensional Radiation Technique for Local Advanced Thoracic Esophageal Squamous Cell Carcinoma: A Phase II Clinical Trial

This trial aimed to explore the feasibility and safety of large-field postoperative radiotherapy for locally advanced (T3-4 or N+, M0) esophageal cancer using three-dimensional radiation technique. This trial is a single-center single-arm, phase II clinical trial initiated in 2014. Patients who underwent a radical transthoracic resection with negative margins within 3 months and histologically confirmed as esophageal squamous cell carcinoma (pT3-4 or N+, M0 according to AJCC 7th) were eligible for this study. Radiotherapy was delivered with total dose of 40Gy in 20 fractions using three-dimensional conformal radiation technique including conformal and intensity modulated radiotherapy. TV included tumor bed, anastomosis site, bilateral supraclavicular region, all mediastinal lymph node site, left gastric and celiac trunk lymph node site. The primary endpoint was 2-year local control rate. The secondary endpoint was overall survival (OS) and adverse events. 70 patients were enrolled in this phase II study from 2014 to 2016. The majority of patients were Ilia (40%), IIIA (27.1%) and IIIB (27.1%). 17 patients died. The 2 year-local control rate is 67.29%. Median OS was 57months. The 1, 2, 3 and 4-year OS rate were 92.75%, 69.57%, 60.87%, 53.47%. Locoregional recurrence was found in 28 patients (40%), most of which in mediastinal lymph node region (16 patients) and supraclavicular lymph node region (10 patients), followed by anastomosis (5 patients), celiac lymph node region (3 patients). 18 patients (25.7%) was found hematogenous recurrence. Nearly all patients complete the whole course postoperative radiotherapy with the completion rate of 97.1%, except for two patients. Although the tumor volume is relatively high with the median PTV volume of 1273.22cm3, despite the average dose of the heart is slightly higher, the dose volume histogram parameters of the other normal tissue and organ dose-volume are relatively ideal. Incidences of acute grade 3 hematological toxicity including 4(5.7%) leukopenia and 1(1.4%) neutropenia. In term of acute grade 3 nonhematological toxicity, nausea and vomiting (7.1%) were the most frequent AE followed by fatigue (2.8%) and radiation induced pneumonitis (1.4%). Nobody suffered grade 4 hematological or nonhematological AE. A No late AE occurred. This study is the first phase II study of postoperative radiotherapy in three-dimensional era, which proves that the dose distribution of large-field radiation is feasible and the toxicity is acceptable. It provides a basis for further exploration of higher dose large-field radiation and combined chemotherapy.

1432P Efficacy and safety of large-field postoperative radiotherapy using 3D radiation technique for locally advanced thoracic esophageal squamous cell carcinoma: A phase II clinical trial

In China, esophageal cancer is one of the most common cancers and the third cause of cancer-related death. Surgery is the main treatment approach. However, the 5-year survival rate of surgical resection alone is 30% and local recurrence and lymph node metastasis are the main causes of failure. Theoretically, postoperative radiotherapy has the effect to kill the subclinical lesions. However, the results of the clinical studies are controversial.