Prognostic significance of PET/CT and its association with immuno-genomic profiling in oesophageal squamous cell carcinoma treated with immunotherapy plus chemoradiotherapy: results from a phase II study.

BACKGROUND: A phase II trial (EC-CRT-001) demonstrated the promising efficacy of combining toripalimab (an anti-PD-1 antibody) with definitive chemoradiotherapy (CRT) for locally advanced oesophageal squamous cell carcinoma (ESCC). Biomarkers are key to identifying patients who may benefit from this therapeutic approach. METHODS: Of the 42 patients with ESCC who received toripalimab combined with definitive CRT, 37 were included in this analysis. Baseline assessments included PET/CT metabolic parameters (SUVmax, SUVmean, SUVpeak, MTV, and TLG), RNA sequencing of tumour biopsies to quantify the tissue mutational burden (TMB), and multiplex immunofluorescence staining to estimate immune cell infiltration in the tumour microenvironment (TME). Frozen neoplastic samples were procured for RNA sequencing to further explore the immune-related TME. RESULTS: Among the 37 patients, high baseline SUVmax (≥12.0; OR = 6.5, 95% CI 1.4-48.2, p = 0.032) and TLG (≥121.8; OR = 6.8, 95% CI 1.6-33.5, p = 0.012) were significantly correlated with lower complete response rates. All five PET/CT parameters were notably associated with overall survival; only SUVmax and TLG were associated with a significantly worse progression-free survival. A trend towards an inverse correlation was observed between SUVmax and TMB (R = -0.33, p = 0.062). PD-1 + CD8 + T cell infiltration was negatively correlated with MTV (R = -0.355, p = 0.034) and TLG (R = -0.385, p = 0.021). Moreover, RNA sequencing revealed that the high TLG subgroup exhibited low immune cell infiltration, indicating an immunosuppressive landscape. CONCLUSIONS: High baseline SUVmax and TLG might predict poorer treatment response and worse survival in patients with ESCC undergoing immunotherapy combined with CRT. In addition, high PET/CT metabolic parameters, particularly TLG, were correlated with an immunosuppressive TME, which warrants further exploration.

The patterns and risk factors for relapse in oesophageal squamous cell cancers that achieve pathological complete response to neoadjuvant chemoradiotherapy.

OBJECTIVES: The goal of this study was to investigate the patterns and risk factors for recurrence in patients with oesophageal squamous cell carcinoma with a pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT). METHODS: Between January 2008 and December 2018, a total of 96 patients with pCR were enrolled in this study. Lymph nodes with a pCR [LN-ypCR response (+)] were defined as those lymph nodes without residual tumour but with the presence of treatment response to nCRT. Prognostic factors for recurrence-free survival (RFS) were analysed with Cox proportional hazards models and Fine-Gray competing risk models. Lymph node (LN) stations were counted according to the Japan Esophageal Society classification. RESULTS: The median follow-up time was 51.5 months. Recurrence occurred in 15 cases (15.6%) with a 9.9-month median time to recurrence and a 15.6-month median survival after recurrence. The majority of recurrent diseases developed within the first 2 years postoperatively. Distant recurrences were detected in 14 cases (14.6%), in which the most common recurrence sites were no.104 LN and the lung, followed by no.16 LN. The mean RFS in the whole cohort was 116.6 months. The LN-ypCR response (+) was identified as the independent prognostic factor for worse RFS in both the multivariate Cox model and the Fine-Gray competing risk model (P = 0.001 and P = 0.002, respectively). CONCLUSIONS: Relapse is not rare in oesophageal squamous cell carcinoma cases with pCR after nCRT. Distant recurrences, the predominant pattern of relapse, occur primarily within the first 2 years after oesophagectomy. Patients with pCR with an LN-ypCR response (+) have a higher risk for postoperative recurrence.

Predictive role of ctDNA in esophageal squamous cell carcinoma receiving definitive chemoradiotherapy combined with toripalimab.

The combination of toripalimab (an anti-PD-1 antibody) with definitive chemoradiotherapy (CRT) demonstrated encouraging efficacy against locally advanced esophageal squamous cell carcinoma (ESCC) in the EC-CRT-001 phase II trial (NCT04005170). The primary endpoint of this trial was the clinical complete response rate (cCR), and the secondary endpoints included overall survival (OS), progression-free survival (PFS), duration of response, and quality of life. The exploratory analyses of EC-CRT-001 include exploring the role of circulating tumor DNA (ctDNA) and blood-based tumor mutational burden (bTMB) in predicting the response and survival. In total, 118 blood and 35 tissue samples from 42 enrolled patients were included in the analyses. We found that ctDNA-negative patients achieved a higher cCR compared to those with detectable ctDNA during CRT (83%, 19/23 vs. 39%, 7/18; p = 0.008) or post-CRT (78%, 21/27 vs. 30%, 3/10; p = 0.017). Patients with detectable ctDNA during CRT had shorter PFS (p = 0.014). Similarly, patients with post-CRT detectable ctDNA had a significantly shorter PFS (p = 0.012) and worse OS (p = 0.004). Moreover, patients with high bTMB levels during CRT had prolonged OS (p = 0.027). In conclusion, ctDNA and bTMB have the potential to predict treatment efficacy and survival in ESCC treated with CRT and immunotherapy.

A phase II clinical trial of toripalimab combined with neoadjuvant chemoradiotherapy in locally advanced esophageal squamous cell carcinoma (NEOCRTEC1901).

Background: To evaluate the efficacy and safety of toripalimab combined with neoadjuvant chemoradiotherapy (NCRT) for locally advanced esophageal squamous cell carcinoma (ESCC). Methods: In this single arm, phase II trial, 44 ESCC patients were enrolled from December 2019 to July 2021 at Sun Yat-sen University Cancer Center (Guangzhou, China). All patients received concurrent radiotherapy (44 Gy in 20 fractions), chemotherapy (paclitaxel 50 mg/m2 and cisplatin 25 mg/m2 on days 1, 8, 15, and 22), and toripalimab (240 mg on days 1 and 22). Within 6-8 weeks of neoadjuvant treatment, patients underwent surgery. The results of the study patients were compared with those of 86 matched patients between July 2015 and March 2022. The primary endpoint was pathological complete response (pCR) rate, and the secondary endpoints were treatment-related adverse events and R0 rates. This trail was registered with ClinicalTrails.gov, NCT04006041. Findings: All patients received neoadjuvant treatment, and 42 completed esophagectomy. Of the 42 patients, 21 (50%; 95% CI 35-65) achieved pCR and 2 (5%) patients were ypT0N+. The R0 resection rate was 98% (41/42). Nine (20%) of 44 patients had grade 3/4 adverse events. Among the perioperative complications (n = 42), anastomotic leakage occurred in five cases (12%), tracheal fistula in three cases (7%), and postoperative death in one case (2%) due to tracheal fistula. Compared with the control cohort, the pCR rate of the study group was higher but without significant difference (50% vs. 36%, P = 0.19). Interpretation: Toripalimab combined with NCRT failed to show significantly better pCR rate than historical data. Nevertheless, considering the signs of efficacy and acceptable safety of this regimen, further evaluation in phase III randomized trials might be warranted. Funding: National Natural Science Foundation of China.

Efficacy and cost-effectiveness analysis of pretreatment percutaneous endoscopic gastrostomy in unresectable locally advanced esophageal cancer patients treated with concurrent chemoradiotherapy (GASTO 1059).

BACKGROUND: We launched a single-arm phase II study to determine the efficacy and cost-effectiveness of percutaneous endoscopic gastrostomy (PEG) before concurrent chemoradiotherapy (CCRT) in patients with esophageal squamous cell carcinoma (ESCC). METHODS: Eligible patients received pretreatment PEG and enteral nutrition during CCRT. The primary outcome was the change of weight during CCRT. The secondary outcome included nutrition status, loco-regional objective response rate (ORR), loco-regional progression-free survival (LRFS), overall survival (OS), and toxicities. A 3-state Markov model was applied for cost-effectiveness analysis. Eligible patients were matched and compared with those who had nasogastric tube feeding (NTF) or oral nutritional supplements (ONS). RESULTS: Sixty-three eligible patients received pretreatment PEG-based CCRT. The mean change of weight during CCRT was -1.4% (standard deviation, 4.4%), and after CCRT, 28.6% of patients gained weight and 98.4% had normal albumin levels. The loco-regional ORR and 1-year LRFS were 98.4% and 88.3%. The incidence of grade ≥3 esophagitis was 14.3%. After matching, another 63 patients were included in the NTF group and 63 in the ONS group. More patients gained weight after CCRT in the PEG group (p = 0.001). The PEG group showed higher loco-regional ORR (p = 0.036) and longer 1-year LRFS (p = 0.030). In cost analysis, the PEG group showed an incremental cost-effectiveness ratio of $3457.65 per quality-adjusted life-years (QALY) compared with the ONS group with a probability of cost-effectiveness of 77.7% at the $10,000 per QALY willingness-to-pay threshold. CONCLUSION: Pretreatment PEG is associated with better nutritional status and treatment outcome in ESCC patients treated with CCRT compared with ONS and NTF. Pretreatment of PEG can be cost-effective because of its significant clinical benefits.

A Surrogate Endpoint for Overall Survival in Locally Advanced and Resectable Esophageal Squamous Cell Carcinoma: A Reanalysis of Data From the NEOCRTEC5010 Trial.

PURPOSE: This study aimed to investigate disease-free survival (DFS) as a surrogate endpoint for overall survival (OS) in patients with locally advanced and resectable esophageal squamous cell carcinoma. METHODS AND MATERIALS: We re-analyzed patient data from the NEOCRTEC5010 randomized controlled trial (N = 451 patients) to compare their OS with that of an age- and sex-matched cohort from the general population of China. We used expected survival and the standardized mortality ratio, respectively, in our analysis of data collected from a neoadjuvant chemoradiation therapy (NCRT) plus surgery group and a surgery-only group. Published data from 6 randomized controlled trials and 20 retrospective studies were used to examine the correlation between DFS and OS at the trial level. RESULTS: The annual hazard rate of disease progression decreased to 4.9% and 8.1% within 3 years in the NCRT and surgery groups, respectively. Patients who were disease-free at 36 months had a 5-year OS of 93.9% (95% CI, 89.7%-98.4%) in the NCRT group with a standardized mortality ratio of 1.1 (95% CI, 0.7-1.8; P = .5639). In contrast, the 5-year OS was only 12.9% (95% CI, 7.3%-22.6%) for patients in the NCRT group who exhibited disease progression within 36 months. At the trial level, DFS and OS were correlated with treatment effect (R2 = 0.605). CONCLUSIONS: Disease-free status at 36 months is a valid surrogate endpoint for 5-year OS in patients with locally advanced and resectable esophageal squamous cell carcinoma. Patients who were disease-free at 36 months showed a favorable OS, which was indistinguishable from that of the age- and sex-matched comparison group from the general population; otherwise, their 5-year OS was extremely poor.

Association Between Lymphopenia and Survival Outcomes in Esophageal Carcinoma Patients Receiving Combined Immunotherapy and Chemoradiotherapy.

BACKGROUND: To investigate the association between absolute lymphocyte count (ALC) nadir and survival outcomes in esophageal squamous cell carcinoma (ESCC) patients who received definitive chemoradiotherapy (CRT) combined with anti-PD-1 immunotherapy, as well as to explore clinical characteristics and dosimetric parameters that affect ALC nadir during CRT. PATIENTS AND METHODS: Patients with ESCC (n = 602) who underwent definitive CRT were analyzed, of whom 166 received combined anti-PD-1 immunotherapy and CRT. Changes in ALC and survival were compared between patients with and without immunotherapy. Propensity score matching (PSM) was performed to minimize the effects of confounding factors. Low ALC was defined as nadir of <0.33 × 103 cells/µL during CRT (top tertile). Univariate and multivariate logistic regression were used to identify predictors of low ALC nadir. RESULTS: Patients with immunotherapy had significantly higher ALC in the first 3 weeks during CRT and higher ALC nadir than those without. Overall survival was more favorable in patients with immunotherapy both before and after PSM. After a median follow-up of 12.1 months, patients with low ALC during CRT had a worse progression-free survival (PFS) (P = .026). In multivariate analysis, low ALC remained a significant prognostic factor for PFS. Planning target volume (PTV) and heart V5 were revealed to be independent predictors of low ALC. CONCLUSIONS: The addition of anti-PD-1 immunotherapy to definitive CRT could mitigate the decline of ALC during radiotherapy and might prolong survival. Low ALC nadir was correlated to worse PFS, larger PTV, and higher heart V5 in patients receiving combined immunotherapy and CRT.

Efficacy and Dose-Response Relationship of Stereotactic Body Radiotherapy for Abdominal Lymph Node Metastases from Hepatocellular Carcinoma.

BACKGROUND: The objective of this study was to investigate the treatment efficacy of stereotactic body radiotherapy (SBRT) and evaluate the influence of radiation dose on local control and survival in patients with abdominal lymph node metastases (LNM) from hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Between 2010 and 2020, data of 148 patients with HCC with abdominal LNM, including 114 who underwent SBRT and 34 who received conventional fractionation radiation therapy (CFRT), were collected. A total radiation dose of 28-60 Gy was delivered in 3-30 fractions, with a median biologic effective dose (BED) of 60 Gy (range, 39-105 Gy). Freedom from local progression (FFLP) and overall survival (OS) rates were analyzed. RESULTS: With a median follow-up of 13.6 months (range, 0.4-96.0 months), the 2-year FFLP and OS rates of the entire cohort were 70.6% and 49.7%, respectively. Median OS of the SBRT group was longer than the CFRT group (29.7 vs. 9.9 months, P = .007). A dose-response relationship was observed between local control and BED in either the entire cohort or the SBRT subgroup. Patients who received SBRT with a BED ≥60 Gy had significantly higher 2-year FFLP and OS rates than those who received a BED <60 Gy (80.1% vs. 63.4%, P = .004; 68.3% vs. 33.0%, P < .001). On multivariate analysis, BED was an independent prognostic factor for both FFLP and OS. CONCLUSIONS: SBRT achieved satisfactory local control and survival with feasible toxicities in patients with HCC with abdominal LNM. Moreover, the findings of this large series suggest a dose-response relationship between local control and BED.

Toripalimab combined with definitive chemoradiotherapy in locally advanced oesophageal squamous cell carcinoma (EC-CRT-001): a single-arm, phase 2 trial.

BACKGROUND: Toripalimab is a PD-1 inhibitor that is approved for the treatment of advanced oesophageal squamous cell carcinoma, but its efficacy in locally advanced disease is unclear. We administered toripalimab with definitive chemoradiotherapy to patients with unresectable locally advanced oesophageal squamous cell carcinoma, and aimed to investigate the activity and safety of this regimen, and potential biomarkers. METHODS: EC-CRT-001 was a single-arm, phase 2 trial done at Sun Yat-sen University Cancer Center (Guangzhou, China). Patients aged 18-70 years with untreated, unresectable, stage I-IVA oesophageal squamous cell carcinoma, with an ECOG performance status of 0-2, and adequate organ and bone marrow function were eligible for inclusion. Patients received concurrent thoracic radiotherapy (50·4 Gy in 28 fractions), chemotherapy (five cycles of weekly intravenous paclitaxel [50 mg/m2] and cisplatin [25 mg/m2]), and toripalimab (240 mg intravenously every 3 weeks for up to 1 year, or until disease progression or unacceptable toxicity). The primary endpoint was the complete response rate at 3 months after radiotherapy by investigator assessment. Secondary endpoints were overall survival, progression-free survival, duration of response, quality of life (not reported here), and safety. All enrolled patients were included in the activity and safety analyses. The trial is registered with ClinicalTrials.gov, NCT04005170; enrolment is completed and follow-up is ongoing. FINDINGS: Between Nov 12, 2019, and Jan 25, 2021, 42 patients were enrolled. The median age was 56 years (IQR 53-63), 39 (93%) of 42 patients had stage III or IVA disease, and 32 (76%) patients were male and 10 (24%) were female. 40 (95%) of 42 patients completed the planned chemoradiotherapy and 26 (62%; 95% CI 46-76) of 42 had a complete response. The median duration of response was 12·1 months (95% CI 5·9-18·2). After a median follow-up of 14·9 months (IQR 11·9-18·4), 1-year overall survival was 78·4% (95% CI 66·9-92·0) and 1-year progression-free survival was 54·5% (41·3-72·0). The most common grade 3 or worse adverse event was lymphopenia (36 [86%] of 42). One (2%) patient died from treatment-related pneumonitis. INTERPRETATION: Combining toripalimab with definitive chemoradiotherapy provided encouraging activity and acceptable toxicity in patients with locally advanced oesophageal squamous cell carcinoma, and this regimen warrants further investigation. FUNDING: National Natural Science Foundation of China and Sci-Tech Project Foundation of Guangzhou. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Association of Sialic Acid-Binding Immunoglobulin-Like Lectin 15 With Phenotypes in Esophageal Squamous Cell Carcinoma in the Setting of Neoadjuvant Chemoradiotherapy.

Importance: Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is a novel immune checkpoint molecule that is highly homologous to programmed cell death ligand 1 (PD-L1), but information remains limited about its role in esophageal squamous cell carcinoma (ESCC). Objective: To explore the expression pattern and association of Siglec-15 with outcomes among patients with ESCC who received neoadjuvant chemoradiotherapy (CRT). Design, Setting, and Participants: This retrospective cohort study was conducted at an academic institution in China. Participants included patients with ESCC who underwent neoadjuvant CRT and esophagectomy between June 2002 and December 2018. Multiplexed immunofluorescence staining was used to evaluate the expression of Siglec-15 and PD-L1 in tumor cells (TCs) or tumor-associated macrophages based on pre-CRT biopsies. Different immune phenotypes have been proposed and further validated in an independent cohort. Data analysis was conducted from January to May 2021. Exposures: Siglec-15 or PD-L1 positivity vs negativity. Main Outcomes and Measures: Pathologic complete response (pCR), overall survival (OS), and recurrence-free survival (RFS). Results: Of 130 participants (median [range] age, 56 [42-73] years; 108 [83.1%] male participants) in the primary cohort, 58 patients (44.6%) achieved a pCR after neoadjuvant CRT. Siglec-15 and PD-L1 were detected in both TCs and macrophages. The percentage of Siglec-15-positive macrophages was notably higher than that of Siglec-15-positive TCs (median [IQR]: 34.4% [12.7%-64.3%] vs 4.8% [0.7%-25.6%]; P < .001). TC-Siglec-15 expression was significantly and positively associated with macrophage-Siglec-15 expression (r = 0.78; P < .001). Siglec-15 positivity was significantly associated with a higher rate of pCR (37 of 70 [52.9%] vs 21 of 60 [35.0%]; P = .04), more favorable OS (hazard ratio [HR], 0.46; 95% CI, 0.25-0.85; P = .01), and RFS (HR, 0.48; 95% CI, 0.26-0.88; P = .02). However, PD-L1 positivity in TCs was negatively associated with survival. Stratification analysis further revealed that patients with combined Siglec-15 positivity and PD-L1 negativity had better survival than those with other phenotypes. Major findings were reproducible in a validation cohort with 55 patients. Conclusions and Relevance: In this cohort study of patients with ESCC receiving neoadjuvant CRT, Siglec-15 positivity was associated with a better pathological response and more favorable survival. Siglec-15 could serve as a novel biomarker to identify potential candidates that may benefit from immunotherapy combined with CRT.

Impact of Lymph Node Dissection on Survival After Neoadjuvant Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma: From the Results of NEOCRTEC5010, a Randomized Multicenter Study.

OBJECTIVE: To clarify whether systemic LND influences the safety of surgery and the survival of patients with locally advanced esophageal squamous cell carcinoma (ESCC) after neoadjuvant chemoradiotherapy (nCRT). SUMMARY OF BACKGROUND DATA: Prognostic impact of systemic lymphadenectomy during surgery after nCRT for ESCC is still uncertain and requires clarification. METHODS: This is a secondary analysis of NEOCRTEC5010 trial which compared nCRT followed by surgery versus surgery alone for locally advanced ESCC. Relationship between number of LND and perioperative, recurrence, and survival outcomes were analyzed in the nCRT group. RESULTS: Three-year overall survival was significantly better in the nCRT group than the S group (75.2% vs 61.5%; P = 0.011). In the nCRT group, greater number of LND was associated with significantly better overall survival (hazard ratio, 0.358; P < 0.001) and disease-free survival (hazard ratio, 0.415; P = 0.001), but without any negative impact on postoperative complications. Less LND (<20 vs ≥20) was significantly associated with increased local recurrence (18.8% vs 5.2%, P = 0.004) and total recurrence rates (41.2% vs 25.8%, P = 0.027). Compared to patients with persistent nodal disease, significantly better survival was seen in patients with complete response and with LND ≥20, but not in those with LND <20. CONCLUSIONS: Systemic LND does not increase surgical risks after nCRT in ESCC patients. And it is associated with better survival and local diseasecontrol. Therefore, systemic lymphadenectomy should still be considered as an integrated part of surgery after nCRT for ESCC.

Trafficking protein TMED3 promotes esophageal squamous cell carcinoma.

BACKGROUND: The molecular mechanisms of esophageal squamous cell carcinoma (ESCC) remain poorly understood. Transmembrane emp24 trafficking protein 3 (TMED3) acts as an oncogene or tumor suppressor gene in different cancers. Our study was to explore the clinicopathological significance and functional roles of TMED3 in ESCC. METHODS: Immunohistochemistry, qPCR, and western blotting were used to analyze the expression of TMED3 in ESCC tissues and cells. Statistical analysis was performed to analyze the relationship between TMED3 expression and tumor characteristics in patients with ESCC. The role of TMED3 in vitro and in vivo was investigated by performing functional verification experiments and using a xenograft mouse model. Proteins that are functionally related to TMED3 were recognized by Affymetrix microarray and Ingenuity Pathway Analysis (IPA). Functional verification experiments were performed to analyze the role of FAM60A (a protein functionally related to TMED3) in vitro. RESULTS: We confirmed the overexpression of TMED3 was correlated with poor prognosis in ESCC patients. When TMED3 was knocked down, ESCC cell proliferation, migration, and invasion were inhibited whereas cell apoptosis was promoted in vitro, and tumorigenicity was inhibited in vivo. We further revealed significant changes in gene expression profile in TMED3 knockdown cells. Among these differentially expressed genes, FAM60A was overexpressed in ESCC tissues. Furthermore, knocking down FAM60A significantly weakened the proliferation ability of ESCC cells and reversed TMED3's tumorigenicity of ESCC cells. CONCLUSION: Our study revealed an oncogenic role of TMED3 in ESCC.

Prognostic value of recurrence pattern in locally advanced esophageal squamous cell carcinoma: Results from the phase III trial NEOCRTEC5010.

OBJECTIVES: The prognosis of patients with locally advanced esophageal squamous cell carcinoma with different recurrence backgrounds is highly heterogeneous. This study aims to explore the effects of recurrence patterns on prognosis. METHODS: The phase III, multicenter, prospective NEOCRTEC5010 trial enrolled 451 patients with stage IIB-III esophageal squamous cell carcinoma randomly assigned to neoadjuvant chemoradiotherapy combined with surgery (NCRT group) or surgery alone (S group) and followed them long-term. We investigated the effects of recurrence patterns on survival in patients undergoing radical esophagectomy. RESULTS: In total, 353 patients were included in the study. The 5-year overall survival of patients with different recurrence patterns was significantly different: recurrence versus recurrence-free (17.8% vs 89.2%; P < .001), early recurrence versus late recurrence (4.6% vs 51.2%; P < .001), and distant metastasis versus locoregional recurrence (17.0% vs 20.0%; P = .666). Patients with early recurrence had significantly shorter survival after recurrence than those with late recurrence (hazard ratio, 1.541; 95% confidence interval, 1.047-2.268, P = .028). There was no significant difference in postrecurrence survival between patients with distant metastasis and locoregional recurrence (hazard ratio, 1.181; 95% confidence interval, 0.804-1.734; P = .396). Multivariate logistic analysis showed that pN1 stage, lymph node dissection <20, and lack of response to NCRT were independent risk factors for postoperative early recurrence. Multivariate Cox regression suggested that NCRT, age ≥60 years, early recurrence, and the pN1 stage were independent risk factors for shortened survival after recurrence. CONCLUSIONS: Prerecurrence primary tumor stage is inaccurate in predicting postrecurrence survival. In contrast, recurrence patterns can guide follow-up while also predicting postrecurrence survival. NCRT prolongs disease-free survival but is associated with a worse prognosis in patients with recurrence, especially early recurrence.

Comparative efficacy and safety of immunotherapy for patients with advanced or metastatic esophageal squamous cell carcinoma: a systematic review and network Meta-analysis.

BACKGROUND: The study aimed to compare efficacy and safety of various immune checkpoint inhibitors for patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC). METHODS: We searched Medline, Web of Science, Cochrane Central Register of Controlled Trials, Embase, Clinical Trials.gov and several international conference databases from January 1, 2000 to December 19, 2021. We conducted Bayesian network meta-analysis to assess the relative effects among treatments. Outcomes included overall survival (OS), progression-free survival (PFS), overall response rate and adverse events. RESULTS: Ten eligible trials with 5250 patients were included. Toripalimab and Camrelizumab plus chemotherapy were preferred to rank first on OS (probability, 61%) and PFS (probability, 37%) in the first-line setting, respectively. In refractory patients, Sintilimab and Camrlizumab were most likely to be ranked first on OS (probability, 37%) and PFS (probability, 94%). The toxicity related to immunotherapy was manageable in clinical trials. Camrelizumab and Nivolumab had the less adverse events of grade 3 or higher in the first and refractory setting, respectively. CONCLUSIONS: This study found that Toripalimab and Camrelizumab plus chemotherapy were likely to be the best option in terms of OS and PFS in the first-line setting for patients with advanced or metastatic ESCC respectively. Sintilimab and Camrelizumab were the preferred options for OS and PFS in refractory patients respectively. The toxicity of immunotherapy was different from conventional chemotherapy, but manageable in patients with ESCC. TRIAL REGISTRATION: PROSPERO registration number: (CRD 42021261554).

Progression-free survival at 3 years is a reliable surrogate for 5-year overall survival for patients suffering from locally advanced esophageal squamous cell carcinoma.

BACKGROUND: Despite 3-year survival being used as a primary endpoint in some randomized controlled trials (RCTs), limited evidence supports the use of intermediate endpoints to evaluate the effect of new therapies in esophageal squamous cell cancer (ESCC). This study aimed to systematically evaluate progression-free survival at 3 years (3-year PFS) and overall survival (OS) among patients with ESCC. METHODS: We identified 528 patients newly diagnosed with locally advanced ESCC who received definitive radiotherapy. OS was compared with an age- and sex-matched general Chinese population using the standardized mortality ratio (SMR). Regression analysis was used to validate the correlation between PFS and OS using published data. RESULTS: The annual risk of progression decreased to 11.5% after 3 years. Patients who did not achieve 3-year PFS had a median postprogression survival (PPS) of 7.3 months, with a 5-year OS rate of 9.6% and a SMR of 15.0 (95% confidence interval [CI], 12.9-17.5). Conversely, the SMR for patients who achieved 3-year PFS was 0.9 (95% CI, 0.6-1.3). We observed a significant correlation between log hazard ratio (HR) (PFS) and log HR (OS) at the trial level (r = 0.89; 95% CI, 0.88-0.90). The strongest correlation was observed between 3-year PFS and 5-year OS in RCTs and retrospective studies. CONCLUSIONS: Patients exhibiting progression within 3 years experienced poor survival, whereas patients achieving 3-year PFS had excellent outcomes. Our study supports 3-year PFS as a reliable primary endpoint for study design and risk stratification in locally advanced ESCC.

Pathological complete response after neoadjuvant treatment determines survival in esophageal squamous cell carcinoma patients (NEOCRTEC5010).

BACKGROUND: Few studies have exclusively investigated the value of pathological complete response (pCR), in esophageal squamous cell carcinoma (ESCC) patients, although it is a clinically significant parameter to evaluate the impact of neoadjuvant chemoradiotherapy (nCRT) on treatment outcome after surgery. The aim of our study was to explore the relationship between pCR after nCRT and survival among patients with local ESCC. METHODS: All patients receiving nCRT followed by surgery in NEOCRTEC5010-trial (NCT01216527) were included. Non-pCR patients were classified into three subgroups: ypTanyN0M0, ypT0NanyM0 and ypTanyNanyM0. The Kaplan-Meier method with log-rank test was employed to evaluate disease-free survival (DFS) and overall survival (OS). Multivariate regression analysis was performed using a Cox proportional hazards model to identify clinicopathological parameters associated with pCR. RESULTS: Among the 185 patients included, 80 (43.2%) achieved pCR after nCRT. The mean survival time of the pCR group was significantly longer than that of the non-pCR group (92.6 vs. 69.2 months; HR, 2.70; 95% CI: 1.48-4.92; P=0.001). The 5-year OS and DFS of the pCR group were 79.3% and 77% respectively, compared to 54.8% and 51.2%, respectively, in the non-pCR group. The results showed that the OS and DFS of the ypTanyN0M0 group were better than those of the ypT0NanyM0 group and the ypTanyNanyM0 group. We also found that the number of dissected lymph nodes and pCR were independent risk factors for DFS and OS rates. CONCLUSIONS: pCR after nCRT is an important prognostic indicator of OS and DFS in patients with ESCC. In addition, lymph-node status could represent an important parameter in the prognostic evaluation of esophageal cancer patients.

Long-term Efficacy of Neoadjuvant Chemoradiotherapy Plus Surgery for the Treatment of Locally Advanced Esophageal Squamous Cell Carcinoma: The NEOCRTEC5010 Randomized Clinical Trial.

Importance: The prognosis of patients with locally advanced esophageal squamous cell carcinoma (ESCC) remains poor after surgery. Neoadjuvant chemoradiotherapy (NCRT) has been shown to potentially improve survival. Objective: To compare the treatment efficacy of NCRT plus surgery with surgery alone for long-term survival among patients with locally advanced ESCC. Design, Setting, and Participants: The Neoadjuvant Chemoradiotherapy for Esophageal Cancer 5010 study was a multicenter open-label randomized phase 3 clinical trial that enrolled patients between June 1, 2007, and December 31, 2014. Follow-up ended on December 31, 2019. The study was conducted at 8 centers in China. A total of 451 patients aged 18 to 70 years with thoracic ESCC stage T1-4N1M0/T4N0M0 were enrolled and randomized. Data were analyzed from December 1, 2019, to June 30, 2020. Interventions: Patients randomized to receive NCRT plus surgery (NCRT group) received preoperative chemotherapy (25 mg/m2 of vinorelbine on days 1 and 8 and 75 mg/m2 of cisplatin on day 1 or 25 mg/m2 of cisplatin on days 1 to 4) every 3 weeks for 2 cycles and concurrent radiotherapy (40.0 Gy, administered in 20 fractions of 2.0 Gy for 5 days per week) followed by surgery. Patients randomized to receive surgery alone (surgery group) underwent surgery after randomization. Main Outcomes and Measures: The primary end point was overall survival in the intention-to-treat population. The secondary end point was disease-free survival. Results: A total of 451 patients (mean [SD] age, 56.5 [7.0] years; 367 men [81.4%]) were randomized to the NCRT (n = 224) and surgery (n = 227) groups and were eligible for the intention-to-treat analysis. By December 31, 2019, 224 deaths had occurred. The median follow-up was 53.5 months (interquartile range, 18.2-87.4 months). Patients receiving NCRT plus surgery had prolonged overall survival compared with those receiving surgery alone (hazard ratio, 0.74; 95% CI, 0.57-0.97; P = .03), with a 5-year survival rate of 59.9% (95% CI, 52.9%-66.1%) vs 49.1% (95% CI, 42.3%-55.6%), respectively. Patients in the NCRT group compared with the surgery group also had prolonged disease-free survival (hazard ratio, 0.60; 95% CI, 0.45-0.80; P < .001), with a 5-year survival rate of 63.6% (95% CI, 56.0%-70.2%) vs 43.0% (95% CI, 36.0%-49.7%), respectively. Conclusions and Relevance: In this randomized clinical trial, treatment with NCRT plus surgery significantly improved long-term overall survival and disease-free survival and therefore may be considered a standard of care for patients with locally advanced ESCC. Trial Registration: ClinicalTrials.gov Identifier: NCT01216527.

Induction chemotherapy followed by definitive chemoradiotherapy versus chemoradiotherapy alone in esophageal squamous cell carcinoma: a randomized phase II trial.

This randomized phase II trial aims to compare the efficacy and safety of induction chemotherapy followed by definitive chemoradiotherapy (CRT) versus CRT alone in patients with esophageal squamous cell carcinoma (ESCC) unsuitable for surgery (N = 110). The primary outcome was overall response rate (ORR), whereas the secondary outcome was overall survival. This trial did not meet pre-specified endpoints. The ORR was 74.5% in the induction chemotherapy group versus 61.8% in the CRT alone group (P = 0.152). The 3-year overall survival rate was 41.8% in the induction chemotherapy group and 38.1% in the CRT alone group (P = 0.584; hazard ratio, 0.88; 95% CI, 0.54-1.41). Grade 3-5 adverse events were similar. Patients who responded to induction chemotherapy had improved survival in the post-hoc analysis. These results demonstrate no improvement in response rate or survival with the addition of induction chemotherapy to CRT in unselected patients with ESCC. Trial number: NCT02403531.

TRIM25 regulates oxaliplatin resistance in colorectal cancer by promoting EZH2 stability.

Resistance to chemotherapy remains the major cause of treatment failure in patients with colorectal cancer (CRC). Here, we identified TRIM25 as an epigenetic regulator of oxaliplatin (OXA) resistance in CRC. The level of TRIM25 in OXA-resistant patients who experienced recurrence during the follow-up period was significantly higher than in those who had no recurrence. Patients with high expression of TRIM25 had a significantly higher recurrence rate and worse disease-free survival than those with low TRIM25 expression. Downregulation of TRIM25 dramatically inhibited, while overexpression of TRIM25 increased, CRC cell survival after OXA treatment. In addition, TRIM25 promoted the stem cell properties of CRC cells both in vitro and in vivo. Importantly, we demonstrated that TRIM25 inhibited the binding of E3 ubiquitin ligase TRAF6 to EZH2, thus stabilizing and upregulating EZH2, and promoting OXA resistance. Our study contributes to a better understanding of OXA resistance and indicates that inhibitors against TRIM25 might be an excellent strategy for CRC management in clinical practice.

Survival After Combining Stereotactic Body Radiation Therapy and Tyrosine Kinase Inhibitors in Patients With Metastatic Renal Cell Carcinoma.

BACKGROUND: Stereotactic body radiation therapy (SBRT) and tyrosine kinase inhibitors (TKIs) are effective treatments for metastatic renal cell carcinoma, but data on combining these two modalities are scarce. We aimed to investigate the survival outcomes of SBRT plus TKIs. METHODS: Data of patients treated with TKIs from December 2007 to June 2019 were collected. Patients received SBRT plus TKIs (TKI + SBRT group) or TKIs alone (TKI alone group). Local control (LC), time to change of systemic therapy (TTS), and overall survival (OS) were assessed. RESULTS: A total of 190 patients were included, and 85 patients received TKI + SBRT. The 2-year LC rate was 92.8%. The median OS in the TKI + SBRT group was significantly longer than that of the TKI alone group (63.2 vs 29.8 months; P < 0.001). In multivariate analysis, IMDC intermediate (HR 1.96; 95% CI 1.10-3.48; P = 0.022) and poor risk (HR 2.43; 95% CI 1.25-4.75; P = 0.009), oligometastasis (HR 0.41; 95% CI 0.26-0.65; P < 0.001), and the addition of SBRT (HR 0.48; 95% CI 0.31-0.75; P = 0.001) were prognostic factors for OS. Patients with oligometastasis (P = 0.009) and those with IMDC favorable (P = 0.044) or intermediate (P = 0.002) risk had significantly longer OS with TKI + SBRT. The median TTS were 21.5, 6.4, and 9.0 months in patients receiving SBRT before first-line TKI failure, SBRT after first-line TKI failure, and first-line TKI alone (P < 0.001). Five patients (5.9%) experienced SBRT-related grade 3 toxicities. CONCLUSIONS: Combining SBRT with TKIs is tolerable and associated with longer OS in selected patients, such as those with oligometastasis and favorable or intermediate risk.