PurposeThe efficacy of neoadjuvant chemoradiotherapy (NCRT) plus surgery for locally advanced esophageal squamous cell carcinoma (ESCC) remains controversial. In this trial, we compared the survival and safety of NCRT plus surgery with surgery alone in patients with locally advanced ESCC.Patients and MethodsFrom June 2007 to December 2014, 451 patients with potentially resectable thoracic ESCC, clinically staged as T1-4N1M0/T4N0M0, were randomly allocated to NCRT plus surgery (group CRT; n = 224) and surgery alone (group S; n = 227). In group CRT, patients received vinorelbine 25 mg/m2 intravenously (IV) on days 1 and 8 and cisplatin 75 mg/m2 IV day 1, or 25 mg/m2 IV on days 1 to 4 every 3 weeks for two cycles, with a total concurrent radiation dose of 40.0 Gy administered in 20 fractions of 2.0 Gy on 5 days per week. In both groups, patients underwent McKeown or Ivor Lewis esophagectomy. The primary end point was overall survival.ResultsThe pathologic complete response rate was 43.2% in group CRT. Compared with group S, group CRT had a higher R0 resection rate (98.4% v 91.2%; P = .002), a better median overall survival (100.1 months v 66.5 months; hazard ratio, 0.71; 95% CI, 0.53 to 0.96; P = .025), and a prolonged disease-free survival (100.1 months v 41.7 months; hazard ratio, 0.58; 95% CI, 0.43 to 0.78; P < .001). Leukopenia (48.9%) and neutropenia (45.7%) were the most common grade 3 or 4 adverse events during chemoradiotherapy. Incidences of postoperative complications were similar between groups, with the exception of arrhythmia (group CRT: 13% v group S: 4.0%; P = .001). Peritreatment mortality was 2.2% in group CRT versus 0.4% in group S (P = .212).ConclusionThis trial shows that NCRT plus surgery improves survival over surgery alone among patients with locally advanced ESCC, with acceptable and manageable adverse events.

The biological functions of N6-methyladenosine (m 6 A) RNA methylation are mainly dependent on the reader; however, its role in lung tumorigenesis remains unclear. Here, we have demonstrated that the m 6 A reader YT521-B homology domain containing 2 (YTHDC2) is frequently suppressed in lung adenocarcinoma (LUAD). Downregulation of YTHDC2 was associated with poor clinical outcome of LUAD. YTHDC2 decreased tumorigenesis in a spontaneous LUAD mouse model. Moreover, YTHDC2 exhibited antitumor activity in human LUAD cells. Mechanistically, YTHDC2, via its m 6 A-recognizing YTH domain, suppressed cystine uptake and blocked the downstream antioxidant program. Administration of cystine downstream antioxidants to pulmonary YTHDC2-overexpressing mice rescued lung tumorigenesis. Furthermore, solute carrier 7A11 (SLC7A11), the catalytic subunit of system X C − , was identified to be the direct target of YTHDC2. YTHDC2 destabilized SLC7A1 1 mRNA in an m 6 A-dependent manner because YTHDC2 preferentially bound to m 6 A-modified SLC7A1 1 mRNA and thereafter promoted its decay. Clinically, a large proportion of acinar LUAD subtype cases exhibited simultaneous YTHDC2 downregulation and SLC7A11 elevation. Patient-derived xenograft (PDX) mouse models generated from acinar LUAD showed sensitivity to system X C − inhibitors. Collectively, the promotion of cystine uptake via the suppression of YTHDC2 is critical for LUAD tumorigenesis, and blocking this process may benefit future treatment.

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IMPORTANCEThe 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 PARTICIPANTSThe 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/m 2 of vinorelbine on days 1 and 8 and 75 mg/m 2 of cisplatin on day 1 or 25 mg/m 2 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 MEASURESThe 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 RELEVANCEIn 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.