Ten-Year Outcome of Neoadjuvant Chemoradiotherapy Plus Surgery for Esophageal Cancer: The Randomized Controlled CROSS Trial

Abstract

PURPOSE Preoperative chemoradiotherapy according to the chemoradiotherapy for esophageal cancer followed by surgery study (CROSS) has become a standard of care for patients with locally advanced resectable esophageal or junctional cancer. We aimed to assess long-term outcome of this regimen. METHODS From 2004 through 2008, we randomly assigned 366 patients to either five weekly cycles of carboplatin and paclitaxel with concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week) followed by surgery, or surgery alone. Follow-up data were collected through 2018. Cox regression analyses were performed to compare overall survival, cause-specific survival, and risks of locoregional and distant relapse. The effect of neoadjuvant chemoradiotherapy beyond 5 years of follow-up was tested with time-dependent Cox regression and landmark analyses. RESULTS The median follow-up was 147 months (interquartile range, 134-157). Patients receiving neoadjuvant chemoradiotherapy had better overall survival (hazard ratio [HR], 0.70; 95% CI, 0.55 to 0.89). The effect of neoadjuvant chemoradiotherapy on overall survival was not time-dependent ( P value for interaction, P = .73), and landmark analyses suggested a stable effect on overall survival up to 10 years of follow-up. The absolute 10-year overall survival benefit was 13% (38% v 25%). Neoadjuvant chemoradiotherapy reduced risk of death from esophageal cancer (HR, 0.60; 95% CI, 0.46 to 0.80). Death from other causes was similar between study arms (HR, 1.17; 95% CI, 0.68 to 1.99). Although a clear effect on isolated locoregional (HR, 0.40; 95% CI, 0.21 to 0.72) and synchronous locoregional plus distant relapse (HR, 0.43; 95% CI, 0.26 to 0.72) persisted, isolated distant relapse was comparable (HR, 0.76; 95% CI, 0.52 to 1.13). CONCLUSION The overall survival benefit of patients with locally advanced resectable esophageal or junctional cancer who receive preoperative chemoradiotherapy according to CROSS persists for at least 10 years.

Inhibition of Wnt/β-Catenin Signaling Sensitizes Esophageal Cancer Cells to Chemoradiotherapy

“…Treatment resistance represents a fundamental problem in clinical oncology. In this context, esophageal cancer represents a prime example, because success rates remain low with dismal outcomes and 5-year survival rates ranging from 20% to 38% [1,7,9], indicating that for only a subset of patients, multimodal treatment concepts are effective [10,11].…”

“…A prime example is the CROSS trial, which demonstrated that the median overall survival (OS) was significantly higher in the CRT-plus-surgery group compared to the surgery-only group (48.6 months versus 24.0 months, respectively) [7,8]. Very recently, the follow-up data from the CROSS trial were published, with a 10-year OS of 38% for patients in the CRT-plus-surgery group compared with 25% for patients in the surgery-only group, respectively [9]. Nevertheless, many patients do not benefit from the advances in current treatment strategies, but are exposed to the potential side effects of both CT and irradiation.…”

Effects of preoperative radiotherapy on survival of patients with stage II and III esophageal squamous cell carcinoma

“…[ 18 ] The results of the randomized controlled CROSS trial suggested that the OS benefit of patients with locally advanced resectable esophageal or junctional cancer who received preoperative chemoradiotherapy according to CROSS persisted for more than 10 years, which strongly indicated that patients with locally advanced resectable esophageal or junctional cancer could benefit from preoperative neoadjuvant chemoradiotherapy. [ 19 ]…”

Immunotherapy for Esophageal Cancers: What Is Practice Changing in 2021?

“…In 2012, the results of the CROSS trial presented a major breakthrough due to improved survival with preoperative chemoradiotherapy among patients with potentially curable esophageal or gastroesophageal junction cancer (included patients: 275 (75%) patients with AC, 84 (23%) patients with SCC, and 7 (2%) patients with large-cell undifferentiated carcinoma) [10]. Recently published data on 10-year-survival outcomes (median followup 147 months) affirm the overall survival benefit for patients receiving neoadjuvant chemoradiotherapy compared to surgery alone (HR 0.70; 95% CI 0.55-0.89; overall OS benefit 13% (38% versus 25%, respectively)) [11].…”