Among patients with locally advanced resectable esophageal or junctional cancer, the overall survival benefit conferred by preoperative chemoradiotherapy persists for at least 10 years, according to long-term results of the Chemoradiotherapy for Esophageal Cancer Followed by Surgery Study (CROSS). As a result of earlier publication of CROSS data, chemoradiotherapy followed by surgery has become one of the standards of care for patients with locally advanced resectable esophageal cancer, stated lead author Ben M. Eyck, MD, of Erasmus University Medical Center, Rotterdam, the Netherlands, and colleagues in the Journal of Clinical Oncology.
In the multicenter, randomized trial, initiated in 2004, 178 patients randomized to chemoradiotherapy with subsequent surgery and 188 patients randomized to surgery alone were followed with overall survival as the primary, and cause-specific survival and risks of locoregional and distant relapse as the secondary endpoints. Chemoradiotherapy consisted of 5 weekly cycles of carboplatin (area under the curve of 2 mg/mL/min) and paclitaxel (50 mg/m2 body surface area on days 1, 8, 15, 22, and 29) with concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week. Mean age was 60 years (around 78% male), with squamous cell carcinoma (23%) and adenocarcinoma (75%) as the predominant histologies.
The first analysis showed low short-term toxicity and 2-year survival increased from 50% for patients receiving surgery alone to 67% for neoadjuvant chemoradiotherapy plus surgery. Five-year follow-up data were consistent with initial reporting. Long-term benefits and harms of this regimen remain unclear, according to the researchers. Neoadjuvant chemoradiotherapy’s side effects could lead to long-term death from other causes than esophageal cancer, and may not be preventing but rather merely postponing cancer-related death. The aim of the current analysis was to determine whether the observed benefits persisted beyond 5 years.
As of Dec. 31, 2018, 117/178 patients in the chemoradiotherapy-surgery arm and 144/188 in the surgery arm had died. Median follow-up for surviving patients was 147 months. Patients in the chemoradiotherapy surgery arm had better overall survival than patients in the surgery arm (hazard ratio, 0.70; 95% confidence interval, 0.55-0.89; P = .004), with a 10-year overall survival of 38% (95% CI, 31-45) and 25% (95% CI, 19-32), respectively. No significant subgroup differences were observed for overall survival. Also, there was no evidence of a time-dependent effect of neoadjuvant chemoradiotherapy on overall survival. The major effect of neoadjuvant chemoradiotherapy, landmark analyses showed, was in the first 5 years of follow-up, with the effect on overall survival stabilized thereafter, with a hazard ratio approaching 1.00.
Cause-specific mortality
Eighty-four of 178 patients in the chemoradiotherapy-surgery arm died of esophageal cancer, with 32 dying of other causes. In the surgery arm, 121/188 died of esophageal cancer and 22 of other causes. The hazard ratio for esophageal cancer death in the chemoradiotherapy-surgery arm was 0.60 (95% CI, 0.46 to 0.80), with 10-year absolute risks of 47% (95% CI, 40-54) and 64% (95% CI,57-71), respectively, in the two arms. Death from other causes was comparable, with 10-year absolute risks of 15% (95% CI, 10-21) and 11% (95% CI, 7-16), respectively, for chemoradiotherapy-surgery versus surgery alone.