Standard versus prolonged intervals to surgery in resectable esophageal cancer: does timing matter?

The incorporation of neoadjuvant chemoradiotherapy (nCRT) in addition to surgery of locally advanced esophageal cancer (EC) after publication of the landmark CROSS trial 1 van Hagen P. Hulshof M.C.C.M. van Lanschot J.J.B. et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012; 366: 2074-2084 Crossref PubMed Scopus (3981) Google Scholar has yielded a remarkable improvement in long-term prognosis of patients with EC. In the CROSS trial, patients were administered weekly cycles of carboplatin and paclitaxel with concurrent radiotherapy (41.4 Gy in 23 fractions) followed by surgery, or surgery alone. This approach has improved median overall survival from 24.0 to 49.4 months and, consequently, has become a standard of care. According to the protocol of the CROSS trial, patients underwent surgery as soon as possible after randomization (control arm) or after completion of nCRT (intervention arm), preferably within 4-6 weeks. In practice, the median time between the end of chemoradiotherapy and surgery was 6.6 weeks (interquartile range 5.7-7.9 weeks). The optimal time to surgery after nCRT is, however, not known and depends on several factors, including time patients need to recuperate from nCRT, the attainment of maximum therapeutic efficacy from nCRT, and the potential for cancer cell regrowth and progression over time. Thus, ‘timing matters’: the best timing for surgery is pivotal in securing optimal patient outcomes during the perioperative period, and at the same time secure long-term survival. In real-life world scenarios, the time to surgery often exceeds 6 weeks due to patient-related or logistical reasons, raising important questions about its potential consequences for prognosis.