CROSS trial: 10-year persistent survival benefits with neoadjuvant chemoradiotherapy plus surgery in esophageal cancer

When managing patients with esophageal cancer, surgery alone remains a mainstream treatment for long but its isolated use is still subjected to many limitations.1 Gradually, these limitations give rise to a multimodality therapeutic approach that leverages the strengths of different treatments to better improve outcome and survival while minimizing morbidity.1 In the application of preoperative chemoradiotherapy followed by surgery, the CROSS trial demonstrated that the overall survival (OS) benefits derived from this combination regimen for the treatment of locally advanced resectable esophageal or junctional cancer are not only superior to surgery alone, but also persistent for at least 10 years.2 These long-term results have recently been published in the Journal of Clinical Oncology.2

Being the sixth most common cancer-related mortality globally due to its poor prognosis and high malignant potential, esophageal cancer remains a major health challenge in clinical practice.1,3 Because of the shortcomings bounded with surgery such as the presence of inoperable disease and the association with unfavorable morbidity and mortality, a multimodal therapeutic strategy, which combines both surgical and non-surgical options, has become more compelling in managing patients with esophageal cancer to improve survival outcomes and reduce post-treatment complications.1

When treating early-stage esophageal cancer where tumors are still resectable, neoadjuvant chemoradiotherapy, despite being previously criticized for lacking clinical evidence support and causing postoperative adverse outcomes, was recently demonstrated by meta-analyses to provide survival benefits to patients.4 Moreover, a phase 2 study showed that the regimen of carboplatin, paclitaxel, concurrent radiotherapy plus surgical resection helped all study subjects to achieve a complete resection, with no tumor being identified within the specified resection margins.4 This has thus encouraged investigators to study this regimen further through the initiation of the CROSS trial.4

CROSS was a multicenter, randomized, controlled, phase 3 study that randomly assigned 366 patients with clinically resectable, locally advanced cancer of the esophagus or esophagogastric junction 1:1 to either 5 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.2,5 Following the previous publication of the 5-year follow-up results, the investigators now report the 10-year findings, which have assessed OS, cause-specific survival, and the risks of locoregional and distant relapse using Cox regression analyses.2

With a median follow-up of 147 months, patients receiving neoadjuvant chemoradiotherapy plus surgery achieved better OS than surgery alone (HR=0.70; 95% CI: 0.55-0.89) which was consistent and comparable to the OS result reported previously in the 5-year analysis (HR=0.68; 95% CI: 0.53-0.88; log-rank p=0.003).2 This benefit of neoadjuvant chemoradiotherapy plus surgery on OS was not significantly time-dependent (pinteraction=0.73) as was maintained throughout the 10 years of follow-up.2 The 10-year OS rate of the neoadjuvant chemoradiotherapy plus surgery was 38% which was higher than surgery alone of 25%, translating to an absolute 10-year OS benefit of 13% for the former regimen.2

The risk of death from esophageal cancer was much lower in the neoadjuvant chemoradiotherapy arm (HR=0.60; 95% CI: 0.46-0.80), but that from other causes was similar between the 2 study groups (HR=1.17; 95% CI: 0.68-1.99).2 At 10 years, while the risk of isolated distant relapse was deemed comparable between arms (HR=0.76; 95% CI: 0.52-1.13), a persistently lower risk of isolated locoregional (HR=0.40; 95% CI: 0.21-0.72) as well as synchronous locoregional plus distant relapse (HR=0.43; 95% CI: 0.26-0.72) was observed in the neoadjuvant chemoradiotherapy arm.2

In summary, the favorable survival benefits acquired from the use of neoadjuvant chemoradiotherapy plus surgery over surgery alone were not only consistent with the 5-year results but also sustained for up to 10 years.2,5 Dr. Ben M. Eyck, lead investigator of the CROSS trial from the Department of Surgery, Erasmus MC-University Medical Center Rotterdam, concluded, “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.”

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