CROSS: New Standard for Esophageal Neoadjuvant Therapy?

Alok A. Khorana, MD


August 06, 2012

Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer

van Hagen P, Hulshof MC, van Lanschot JJ, et al; CROSS Group
N Engl J Med. 2012;366:2074-2084

Study Summary

The investigators randomly assigned patients with resectable cancers to undergo surgery alone or receive weekly carboplatin (area under the curve, 2) and paclitaxel (50 mg/m2) for 5 weeks and concurrent radiotherapy, followed by surgery. The study population analyzed included 366 patients with a mix of histologies: 275 (75%) had adenocarcinoma, 84 (23%) had squamous cell carcinoma, and 7 (2%) had large-cell undifferentiated carcinoma.

R0 resection was achieved in 92% of patients in the neoadjuvant therapy group vs 69% in the surgery group (P < .001). A pathological complete response was achieved in 29% of patients after neoadjuvant therapy. Postoperative complications and in-hospital mortality were similar. Median overall survival was 49.4 months in the chemoradiation/surgery group vs 24.0 months with surgery alone (hazard ratio [HR] for survival, 0.657; 95% CI, 0.495-0.871; P = .003). However, the HR for esophageal adenocarcinoma was only marginally statistically significant (adjusted HR, 0.74, 95% CI, 0.54-1.02; P = .07).


This trial confirms that preoperative chemoradiation for resectable esophageal cancer is safe and, compared with surgery alone, is associated with pathological complete responses, higher rates of R0 resection, and prolonged survival. However, the findings support preoperative chemoradiation as one of several care options rather than establishing it as the premier standard of care. Current options for resectable esophageal cancer include preoperative cisplatin-based radiotherapy and preoperative or perioperative chemotherapy alone (either 5-fluorouracil/cisplatin, as in the UK Medical Research Council study,[1] or epirubicin, cisplatin and fluorouracil, as in the MAGIC study[2]).

The CROSS trial compared weekly paclitaxel/carboplatin with the standard of surgery alone rather than other established preoperative regimens. In addition, it did not include gastric cancers, as many other studies have done. Finally, the study was only marginally significant for adenocarcinomas, despite these being the majority of cases. In other words, the preponderance of benefit was driven by benefit for squamous cell carcinoma of the esophagus, which is less frequent in the United States.

This study therefore offers a new option of weekly chemotherapy with concurrent radiotherapy for patients with resectable esophageal (but not gastric) cancers. Ongoing efforts to improve response rates and identify the ideal preoperative regimen will clarify matters in the next few years.



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