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Squamous cell carcinoma is rampant in certain parts of the world and it is the most common histologic subtype of esophageal cancer globally. Compared to adenocarcinoma, where obesity, gastroesophageal reflux, and Barrett esophagus seem to play a role, tumorigenesis of squamous cell carcinoma of the esophagus is associated with smoking, alcohol consumption, and poor nutrition (or nutritional deficiencies). Recent molecular studies have identified a subgroup of tumor initiating cells for squamous cell carcinoma with TGF-b and integrin/focal adhesion kinase (FAK) signaling and a cancer stem cell signature has been correlated with a number of self-renewal genes orchestrated by Bmi1, Hmaga2, and Sox2. Genome-wide association studies have also identified three susceptibility loci related to tobacco and alcohol. Further molecular studies are needed to develop better risk stratification and therapeutics for squamous cell carcinoma patients. For patients with localized squamous cell carcinoma, surgery as primary therapy is commonly used in many regions of the world, but results are uniformly poor. We recommend surgery for patients with T1b cancer, but patients with tumors higher that T1b should be considered for combined modality therapy. Preoperative chemoradiation seems to provide the strongest level 1 evidence based on the Dutch trial of preoperative chemoradiation versus surgery. In this issue, Ando et al. discuss their results of a phase III trial comparing preoperative cisplatin/fluorouracil with postoperative cisplatin/fluorouracil in patients with localized squamous cell carcinoma of the esophagus. A total of 330 patients were randomized, and the authors found that the overall survival (OS) of patients who received preoperative chemotherapy was superior to that for patients who received postoperative chemotherapy. The authors claim that preoperative chemotherapy should therefore be regarded as standard treatment. We acknowledge that the conception and execution of a phase III trial requires mobilization of many resources, including commitment of many dedicated investigators, time, cost, and labor. However, a phase III trial, if properly conceived and completed, provides the best tool to sort out the true contributions of a therapy or approach of interest. Let us examine the trial being published by Ando et al. The current trial was based on their previous experience with JCOG9204, which randomized 242 patients with squamous cell carcinoma to surgery alone or postoperative cisplatin/fluorouracil. The primary end point of diseasefree survival (DFS) was increased in the postoperative chemotherapy arm (P = 0.037) but the overall survival was not different for the two groups (P = 0.13). A subgroup analysis of JCOG9204 showed that patients with node-negative cancer did not benefit from postoperative chemotherapy. The current trial randomized localized squamous cell carcinoma patients to receive either postoperative chemotherapy or preoperative chemotherapy with the primary end point of DFS. Unfortunately, the trial design of this study had a major flaw that precludes any meaningful conclusions to be drawn. In the postoperative treatment arm, patients with node negative cancer did not receive chemotherapy because JCOG 9204 did not find a benefit for adjuvant chemotherapy in a subset analysis of node-negative patients. Because of this design, 140 patients receive preoperative chemotherapy, while only 81 patients Society of Surgical Oncology 2011

Preoperative Chemotherapy for Localized Squamous Cell Carcinoma of the Esophagus? We Should Go Back to the Drawing Board!