Esophageal cancer is the eighth most common cancer worldwide encompassing more than 480,000 diagnoses and causing 400,000 deaths annually.1,2 Localized esophageal cancer has an estimated 5-year survival rate of 37% with appropriate treatment. If esophageal cancer has spread to organs, the 5-year survival rate is estimated to be 3%.3 The benefit from neoadjuvant chemoradiotherapy for the treatment of localized esophageal cancer has yet to be confirmed. The CROSS study was a randomized phase III trial conducted in 360 patients with potentially curable esophageal esophagogastric-junction carcinoma.4 Patients included in the study were between 18-75 years of age and had a World Health Organization (WHO) performance status of <2. The two arms of the study were neoadjuvant chemoradiotherapy using a carboplatin and paclitaxel regimen followed by surgery (n=178) versus surgery alone (n=188).
In the neoadjuvant chemoradiotherapy-surgery arm, carboplatin (area under the curve of 2mg/ml/min) and paclitaxel (at a dose of 50 mg/m2) was administered on days 1, 8, 15, 22, and 29. Total radiotherapy dose was 41.4 gray (Gy) delivered using external beam radiation. Each radiation fraction was 1.8Gy given 5 times a week for a total of 23 fractions. Surgery was performed preferably 4-6 weeks after chemotherapy. Stratification factors included histology, treatment center, lymph-node stage, and WHO performance score. All data was analyzed according to the intention-to-treat principle. van Hagen et al. calculated that 175 patients were needed in each arm to detect any statistically relevant difference in median overall survival within the study. The primary endpoint was overall survival.
The median overall survival was 24.0 months in the surgery alone arm, compared to 49.4 months in the chemoradiotherapy-surgery arm (P = 0.003) with a median follow-up of 45.4 months within the study. A pathological assessment revealed that 31% of the patients in the chemoradiotherapy-surgery arm had positive lymph-node findings, versus 75% in the arm with surgery alone. Of those patients who expired, majority of deaths were attributed to recurrent cancer; 85% in the chemoradiotherapy-surgery arm versus 94% in the arm with surgery alone. Of the patients in the chemoradiotherapy-surgery arm, the entire chemotherapy treatment regimen was administered to 91% of patients and the entire dose of radiotherapy was administered to 92% of patients. Only 7% of patients in the chemoradiotherapy-surgery arm experienced a grade 3 hematologic toxicity and only 1 patient developed a grade 4 hematologic toxicity and neutropenic fever. Less than 13% of patients in the chemoradiotherapy-surgery arm experienced grade 3 or higher major nonhematologic toxicities. Complications of surgery were no different between study arms.
The authors concluded patients in neoadjuvant chemoradiotherapy-surgery arm had a better overall survival for potentially curable esophageal or esophagogastric-junction cancer compared to those who received surgery alone. Areas of concern about neoadjuvant chemoradiotherapy-surgery included rate of surgical complications and toxicity of the regimen. However, van Hagen and colleagues demonstrated similar rates of chemoradiotherapy toxicity and surgical complications between both arms of the study.
Notable features of this trial include: it is a well-designed study, adequate risk factor stratification and randomization, conducted in medically fit patients, and had an appropriately selected chemoradiotherapy treatment and ...