The largest study to date to look at the effects of preoperative chemoradiotherapy in advanced esophageal cancer has found that a combination regimen of chemotherapy and radiation before resection is superior to surgery alone, according to an abstract presented at the 2010 ASCO Annual Meeting. In the phase III multicenter CROSS trial, involving 364 patients in the Netherlands with resectable esophageal adenocarcinoma or squamous cell carcinoma, the median survival of patients who received chemoradiation (CRT) and surgery was 49 months, compared to 26 months for those who received surgery alone. With a median follow-up of 32 months, 70 patients had died in the CRT group vs 97 in the surgery-alone group, and 3-year overall survival was superior in the CRT arm (HR = 0.67, P = .011)

Data Differed for Squamous Cell vs Adenocarcinoma

"This is a nicely performed trial that suggests that esophageal cancer patients with T2N1 or T3N0-1 tumors should be treated with chemoradiation followed by surgery," said James L. Abbruzzese, MD, Professor of Medicine, and Chairman of the Department of Gastrointestinal Medical Oncology at The University of Texas M. D. Anderson Cancer Center. Dr. Abbruzzese presented the study's results at the Best of ASCO Meeting in San Francisco. "The trial supports the authors' conclusions that chemotherapy with carboplatin and paclitaxel, combined with radiotherapy does improve survival compared to surgery alone," he said.

Dr. Abbruzzese pointed out that the CRT regimen used in the CROSS trial-paclitaxel with carboplatin and 41.4 Gy radiotherapy-was well tolerated, probably more so than regimens with fluorouracil. "I'm impressed with the results of combining carboplatin and paclitaxel with radiation in this patient group," he said.

Yet Dr. Abbruzzese also noted that CRT with surgery improved outcomes most for patients with squamous cell carcinoma (HR = 0.34), who comprised 23% of patients treated in both arms of the trial. By contrast, those with adenocarcinoma derived less benefit from CRT combined with surgery (HR = 0.82).

"These results highlight the difficulty of treating patients with adenocarcinoma of the esophagus. In fact, patients with squamous cell carcinomas can be cured with chemoradiation alone without surgery," Dr. Abbruzzesse said. He noted that more research needs to delve into how to improve outcomes for adenocarcinoma patients, and that to better understand the impact of various treatments, adenocarcinoma patients should be separated from those with squamous cell carcinoma in clinical trials. Combining these two groups in a clinical trial has the potential to confound results, Dr. Abbruzzesse said.

Typical U.S. Esophageal Cancer Population

In the CROSS trial, patients had esophageal squamous cell or adenocarcinoma T1N1 or T2-3Nx, M0. The greatest numbers of patients in the trial had T3N0 or T3N1 tumors, followed by T2N0 or T2N1 tumors. Patients with T1N0 or metastatic disease were excluded. Most patients (74% in both arms) had adenocarcinoma, and the great majority also had distal tumors.

"This really mirrors the population that we're likely to see in the United States at this time," Dr. Abbruzzesse said. In the CRT arm, patients received weekly paclitaxel at 50 mg/m² plus carboplatin at AUC2 as well as concurrent radiotherapy of 41.4 Gy in 23 fractions of 1.8 Gy. Patients on the intervention arm underwent surgery within 6 weeks of completion of their CRT regimen. Most patients-85% to 90%-were able to have surgery, even if they had received prior CRT.

Results indicated that 67% of those on the surgery-alone arm had R0 resection margins-defined as no tumor within 1 mm of resection margins-while 92.3% in the CRT arm achieved R0 resection margins. Using 158 available resection specimens, the investigators found that 32% of patients on the CRT arm had a pathologic complete response in their primary tumors. The 2-year and 3-year survival rates were 52% and 48% in the surgery-alone arm vs 67% and 59% in the CRT arm. Postoperative morbidity and mortality rates were similar in both groups, with the greatest percentage due to pulmonary complications or anastomotic leakage.

In the CRT arm, all major toxicities of grade 3 or greater were nonhematologic, affecting 16% of patients. Just under 7% of patients who received CRT experienced hematologic toxicities. Most toxicities were grade 3, and only two patients experienced grade 4 or 5 toxicities. "These numbers reflect the excellent tolerability of the preop program," Dr. Abbruzzese said. ■

Reference

1. Van Der Gaast A, van Hagen P, Hulshof M, et al: Effect of preoperative concurrent chemoradiotherapy on survival of patients with resectable esopahageal or esophagograstic junction cancer: Result from a multi-center randomized phase III study. Best of ASCO Annual Meeting San Francisco. Abstract 4004. Presented July 17, 2010, by James L. Abbruzzese, MD.