A randomized phase III trial of preoperative chemoradiation followed by surgery (CR-S) versus surgery alone (S) for localized resectable cancer of the esophagus
Reviewer: Mary Kara Bucci, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 20, 2002
Presenter: B. H. Burmeister
Presenter's Affiliation: Trans Tasmanian Radiation Oncology Group, Australasian Gastrointestinal Trials Group, and Clinical Trials Centre, Sydney, Australia
Type of Session: Scientific
Previous randomized studies have suggested a role for pre-operative chemoradiation in the treatment of esophageal cancer, not only to increase tumor resectability, but also to improve overall survival. Some studies have suggested a 3-year relapse-free survival rate as high as 35% with pre-operative chemoradiation, a large improvement over the approximately 20% 3-year overall survival rate seen with surgery alone. This study was designed to test the hypothesis that the addition of pre-operative chemoradiation improves survival over surgery alone in this disease, and was powered to detect a 15% survival difference.
Materials and Methods
- 257 patients from 25 centers in 3 countries were randomized to pre-operative chemoradiation followed by surgery, or surgery alone. One patient was later found to be ineligible and excluded from analysis.
- 157 pts (61%) had adenocarcinoma, and 36% had squamous cell histology. The remaining 3% had mixed or undifferentiated histology.
- All patients were staged by CT scan. Later patients also underwent staging laparoscopy. PET scanning and endoscopic ultrasound were not performed, due to the relative inavailabilty of these modalities in the countries where this study was conducted (Australia and New Zealand).
- Chemotherapy consisted of Cisplatin (80 mg/m2) on day 1 and 5 FU (800 mg/m2) by 96-hour infusion, days 2-5.
- Radiation therapy was 35 Gy in 15 fractions over 3 weeks, staring day 1 of chemotherapy.
- Patients went on to receive surgery 4-6 weeks after the completion of radiation therapy.
- End-points of this study were Relapse-Free Survival (RFS), Overall Survival (OS), toxicity, and tumor response.
- 205 patients completed treatment as planned.
- 70-80% of patients underwent a curative (R0) resection. This was not statistically different on either arm.
- Median length of post-operative hospital stay was equivalent between the two arms.
- There was no difference in post-operative complications.
- Treatment-related mortality was not different between the two arms. Overall treatment-related mortality was 4.6%. Non-treatment-related mortality was 3.1%.
- Patients in the chemoradiation arm had a pathologic complete response rate of 15% [26% for squamous cell carcinoma (SCCA), 9% for adenocarcinoma (AC)].
- Median OS was not significantly different between the two groups; 21.7 months (CR-S) and 18.5 months (S) (p=0.38).
- By histology subgroup, there was a trend towards benefit for SCCA in OS (p=0.11) and RFS (p=0.07). Patient analysis by gender also showed a trends towards significance in RFS for females (p=0.04); however, the confidence intervals crossed 1.0.
- There was no difference in sites of failure, local v. distant v. both, between the two arms.
The authors conclude that the benefits of pre-operative chemoradiation are limited compared to surgery alone.
Previous trials that have shown a benefit to pre-operative chemoradiation have been criticized for having sub-optimal results in the surgery-alone arm (as low as 12 months median survival). The median survival for the surgery alone arm in this trial is 18.5 months, which is consistant with trials that have not shown a benefit to pre-operative CRT, and superior