Preoperative chemotherapy (CTX) versus preoperative chemoradiotherapy (CRTX) in locally advanced esophagogastric adenocarcinomas: First results of a randomized phase III trial
Reviewer: Eric Shinohara MD, MSCI
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 3, 2007
Presenter: M. Stahl Presenter's Affiliation: University of Essen, Germany Type of Session: Scientific
Neoadjuvant chemoradiation is frequently used in the treatment of localized adenocarcinomas of the esophagus. Prior studies (CALGB 9781) have demonstrated the superiority of trimodality therapy compared with surgery alone in esophageal cancer.
However, there are not clear guidelines regarding the treatment of esophagogastric (GE) junction adenoncarcinomas. No previous randomized studies have addresses whether the addition of neoadjuvant radiation to neoadjuvant chemotherapy improves outcomes.
Prior studies have suggested that the addition of neoadjuvant chemotherapy results in three year overall survival rates (OS) of 25%.
Materials and Methods
The present study is a Phase III randomized trial comparing neoadjuvant chemoradiation with neoadjuvant chemotherapy in the treatment of adenocarcinomas of the GE junction.
The primary endpoint of this study was overall survival. Secondary endpoints included the percent of patients with a complete resection (R0), local tumor control, and surgical mortality.
Patients with T3 or T4 Nx M0 adenocarcinoma of the GE junction per EGD, EUS, CT and laparoscopy were eligible for this study.
All patients underwent laparoscopy to evaluate for peritoneal disease.
Based on the results from a previous phase II study, it was estimated that three year OS with chemotherapy was 25%. Based on the prediction that radiation could improve OS to 35%, 394 patients would be needed to adequately power the study.
Patients were randomized to either arm A or arm B. Arm A consisted of treatment with 2.5 cycles of chemotherapy with cisplatin 50mg/m2 on days one, 15, and 29, folinic acid 500 mg/m2 and 5-FU 2g/m2 as a 24h-infusion. Each cycle lasted six week. Arm B consisted of 2 courses of the same chemotherapy followed by three weeks of chemoradiotherapy consisting of 30 Gy (using extended fields to encompass all possible nodal regions), cisplatin 50 mg/m2 on days two and eight and etoposide 80 mg/m2 on days three through five.
Epoetin alpha was recommended to keep the hemoglobin above 12.5 g/dl.
Surgical resection was planned 3 to 4 weeks after the end of preoperative therapy in both arms.
No post-operative chemotherapy was given.
From December of 2000 to December of 2005 a total of 126 patients from 19 cancer centers in Germany were accrued and randomized. The trial was subsequently closed due to poor accrual. Ultimately, 120 patients were eligible, 60 in each treatment arm.
Arm A had limited toxicitiy with 88% of patients being able to go on to surgery.
35% of patients in arm B had severe leucocytopenia and 16% had severe thrombocytopenia during chemotherapy. Ultimately, 82% of patients in arm B were able to go on to surgery.
Complete surgical resection was possible in 77% of patients in arm A and 85% of patients in arm B. However, there was no difference in the number of R0 resections between the two arms.
Pathologic complete response rates were 2.5% in arm A and 17% in arm B (p=0.06)
There was increased postoperative mortality in arm B (10.2%, N=5) compared to arm A (3.8%, N=2). However, despite this, three year overall survival in arm B (47.4%) was better than three year survival in arm A (27.7%), though this difference did not reach statistical significance (p=0.07).
Median OS was 33.1 months in arm B and 21.1 months in arm A.
Local control was superior in arm B (76.5%) compared with A (59%), though this did not reach statistical significance (p=0.06).
There was a strong trend towards significant improvements in local control, pathological complete response, and OS with combined chemoradiation treatments. These results are comparable to similar trials conducted previously.
Pre-operative chemoradiation remains a problem due to toxicity and postoperative mortality. However, despite this, there was still an improvement in OS in the combined treatment group. Greater surgical complications may have been due to the lower volume at some centers. Of the 19 cancer centers involved with the trial, three contributed more than 10 patients.
Though large fields of radiation were used, the dose of radiation was low. The authors believe that it would be possible to go to higher doses of 40 to 50 gray if toxicity could be managed.
Results from this study suggest that combined chemoradiation leads to improved local control and OS compared to chemotherapy alone in patients with locally advanced adenocarcinomas of the GE junction. Unfortunately, due to the poor accrual, statistical significance was not reached, but results are clearly trending towards a significant difference. Likely with a larger number of patients a significant difference would have been seen. OS in the control arm was similar to previous phase II trials.
Ways to limit toxicity may help reduce postoperative mortality and improve outcomes as well as allow higher doses of radiation to be used. No information was provided regarding supportive care for patients during treatment. Differences in weight loss between the two groups may indicate that the combined treatment group needs more aggressive nutritional or hydration support, which may improve surgical outcomes. Oxaliplatin may be better tolerated in combination with radiation that cisplatin. Furthermore, improvements in surgical technique may further reduce postoperative mortality.
Prior studies have suggested superior outcomes with trimodality therapy with similar outcomes in the trimodality arm compared with the present study (CALGB 9781). Results from these studies suggest that trimodality therapy is superior and accrual to future studies should improve with the data from these studies.
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