Randomized phase III trial in locally advanced esophageal cancer: radiochemotherapy followed by surgery versus radiochemotherapy alone (FFCD 9102)
Reviewer: Mary Kara Bucci, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 20, 2002
Presenter: L. Bedenne
Presenter's Affiliation: Sevice de Hepato-Gastroenterologie-Chu-Le Bocage, Dijon-Cedex, France
Type of Session: Scientific
While surgical resection remains part of the standard of care for locally advanced esophageal cancer, non-randomized studies have demonstrated outcomes for radiochemotherapy alone that are comparable to historical controls. This randomized trial was designed to test this hypothesis. The primary end-point was overall survival, and the study was powered to detect a 15 % difference between the two arms.
Materials and Methods
- Patients with locally advanced but resectable esophageal cancer of the thoracic or distal esophagus were eligible for this trial. Patients with cancer of the cervical esophagus were excluded. Tumors were T1-3, N0-1, with histology of either squamous cell or adenocarcinoma.
- All patients received induction radiochemotherapy (RCT). Those who demonstrated at least a partial response were randomized to surgery (arm A) or further RCT (arm B).
- Induction RCT consisted of 5FU (800 mg/m2 96-hour infusion) days 1-5 and 22-26, and cisplatin (75 mg/m2) on days 2 and 23. Prior to 1999, radiation was given split course, 15 Gy x 2, days 1-5 and 22-26. After 1999, radiation was continuous course, 46 Gy/4.5 weeks.
- The continuation of RCT for patients randomized to arm B included 3 further cycles of 5FU/Cisplatin, with the first of these 3 cycles given with either 15 Gy (split course prior to 1999) or 20 Gy continuous course radiation.
- The median patient age was 58. Patients were equally balanced between the two randomization groups with respect to weight loss, dyphagia, tumor histology.
- Between 1/93 and 11/00, 455 patients received induction RCT. Of these, 259 patients were randomized for further treatment.
- Grade 3-4 toxicities included neutropenia (20%), febrile neutropenia (2%), Thrombocytopenia (6%), and nausea/vomiting (6%). These toxicities were not significantly different between the two groups.
- 3- and 5-year overall survival (OS) was not significantly different between the two groups, 29% (arm A) versus 32% (arm B) at 3-years (p=0.56), and 21% (arm A) versus 19% (arm B) at 5 years.
- Death rate within 3 months of starting treatment was improved for arm B; 9% for arm A v. 1% for arm B (p=0.002).
- Length of overall hospital stay was significantly different; median 68 days for arm A and 52 days for arm B, p=0.02.
- More patients in arm B needed palliative procedures: esophageal dilatation alone, 19% arm A, 14% arm B; esophageal stenting alone, 4% for arm A and 13% for arm B; both dilatation and stenting, 1% arm A and 19% arm B, p<0.001. 76% of patients on arm A needed no palliative intervention, compared with 54% of patients on arm B.
- When patients on arm A were analyzed according to type of radiation received, split-course v. continuous, there was difference in OS; however, patients who received continuous radiation needed fewer palliative interventions than those who received split-course radiation.
- 4 patients in the CRT arm were salvaged surgically.
- In this trial, there were more early deaths in the surgical arm, but more palliative procedures performed in the RCT arm.
- The authors conclude that RCT alone is a valuable alternative to surgery.
This large randomized trial, the first of its kind, was unable to detect a survival advantage to RCT followed by surgery over RCT alone for patients who responded to neoadjuvant RCT. The type of radiation (split-course) given over the first 7 years of this 8 year study was shown in 1999 to be sub-optimal, and was then changed to continuous radiation. The patients who received split-course radiation were more likely to need palliative intervention; therefore it is impossible to apply any conclusion to patients who are treated with optimal radiotherapy. Based on this trial, definitive non-surgical treatment for locally advanced but resectable esophageal cancer is a reasonable alternative to surgery.
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