Preoperative chemotherapy for resectable thoracic esophageal cancer.
BACKGROUND
Surgery has been the treatment of choice for localized esophageal cancer. A number of studies have investigated whether preoperative chemotherapy followed by surgery leads to an improvement in cure rates, but the individual reports have been conflicting. An explicit systematic update of the role of preoperative chemotherapy in the treatment of resectable thoracic esophageal cancer is therefore warranted.


OBJECTIVE
The objective of this review is to determine the role of preoperative chemotherapy on patients with resectable thoracic esophageal carcinomas.


METHODS
Trials were identified by searching the Cochrane Controlled Trials Register, MEDLINE (1966 - 2003), EMBASE (1988 - 2003) and CancerLit (1993 - 2003). There were no language restrictions.


METHODS
Types of studies. Studies that randomised patients with potentially resectable carcinomas of the esophagus (of any histologic type) to chemotherapy or no chemotherapy before surgeries were included in this review. Types of participants. The participants consisted of patients with localized potentially resectable thoracic esophageal carcinomas. Trials involving patients with carcinomas of the cervical esophagus were excluded. Types of interventions. Trials that compared chemotherapy before surgery (esophagectomy) with surgical resections alone (esophagectomy) were included. Types of outcome measures. The primary outcome was overall survival at yearly intervals after randomisation. Secondary outcomes of interest included rates of resections, response to chemotherapy, rates of local and distant recurrences, quality-of-life, and treatment morbidity and mortality.


METHODS
All analyses were carried out on intention-to-treat. Survival at 1, 2, 3, 4 and five years were used as endpoints of clinical relevance along with the median survival. The risk ratio (relative risk; RR) was the primary measure of effect for survival, rates of resections, and tumour recurrences. The risk difference (RD) was used to describe differences in response to chemotherapy, treatment morbidity and mortality.


RESULTS
There were 11 randomised trials involving 2051 patients. At 1- year and 2-year the risk ratios showed no difference in survival between preoperative chemotherapy and surgery alone. The 3-year risk ratios found a 21% increase in survival (RR = 1.21; 95% CI 0.88 to 1.68; p = 0.25) and a 24% increase in survival with preoperative chemotherapy at 4 years (RR = 1.24; 95% CI 0.92 to 1.68; p = 0.15) but they did not reach statistical significance. Only at 5 years did the results become significant (RR = 1.44; 95% CI 1.05 to 1.97; p = 0.02). The overall rate of resections and the rate of complete resections (R0) did not differ between the preoperative chemotherapy arm and surgery alone. The pooled clinical response to chemotherapy was about 36% (RD = 0.36; 95% CI 0.26 to 0.47) but the complete pathologic response was a disappointing 3% (RD = 0.03; 95% CI 0.01 to 0.04). No single agent or combination of chemotherapeutic agents was found to be superior to the others. There was a 19% reduction in local recurrence with preoperative chemotherapy, but this was not significant (RR = 0.81; 95% CI 0.54 to 1.22; p = 0.3). Preoperative chemotherapy was somewhat more harmful to patients than surgery alone.


CONCLUSIONS
In summary, preoperative chemotherapy plus surgery appears to offer a survival advantage at 3, 4, and 5 years, which reached significance only at 5 years compared to surgery alone for resectable thoracic esophageal cancer of any histologic type. The number needed to treat for one extra survivor at five years is eleven patients. The results are tempered by the increased toxicity and mortality associated with chemotherapy. The most beneficial chemotherapy combination appears to be cisplatin and 5-flurouracil based, however, the dosing is unclear.
Malthaner
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Department of Surgery, University of Western Ontario, London Health Sciences Centre, 375 South Street, Suite N345, London, Ontario, Canada, N6A 4G5. richard.malthaner@lhsc.on.ca
Fenlon
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D000970:Antineoplastic Agents / Q000627:therapeutic use; D003131:Combined Modality Therapy; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery; D006801:Humans; D011300:Preoperative Care; D011788:Quality of Life; D016032:Randomized Controlled Trials as Topic
D000970:Antineoplastic Agents