Combined chemotherapy and radiotherapy (without surgery) compared with radiotherapy alone in localized carcinoma of the esophagus.
BACKGROUND
Esophageal carcinoma can be managed primarily with either a surgical or radiotherapeutic (non surgical) approach. Strategies to improve the outcome of either modality alone include the use of combined modalities. Combination chemotherapy radiotherapy is one approach that has been explored over the years with increasing application in clinical practice especially in North America.


OBJECTIVE
To evaluate the effectiveness of combined chemotherapy and radiotherapy versus radiotherapy alone in the outcome of patients with localized esophageal carcinoma. Outcomes of interest include overall survival, cause specific survival, local recurrence, dysphagia relief, quality of life, acute and chronic toxicities.


METHODS
The Cochrane strategy for identifying randomized trials was combined with MeSH headings including esophageal neoplasms, radiotherapy, chemotherapy combined modality, drug therapy combination. Medline, Cancerlit and Embase were searched using this strategy. In addition, the Cochrane library was also searched. References from relevant articles and personal files were included.


METHODS
Randomized controlled trials in patients with localized esophageal cancer, with one arm employing radiotherapy alone, and one arm employing combination radiotherapy chemotherapy were included. Studies comparing non chemotherapy agents such as pure radiotherapy sensitisers, immunostimulants, planned esophagectomy, were excluded.


METHODS
Data were extracted by two independent reviewers, and the trial quality was assessed using both the Jadad scoring and Detsky checklist. Sensitivity analysis was planned to explore sources of heterogeneity where heterogeneity existed. The factors hypothesized a priori included combination versus sequential treatment, quality of study, biological effective radiotherapy dose (i.e. Radiotherapy dose) cisplatin versus non cisplatin containing trials, and 5FU versus non 5FU containing trials. Odds Ratio (OR) and 95% confidence limits were used to assess the significance of the difference between the treatment arms. Absolute risk difference and number needed to treat (NNT) were used to express the magnitude of difference where appropriate.


RESULTS
Thirteen randomized trials were included in the analysis. There were eight concomitant and five sequential radiotherapy and chemotherapy (RTCT) studies. The studies were analyzed separately due to observed heterogeneity across all the studies and biological considerations. Concomitant RTCT provided significant overall reduction in mortality at 1 and 2 years. The mortality in the control arms was 67% and 86% respectively. Combined RTCT provided an absolute reduction of mortality by 9% (95% CI 2-17%) and 8% (95% CI 1-17%) respectively. Expressed as NNT, this is 11 and 10 respectively. At longer follow up, the results were heterogeneous, cautioning against pooling of the data. There was a reduction in the overall local recurrence rate. The local recurrence rate for the control arms was in the order of 69%. Combined RTCT provided an absolute reduction of local recurrence rate of 5% (95% CI 4-26%) with a NNT of 7. There was significant increase of severe and life threatening toxicities with a NNH of 6, with this approach. With the sensitivity analysis, there was a suggestion that cisplatin based and 5FU based chemotherapy studies were reasonable regimens to employ when using this strategy. The results from the sequential RTCT studies were heterogeneous and could not be pooled. Factors hypothesized a priori did not identify any single source that could account for a significant component of the heterogeneity. Examining the results individually, there was no data to support clinical benefit. This approach was also accompanied by significant toxicities.


CONCLUSIONS
When a non-operative approach is selected, then concomitant RTCT is superior to the RT alone. This approach is accompanied by significant toxicities. In patients who are in good general condition, and the risk benefit has been thoroughly discussed with the patient, concomitant RTCT should be considered for the management of esophageal cancer compared with radiotherapy alone.
Wong
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Radiation Oncology, Toronto Sunnybrook Regional Cancer Center, 2075 Bayview Avenue, Toronto, Canada, M4N 3M5. rebecca wong@cancercare.on.ca
Malthaner
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D003131:Combined Modality Therapy; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D009364:Neoplasm Recurrence, Local; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis