Efficacy
Definitive chemoradiation therapy versus radiation therapy alone
The key evidence supporting the use of this protocol comes from the landmark RTOG 8501, a phase III trial, which randomised patients to receive radiation therapy (RT) alone (64 Gy in 32 fractions, n = 62) versus chemoradiation therapy (CRT) (4 cycles of cisplatin and fluorouracil commencing on day 1 of RT (50 Gy in 25 fractions, n = 61).r The trial was closed prematurely with 123 patients, when an interim analysis showed a significant survival advantage for CRT (5-year survival 26% versus 0%; 95% CI:15-37%). Analysis of failure patterns showed a significant reduction in both locoregional and distant failure for CRT. Almost half of the patients in the definitive CRT group developed locoregional relapse.
Definitive chemoradiation therapy versus surgery alone in squamous cell carcinoma histology
A Cochrane review and meta-analysis of eight randomised trials comparing RT or CRT to surgery alone, concluded that CRT appears to be at least equivalent to surgery in terms of short term and long term survival in people with squamous cell carcinoma (SCC) histology oesophageal cancer who are fit for surgery.rr Short term quality of life data favoured non-surgical treatment. The meta-analysis by Ma et al. of trials comparing definitive CRT to surgery alone included two randomised controlled trials.r This showed no difference in overall survival (OS) between surgery and definitive CRT. Pooled odd ratios for 2 and 5 year OS were 1.199 (95% CI:0.922-1.560; p = 0.177) and 0.947 (95% CI:0.628-1.429; p = 0.796), respectively. A subgroup analysis of patients with node positive disease showed a trend towards improved OS, however this difference was not statistically significant (p = 0.076).
Teoh et al. undertook a randomised controlled trial comparing CRT to surgery alone, two thirds of these patients had oesophageal cancer with SCC histology.r This showed improved disease free survival after 5 years in patients with definitive CRT (47.2% vs. 25%, p = 0.07), and also long term OS was increased in this treatment group (5-year survival 50% vs. 29.4%; p = 0.15). The advantage in favour of definitive CRT was more pronounced in patients with clinically involved lymph nodes (5-year survival rate 47.4% vs. 11.8%, p = 0.06).
Definitive chemoradiation therapy vs surgery alone in adenocarcinoma histology
Both a Cochrane review and meta-analysis had inadequate numbers to show differences in outcomes with patients with adenocarcinoma histology.rr No other trials have had sufficient numbers of patients with adenocarcinoma histology to show any significant differences between these treatments.
Definitive chemoradiation therapy versus trimodality treatment
Two trials have compared definitive CRT to tri-modality treatment, both of these trials were predominantly SCC histology.r In the trial by Bedenne et al. definitive radiation therapy doses were either split-course treatment (total dose of 45 Gy in 15 fractions) or conventional treatment (total dose of 66 Gy in 33 fractions) noting fractionation was the clinicians’ choice.r This trial found survival times were comparable between the surgery alone and CRT treatment groups (2-year survival probability rate 33.6% versus 39.8%, respectively (p = 0.03) for non-inferiority at a difference below 10%. The rate of early death was significantly higher with surgery compared to CRT (3-month mortality 9.3% versus 0.8%), as was local tumour control at 2 years (66.4% versus 57.0%).
Dose escalation
The question of dose escalation was explored in the INT 0123 study.r In this study, 236 patients with non-metastatic oesophageal SCC or adenocarcinoma were randomly assigned to receive 50.4 Gy in 28 fractions (1.8 Gy per fraction, 5 fractions per week) or 64.8 Gy in 36 fractions (1.8 Gy per fraction, five fractions per week) with concurrent cisplatin and fluorouracil. Higher RT doses were not associated with a higher median (13 versus 18.1 months) or two-year survival (31% versus 40%); or with the incidence of locoregional persistent or recurrent disease (56% versus 52% for the high dose and control groups, respectively). High-dose RT was significantly more toxic.
Retrospective data suggests dose escalation to a median of 60 Gy using modern radiation techniques results in improved local control with a similar profile, although a survival benefit has not been shown.r One retrospective series included 72 patients who received radical intent CRT to a median dose of 60 Gy (range 56-66 Gy).r 3-year in-field control, OS and relapse-free survival was 64%, 42% and 38%, respectively. In this trial isolated locoregional relapse occurred in 22%, with a 15% isolated in-field recurrence rate. Distant failure as the first site of relapse occurred in 25 patients (35%). Randomised trials are ongoing, but as yet unreported.
Elective nodal irradiation
While some international guidelines recommend elective nodal irradiation, there is limited evidence to support this.r