Definitive CRT vs RT alone
The key evidence supporting the use of this protocol comes from the landmark RTOG 8501, a phase 3 trial, which randomised 123 patients to receive radiotherapy (RT) alone (64Gy, n=62) vs chemoradiotherapy (CRT) (4 cycles of cisplatin and fluorouracil commencing on day 1 of RT [50Gy in 25#], n=61).r The trial was closed prematurely with 123 patients, when an interim analysis showed a significant survival advantage for CRT (five-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 CRT vs surgery alone in squamous cell carcinoma (SCC) histology
A Cochrane review and meta-analysis of eight randomised trials comparing radiotherapy 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 SCC histology oesophageal cancer who are fit for surgery.rr Short term quality of life data favoured non-surgical treatment. The meta-analysis performed by Ma et al. 2018 of trials comparing definitive CRT to surgery alone included 2 randomised controlled trials.r This showed no difference in OS between surgery and definitive CRT. Pooled ORs for 2 and 5 year OS was 1.199 (95% CI 0.922-1.560; P=0.177) and 0.947 (95% CI 0.628-1.429; P=0.796), respectively. Of note 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. 2014 undertook a randomised controlled trial comparing CRT to surgery alone, 2/3 oesophageal cancer patients 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 CRT 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 CRT vs trimodality treatment
Two trials have compared definitive CRT to tri-modality treatment, both of these trials were predominantly SCC histology.r
One of these trials by Bedenne et al. where definitive radiotherapy doses in this trial were either split course treatment using total dose of 45Gy in 15 fractions or conventional treatment to a total dose of 66Gy in 33 fractions (fractionation was clinicians’ choice).r This trial found that survival times were comparable between the surgery alone and CRT treatment groups (2-year survival probability rate 33.6% vs. 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% vs. 0.8%, respectively), as was local tumour control at 2 years (66.4% vs. 57.0%, respectively).
The question of dose escalation was explored in INT 0123.r In this study 236 patients with non-metastatic oesophageal SCC or adenocarcinoma were randomly assigned to one of two different RT doses: 50.4Gy (28 fractions of 1.8Gy each, five fractions per week) or 64.8Gy (36 fractions of 1.8Gy each, 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 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 60Gy 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 underwent radical intent CRT to a median dose of 60Gy (range 56-66Gy).r In this study 3 year in-field control, overall survival 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.