Efficacy
For resectable oesophageal cancer, surgery is generally considered a preferred component of management. However, for squamous cell carcinoma definitive chemoradiation therapy (CRT) followed by response assessment with or without salvage surgery is a reasonable alternative. The key evidence supporting the use of this protocol comes from the updated meta-analysis of 24 studies by the Australasian Gastro-Intestinal Trials Group (AGITG),r CROSS,r POET,r NEOCRTEC5010,r and CALBG-9781.r
The updated meta-analysis by the AGITG involved 24 randomised control trials with 4,188 patients comparing either neoadjuvant chemotherapy or neoadjuvant CRT followed by surgery, versus surgery alone in resectable oesophageal or gastroesophageal junction carcinoma.r The primary outcome of interest was all-cause mortality and the secondary endpoint was the effect of treatment on all-cause mortality for each histological subtype. For the trials that compared neoadjuvant CRT followed by surgery to surgery alone, the pooled HR was 0.78 (95% CI:0.70-0.88, p <0.0001) correlating with an absolute survival benefit of 8.7% at 2 years (NNT = 11). The survival benefit for squamous cell carcinoma (HR = 0.80, 95% CI:0.68-0.93; p = 0.004) and adenocarcinoma (HR = 0.75, 95% CI:0.59-0.95; p = 0.02) were similar.
Figure 1. All-cause mortality for chemoradiation therapy compared with surgery alone. Effects of chemoradiation therapy compared with surgery alone on survival in patients with oesophageal cancer.
*Includes all randomised patients. †Includes four patients whose histology was unknown or who had mixed tumours. ‡Includes three patients whose histology was unknown or who had mixed tumours.
© Lancet Oncol 2011r
The CROSS study is a phase III multicentre international randomised trial involving 368 patients comparing neoadjuvant CRT plus surgery, to surgery alone in patients with cT1N1 or cT2-3N0-1 oesophageal or gastroesophageal junction squamous cell carcinoma or adenocarcinoma.r Between March 2004 and December 2008, 180 patients were randomised to receive neoadjuvant CRT plus surgery (carboplatin and paclitaxel with concurrent radiation therapy 41.4 Gy in 23 fractions over 5 days/week) and 188 patients were randomised to receive surgery alone. The primary end point was overall survival and secondary end point was progression-free survival. After a median follow up of 84.1 months, the median overall survival was 48.6 months in the neoadjuvant CRT plus surgery group versus 24 months in the surgery alone group (HR = 0.68, 95% CI:0.53-0.88; p = 0.003).
The effect of neoadjuvant CRT on overall survival was not time-dependent and landmark analyses suggested a stable effect on overall survival up to 10 years of follow up.r The absolute 10-year overall survival benefit was 13% (38% in the CRT plus surgery group versus 25% in the surgery alone group (HR = 0.70, 95% CI:0.55-0.89; p = 0.004). The median relapse-free interval was 15.1 months versus 9 months in the respective arms. There was a clear persisting effect on the isolated locoregional and synchronous locoregional plus distant relapse. However, the effect on the isolated distant relapse was comparable.
The optimal regimen of neoadjuvant chemoradiation therapy is unknown. In the CROSS study, recurrence within the radiation treatment volume was low (5%) suggesting dose escalation above 41.4 Gy may not be warranted.rr
Figure 2. Overall survival by treatment group
© J Clin Oncol 2021r
Figure 3. Hazard ratio for all-cause mortality
© J Clin Oncol 2021r
Figure 4. Ten year outcomes
© J Clin Oncol 2021r
Elective nodal irradiation
While some international guidelines recommend elective nodal irradiation, there is limited evidence to support this.r
Role of adjuvant anti-cancer therapy
Immunotherapy is being incorporated in some trials but is not yet considered standard of care. CheckMate 577 is a global randomised, double-blind, placebo-controlled phase III trial evaluating nivolumab as an adjuvant therapy in patients with stage II or III oesophageal or gastroesophageal junction cancer who received neoadjuvant chemoradiation therapy and had residual pathological disease.r