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-9781r.
The updated meta-analysis by the AGITG involved 24 RCTs with 4188 patients comparing either neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy followed by surgery versus surgery alone in resectable oesophageal or gastro-oesophageal junction carcinoma.r The primary outcome of interest was all-cause mortality and secondary endpoint was the effect of treatment on all-cause mortality for each histological subtype. For the trials that compared neoadjuvant chemoradiotherapy followed by surgery with surgery alone, the pooled HR was 0.78 (CI 95% 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, CI 95% 0.68-0.93; p=0.004) and adenocarcinoma (HR 0.75, CI 95% 0.59-0.95; p=0.02) were similar.
Figure 1: All-cause mortality for chemoradiotherapy compared with surgery alone.r Effects of chemoradiotherapy 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 2011
The CROSS study is a phase 3 multicentre international randomised trial involving 368 patients comparing neoadjuvant chemoradiotherapy plus surgery with surgery alone in patients with cT1N1 or cT2-3N0-1 oesophageal or gastro-oesophaegal junction squamous cell carcinoma or adenocarcinoma.r Between March 2004 and Dec 2008, 180 patients were randomised to receive neoadjuvant chemoradiotherapy plus surgery (carboplatin and paclitaxel with concurrent radiotherapy 41.4Gy 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 chemoradiotherapy plus surgery group versus 24 months in the surgery alone group (HR 0.68, CI 95% 0.53-0.88; p=0.003).
Figure 2: Overall survival by treatment group.r
© Lancet Oncol 2015
The POET study is a phase 3 multicentre international randomised trial involving 119 patients comparing preoperative chemotherapy with induction chemotherapy and chemoradiotherapy followed by surgery in patients with cT3 or cT4 gastro-oesophageal junction adenocarcinoma.r Between November 2000 and December 2005, 59 patients were randomised to chemotherapy with weekly 5-fluorouracil/folinic acid and biweekly cisplatin within 14 weeks and 60 patients were randomised to receive the same chemotherapy followed by concurrent CRT (cisplatin and etoposide) and RT (30Gy in 15 fractions over 3 weeks). Both arms were followed by surgery 3 to 6 weeks after the end of preoperative therapy. The primary end point was overall survival and secondary end points were progression-free survival, and local progression-free survival. After a median follow up of 126.5 months, the median overall survival was 21.1 months in the chemotherapy plus surgery group versus 30.8 months in the CRT plus surgery group (HR = 0.65, CI 95% 0.42-1.01; p=0.055 in favour of the CRT group). Five year progression free survival was 21% in the chemotherapy plus surgery group versus 38% in the CRT plus surgery group (HR 0.64, CI 95% 0.39-1.06; p=0.03 in favour of the CRT group).
Figure 3: Overall survival by treatment group.r
© Eur J Cancer 2017
The NEOCRTEC study is a phase 3 multicentre Chinese randomised trial involving 451 patients comparing neoadjuvant CRT plus surgery with surgery alone in patients with Stage IIB and III potentially resectable thoracic oesophageal squamous cell carcinoma.r Between June 2007 and Dec 2014, 224 patients were randomised to receive CRT vinorelbine and cisplatin with concurrent RT (40Gy in 20 fractions over 5 days/week) versus surgery alone. The primary end point was overall survival and secondary end points were disease-free survival, safety profile, R0 resection rate, and pathologic response. After a median follow up of 41 months, the median OS was 100.1 months in the CRT group versus 66.5 months in the surgery alone group (HR 0.71; CI 95% 0.53-0.96; p= 0.025). The median disease-free survival was 100.1 months in the CRT group versus 41.7 months in the surgery alone group (HR 0.58; CI 95% 0.43-0.78; p < 0.001).
The CALBG-9781 study is a phase 3 multicentre randomised trial involving 56 patients comparing tri-modality therapy versus surgery alone in patients with T1-3 N0-1 thoracic oesophageal or gastro-oesophageal junction squamous cell carcinoma or adenocarcinoma.r Between October 1997 and March 2000, 30 patients were randomised to trimodality therapy (neoadjuvant cisplatin/FU with concurrent radiotherapy 50.4Gy in 28 fractions over 5 days/week followed by surgery) and 26 were randomised to surgery alone. The primary endpoint was overall survival and secondary endpoints included response, local and distant control rates and progression-free survival. After a median follow up of 6 years, the median overall survival was 4.48 years in the trimodality group versus 1.79 years in the surgery alone group (CI 95% HR 1.46-5.69). The median progression-free survival was 3.47 years in the trimodality group versus 1.01 years in the surgery alone group (CI 95% HR 1.37-5.32).
Optimal regimen of neo-adjuvant chemoradiotherapy and radiation doses
The optimal regimen of neoadjuvant chemoradiotherapy is unknown. The evidence supporting the regimen used in this protocol is provided by the CROSS study.r This study used a radiation dose of 41.4Gy in 23 fractions with concurrent carboplatin and paclitaxel. Recurrence within the radiation treatment volume in this trial was low at 5% suggesting that dose escalation above 41.4Gy may not be warranted.r
Elective nodal irradiation
While some international guidelines recommend elective nodal irradiation, there is limited evidence to support this.r