The key evidence supporting the use of this protocol comes from the updated meta-analysis of 24 studies (4188 patients) by the AGITG,r the PHIII POET studyr (119 patients) and the CROSS studyr (368 patients) comparing the use of preoperative chemotherapy vs preoperative chemoradiotherapy in patients with locally advanced oesophageal cancer. The updated meta-analysis provides strong evidence for a survival benefit of neoadjuvant chemoradiotherapy over surgery alone. The meta-analysis does not guide whether neoadjuvant chemotherapy or chemoradiation is the better strategy.
The efficacy of neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy is debatable. There are numerous randomised studies in oesophageal cancer (including gastro-oesophageal cancer) that have shown the efficacy of neoadjuvant chemotherapy then surgery versus surgery alone (MAGIC,r MRCr). There is also level one evidence that neoadjuvant concurrent chemoradiotherapy followed by surgery offers better 3 year survival compared to surgery alonerr and in an updated meta-analysis by Sjoquist et al,r when comparing neoadjuvant chemoradiation followed by surgery to surgery alone, the pooled HR was 0.78 (95% CI 0.7-0.88; p<0.0001) which corresponds to an absolute 8.7% survival benefit at 2 years. The survival benefits for neoadjuvant chemoradiation were similar in the tumour type subgroups: squamous cell carcinoma (HR 0.80, 95% CI 0.68-0.93; p=0.004) and adenocarcinoma (0.75, 0.59-0.95; p=0.02).r
© Lancet Oncol 2011 Sjoquist et alr
In the Dutch CROSS group studyr 368 patients were randomised to receive either chemoRT followed by surgery (n=178) or surgery alone (n=188) with significantly improved overall survival for the chemoRT–surgery group when compared to surgery alone (hazard ratio 0.657; 95% CI, 0.495 to 0.871; p=0.003). Median overall survival was 49.4 months in the chemo-RT-surgery group vs 24 months in the surgery group. Respective overall survival rates at 1,2,3 and 5 years were 82%, 67%, 58% and 47% in the chemoRT-surgery group as compared to 70%, 50%, 44% and 34% in the surgery group.r
© NEJM 2012 van Hagen et alr
There has only been one randomised study comparing neoadjuvant chemotherapy to neoadjuvant chemoradiotherapy in resectable gastro-oesophageal cancer, the multicentre German POET (Preoperative chemotherapy or radiochemotherapy in Esophagogastric adenocarcinoma Trial) which was closed early due to poor accrual with 126 patients.r The 3 year survival showed a potential clinical benefit but statistically insignificant trend in favour of chemoradiotherapy (47% vs 28% p=0.07). Therefore, the choice between neoadjuvant chemotherapy, concurrent neo-adjuvant chemoradiotherapy, definitive chemoradiotherapy or surgery alone should be discussed for each patient in a multi-disciplinary setting.
© JCO 2009 Stahl et alr
Optimal Regimen of Neo-adjuvant Chemoradiotherapy and radiation doses
The optimal regimen of neoadjuvant chemoradiotherapy is unknown. Hypofractionated treatment using a dose of 35Gy in 15 fractions with concurrent chemotherapy (cisplatin 80mg/m2 D1 and fluorouracil 800mg/m2 D1-4) prior to surgery has been compared to surgery alone in a TROG studyr and no survival benefit was demonstrated. The study was not powered to detect differences in survival in sub-groups according to histological sub-type. Subgroup analysis showed that patients with squamous cell carcinoma appeared to derive a survival benefit with the neoadjuvant treatment.
The German POET study radiotherapy arm consisted of a dose of 30Gy in 15 fractions with concurrent cisplatin and etoposide and the outcomes suggested a benefit with radiotherapy.r Although the meta-analyses did not stratify for dose of radiation, it is generally accepted that higher doses in the order of 50Gy are required to kill micrometastases and reduce bulky diseaser and that with conformal radiotherapy, surgical morbidity should be minimised.
The CALBG-9781 prospective randomised trial using tri-modality therapy versus surgery alone for oesophageal cancer used a dose of 50.4Gy with concurrent cisplatin and fluorouracil chemotherapy. Although the study was closed early due to poor accrual, five-year survival was improved with the addition of neoadjuvant chemoradiotherapy, 39% (95% CI, 21% to 57%) vs 16% (95% CI, 5% to 33%) in the tri-modality vs surgery arms respectively.r
The CROSS 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%r suggesting that dose escalation above 41.4Gy may not be warranted. By using paclitaxel this has the potential for an increased risk of pneumonitis and it may be necessary to limit the radiotherapy dose in order to meet tighter DVH lung dose constraints. Despite this, in the RTOG 1010 study (currently open) the same chemotherapy agents are being used to a total dose of 50.4Gy in a 2 phase technique.