Research in context
Evidence before this study
Based on the extensive meta-analysis by Sjoquist and colleagues in 2011, at the initiation of the CROSS trial in 2004, the results from four previous randomised trials comparing neoadjuvant concurrent chemoradiotherapy plus surgery to surgery alone had been reported. Chemotherapy in these trials consisted of cisplatin and fluorouracil (and also vinblastine in one trial), with a total concurrent radiation dose ranging from 40 to 45 Gy. However, these trials included only small numbers of patients and showed opposing results. Our previous non-randomised phase 2 feasibility trial tested a regimen of weekly administrations of carboplatin and paclitaxel with 41·4 Gy concurrent radiotherapy and showed a radical resection percentage of 100%, with low treatment-related toxicity. These promising short-term results provided the rationale to assess this CROSS neoadjuvant chemoradiotherapy regimen in a subsequent randomised phase 3 trial.
Added value of this study
At long-term follow-up, the CROSS trial has now shown that treatment of locally advanced oesophageal or junctional cancer with carboplatin, paclitaxel, and concurrent radiotherapy followed by surgery significantly improves 5-year overall and progression-free survival, compared with treatment with surgery alone.
Implications of all the available evidence
Despite the favourable results of the initial CROSS trial, preoperative or perioperative chemotherapy is still regarded as standard of care in some countries for patients with oesophageal and junctional cancer. This perspective is mainly the consequence of the results of the MAGIC trial, which compared perioperative chemotherapy—consisting of epirubicin, cisplatin, and infused fluorouracil—plus surgery versus surgery alone. However, only a few included patients had distal oesophageal cancers (14%) or junctional cancers (12%), which raises questions about the applicability of these results for oesophageal and junctional cancers. Furthermore, the MAGIC trial, which was published in 2006 after a minimum follow-up of less than 2 years, has not yet reported its long-term results, which makes it unclear whether or not the initially reported survival benefit of perioperative chemotherapy is sustained at long-term follow-up. The ongoing Japanese randomised NExT trial (JCOG1109) and the Irish randomised Neo-AEGIS trial (ICORG 10-14; NCT01726452) will probably provide more definitive evidence about the optimum preoperative or perioperative treatment for oesophageal squamous cell carcinoma and adenocarcinoma, respectively. Future research should focus on more personalised treatment strategies, such as watchful waiting protocols after neoadjuvant therapy, in which surgery is offered only to those patients in whom locoregional disease is detected (in the absence of signs of distant dissemination). Additionally, newer, more effective combinations of systemic agents need to undergo further study, such as the addition of targeted therapy to existing chemoradiotherapeutic treatment regimens.