Neo-AEGIS compares trimodality therapy and perioperative chemotherapy in locally advanced oesophageal adenocarcinoma

Evidence before the study

We searched PubMed and the abstracts from major oncology congresses, including the European Society of Medical Oncology and the American Society of Clinical Oncology. For PubMed, we used full-text search terms for “oesophageal cancer”, “oesophagogastric cancer”, “adenocarcinoma of the oesophagus”, “adenocarcinoma of the oesophagogastric junction”, and “Siewert's cancer”. We searched for research articles published in English, initially from Jan 1, 1990, to Dec 31, 2012, before trial commencement, and regularly updated the search up to the June 30, 2023. International practice before Neo-AEGIS trial design in 2012 was based on published phase 3 randomised trials. The MAGIC trial, published in 2006, provided a standard bearer for perioperative chemotherapy (epirubicin plus cisplatin or oxaliplatin plus fluorouracil or capecitabine; the modified MAGIC regimen), and the CROSS trial, published in 2012, became the standard bearer for trimodality therapy (radiotherapy with carboplatin plus paclitaxel). Both trials showed a clear superiority of each approach compared with surgery alone. The only phase 3 trial of more than 100 patients (POET) comparing trimodality therapy and perioperative chemotherapy (n=119) did not complete and used a different regimen to that used in MAGIC and a lower radiation dose (30 Gy) than that used in CROSS (41·4 Gy). With the CROSS trial generating great interest, Neo-AEGIS set out to address this gap in knowledge, seeking out a gold standard, if one existed, and to provide data to inform international practice, which varies widely. Secondary endpoints were carefully chosen to inform clinician and patient choices if conclusive differences were not apparent in overall survival. The unique elements in trial design included the homogeneity of the study population, mandated staging with CT-PET, radiotherapy quality assurance, and reporting of operative complications using strictly defined criteria.

Added value of the study

This is the first randomised trial to compare the CROSS trimodality regimen with evidence-based perioperative chemotherapy (the modified MAGIC regimen, and from 2018 fluorouracil, leucovorin, oxaliplatin, and docetaxel [FLOT]). With strict inclusion criteria, and uniform staging, our data on 377 patients with locally advanced adenocarcinoma of the oesophagus and oesophagogastric junction inform the literature in several key dimensions despite the early trial termination. For the primary endpoint, similar survival estimates between both treatment groups at the first and second interim futility analyses, and with a median follow-up of longer than 3 years, should support clinical equipoise in decision making, particularly for a cancer for which most recurrences occur within 2 years. It was concluded by the data safety and monitoring board that more patients and longer follow-up would not changes survival metrics. Survival outcomes with trimodality therapy were similar to those in the CROSS trial; however, there was no evidence of superiority over perioperative chemotherapy. Trimodality therapy, as expected, was superior to perioperative chemotherapy in producing complete or major pathological responses and negative surgical margins. However, this did not translate to survival advantage, suggesting that radical en-bloc surgery was a key equalising factor. Perioperative chemotherapy did not reduce systemic failure rates compared with trimodality therapy, suggesting a modest effect on micrometastatic disease of the predominant modified MAGIC regimen, with no conclusions possible for FLOT. Trimodality therapy, despite concerns in this context from other randomised trials (POET and NeoRES) and large series in this context, did not increase operative mortality or major pulmonary morbidity. Both groups had similar health-related quality of life (HRQOL) at 1 and 3 years of follow-up; however, HRQOL was more adversely affected after trimodality therapy given before surgery than after perioperative chemotherapy.

Implications of all the available evidence

Neo-AEGIS set out to compare the trimodality regimen used in the CROSS trial with optimum perioperative chemotherapy. The similar survival metrics that was relevant to trial termination suggest that clinical equipoise between such approaches, specifically trimodality therapy and the modified MAGIC regimen or FLOT, is a reasonable conclusion. The limited FLOT treatment inclusion cannot be interpreted independently, hence the ESOPEC trial will be informative when published. Moreover, data relating to differences in toxicity, tolerance, and HRQOL, might help to inform clinicians and patients in treatment choices. In a dynamic evolving field, as we enter an era in which immunotherapy will be integrated with both these approaches, Neo-AEGIS provides a rich resource of randomised data. These data, as well as the range of secondary outcomes, will inform modern multidisciplinary team discussions and provide benchmark data for both treatment approaches.

Source: The Lancet Gastroenterology & Hepatology