编者按：2024年9月22~24日，第20届国际食管癌大会（ISDE）在苏格兰爱丁堡召开。会上，比较围手术期化疗与CROSS方案（术前化疗联合放疗）在食管癌治疗中的疗效的Neo-AEGIS研究，吸引了全球目光。作为该研究通信作者，爱尔兰圣詹姆斯医院的John Reynolds教授对该研究成果进行了深入解读，并就其对未来食管癌治疗策略的深远影响展开了探讨。现将John Reynolds教授的精彩采访内容整理分享，以供读者参考。

肿瘤瞭望消化时讯：根据Neo-AEGIS研究的主要发现，您认为这些结果将如何影响未来的食管癌治疗策略和临床实践？

Oncology Frontier: Based on the key findings of the Neo-AEGIS study, how do you think these results will impact future treatment strategies and clinical practice for esophageal cancer?

Prof. John Reynolds: The key findings of the Neo-AEGIS study indicate that perioperative chemotherapy and the standard CROSS regimen (preoperative chemoradiotherapy) show no significant difference in efficacy for treating esophageal cancer. In other words, radiation therapy may not be essential for some patients in routine treatment. In this study, we maintained strict control over radiation quality and the assessment criteria for surgical complications. The results showed that preoperative chemoradiation did not lead to increased postoperative mortality or complication rates.

Additionally, although the perioperative chemotherapy group showed poorer pathological response, this did not impact overall survival (OS) or disease-free survival (DFS). This suggests that even if patients exhibit a weak tumor response before surgery, their long-term prognosis is not compromised. These findings advance our understanding of the previous CROSS and MAGIC trials, which addressed different issues at different points in time.

However, the latest data from the ESOPEC study indicates that the CROSS regimen shows superior efficacy compared to the FLOT regimen, prompting a reevaluation of treatment strategy choices. While we still need complete data to confirm these conclusions, it is foreseeable that many clinicians may have already started adjusting their practices to better implement trimodality therapy (preoperative chemoradiotherapy followed by surgery).

In the coming years, as more new studies are published, we anticipate further evolution in treatment strategies, which may significantly impact current therapeutic approaches. Specifically, if we can integrate the data from the Neo-AEGIS and ESOPEC studies, we will gain deeper insights into the relative advantages of different chemotherapy regimens, such as MAGIC and FLOT, compared to the CROSS regimen.

肿瘤瞭望消化时讯：在Neo-AEGIS研究过程中，您遇到了哪些主要挑战？这些挑战如何影响了研究的实施和结果？您和您的团队采取了哪些策略来应对这些挑战？

Oncology Frontier: What were the major challenges you encountered during the Neo-AEGIS study, and how did these challenges affect the implementation and results of the research? What strategies did you and your team employ to address these challenges?

John Reynolds教授：在Neo-AEGIS研究中，我们面临了两个主要挑战。首先，研究设计始于2013年，当时我们比较的是围手术期化疗方案（改良MAGIC方案）与新发布的高影响力CROSS方案。然而，无法预见的是，FLOT4试验的结果在2019年发布，并显示FLOT方案相比MAGIC方案有显著的获益。这使得我们必须迅速调整研究设计，从优越性设计转变为非劣效性设计，这是一个重大挑战。这一变化也引发了我们对放疗必要性的思考。结果表明，放疗并不是必需的，且并未增加手术风险。这一发现出乎意料的同时也为我们带来了统计学上的挑战，并需要进行额外的分析和进一步验证。

Prof. John Reynolds: During the Neo-AEGIS study, we faced two main challenges. First, when we designed the trial in 2013, we compared perioperative chemotherapy (the modified MAGIC regimen) with the newly released high-impact CROSS regimen. However, we could not foresee the outcome of the FLOT4 trial, which was published in 2019 but presented in 2018. This trial demonstrated a significant benefit for FLOT compared to MAGIC, forcing us to quickly adjust our design from a superiority approach to a non-inferiority design. This was a major challenge. 

Additionally, it raised questions about the necessity of radiation therapy, which we found was not essential, and it did not lead to increased surgical risks. This revelation was surprising and required substantial statistical analysis.

The second challenge was the pandemic, which was beyond our control. Recruitment for the trial was already struggling post-FLOT4, but when the pandemic hit, it completely halted recruitment. Given that the survival outcomes from the first and second futility analyses were initially identical for both perioperative chemotherapy and trimodal therapy, we concluded that it was prudent to terminate the trial, as it was unlikely to complete or reveal any significant differences.

Through these challenges, our team learned valuable strategies, including the importance of flexible trial design and timely evaluation of feasibility, which will benefit future research endeavors.

肿瘤瞭望消化时讯：Neo-AEGIS研究的结果是否揭示了进一步研究的新方向或未解的问题？您在未来的研究中有何计划，以进一步探索这些发现？

Oncology Frontier: Did the results of the Neo-AEGIS study reveal any new directions or unresolved issues for further research? What are your plans for future research to further explore these findings?

Prof. John Reynolds: I believe that every trial generates numerous questions. While I can offer some answers, many questions remain unanswered. Currently, no trial has specifically focused on early-stage cancers or biologically distinct cancer types. This means we can only provide a rough interpretation of studies like Neo-AEGIS and ESOPEC concerning the diverse patient groups we encounter in our weekly multidisciplinary discussions. Factors such as patient age and comorbidities significantly influence treatment choices—FLOT, for instance, can be particularly challenging for elderly patients, as trials often include only fit individuals.

There is still much we do not know, and trials must be evaluated in the context of specific cohorts. Otherwise, we struggle to interpret results from studies that do not predominantly include these patient populations.

Additionally, we must prioritize studying biomarkers as thoroughly as possible. While there is an optimistic belief that we will eventually be able to implement personalized treatment plans for patients, I remain cautious and want to see concrete results. Esophageal cancer is highly heterogeneous and notoriously difficult to treat, so we may be waiting a long time for significant breakthroughs in the neoadjuvant setting.

However, we do have emerging techniques, such as circulating tumor DNA analysis, microsatellite instability assessments, and PD-L1 testing. These methods should be incorporated into routine practice. We need to learn from everyday patterns of response and conduct novel clinical trials that will hopefully improve the prognosis for this challenging and hard-to-treat cancer.