编者按：局部进展期结直肠癌新辅助治疗在过去20年已取得较大进步，但仍存在不良反应、器官功能障碍及远期转移控制不理想等局限性。而近年来，随着手术技术的提高和肿瘤分子分型研究的进一步发展，如何进一步提高局部控制率，减少远处转移率，甚至根据临床缓解情况免除手术、保留器官是当前患者的需求所在和研究目标。

在第27届全国临床肿瘤学大会暨2024年CSCO学术年会上，我们针对局部进展期结直肠癌的免疫治疗现状，对英国伦敦大学医院Kai-Keen Shiu教授进行了专访，现将内容整理如下，以飨读者。

肿瘤瞭望消化时讯：能否请您谈谈当前局部进展期结直肠癌新辅助治疗现状及趋势？

Dr. Kai-Keen Shiu: In treating early-stage colorectal cancer, we now distinguish between MMR-proficient and MMR-deficient/MSI-high subtypes, as they require different therapeutic approaches. Traditionally, for MMR-proficient colon cancer, we recommend surgical resection followed by adjuvant chemotherapy, typically for three to six months, using either a single agent or a combination regimen. For rectal cancer, treatment has evolved towards a neoadjuvant approach, involving either chemoradiotherapy or, more recently, total neoadjuvant chemotherapy combined with chemoradiotherapy.

Excitingly, for the MMR-deficient group, immunotherapy has shown remarkable efficacy, particularly in metastatic settings, and is now being explored as a first-line neoadjuvant treatment. In Phase II trials, the results have been extraordinary: a significant proportion of patients experience complete pathological responses, ranging from 50% to 80%. This is a paradigm shift, as these patients are not only seeing tumor downstaging but also achieving excellent surgical outcomes with minimal complications. These trials consistently demonstrate that patients respond well and have low relapse rates.

肿瘤瞭望消化时讯：能否请您谈谈如何筛选新辅助免疫治疗的优势人群？

Dr. Kai-Keen Shiu: Patient selection is indeed crucial. Accurate diagnosis of MMR-deficiency or MSI-high status is the first step, followed by careful radiological staging to avoid overstaging, as MMR-deficient tumors can present with inflammatory lymph nodes. This collaborative approach involves pathologists for diagnosis, gastroenterologists for initial assessments, and surgeons for optimal timing of intervention.

In the UK, I currently offer these therapies within clinical trials, which enables strict criteria for patient eligibility. However, educating pathologists to perform reflex testing and preparing surgeons for neoadjuvant timing are essential steps toward broader implementation. Outside clinical trials, I still advocate surgery as the standard of care for eligible patients, especially given that immunotherapy is most effective in MMR-deficient cases. Administering immunotherapy to MMR-proficient patients offers little benefit, highlighting the need for accurate diagnostics.

肿瘤瞭望消化时讯：能否请您深入探讨一下新辅助免疫治疗在MSI-H局部进展期结直肠癌中的应用前景及其为患者带来的具体临床获益？

Dr. Kai-Keen Shiu: The clinical benefits of neoadjuvant immunotherapy in MSI-high cases are substantial. Although current evidence comes primarily from Phase II trials, the NICHE-2 trial, led by Dr. Myriam Chalabi in the Netherlands, reported 100% disease-free survival at three years. This was presented at ASCO and ESMO and, while not a randomized trial, would likely have ended the control arm early if it had been. The data is compelling: even without a Phase III confirmation, these findings suggest tremendous potential for durable outcomes. Other Phase II trials, such as NEOPRISM, NEOSHOT, and IMHOTEP, reinforce this benefit.

Our next steps involve collaboration—between oncologists, pharmaceutical companies, and regulatory bodies—to bring these therapies to patients. If optimized, this approach could allow us to cure over 90% of MSI-high patients with brief treatment durations. Patients are increasingly informed about immunotherapy's benefits and often initiate discussions on their own, highlighting the demand and the need for our teams to remain updated.

肿瘤瞭望消化时讯：能否分享一下你们对新辅助免疫治疗在MSI-H局部进展期结直肠癌领域未来研究方向？

Dr. Kai-Keen Shiu:  Many ongoing trials integrate extensive biomarker analysis, including liquid biopsies, cDNA, TCR complexity, whole-exome and whole-genome sequencing, and even patient-derived organoids from biopsies for personalized drug testing.

We’re gaining insights that not only help in MSI-high settings but also might apply to more advanced cases. Some of our research focuses on biomarkers that predict resistance, potentially allowing us to extend the benefits of immunotherapy to the MMR-proficient population. Additionally, circulating DNA (cDNA) could support non-operative management strategies—a crucial factor for patients who are resistant to surgery, like some with Lynch syndrome who may wish to preserve their bowel function.

Ultimately, these biomarkers will not only enhance treatment precision for MSI-high tumors but could also expand immunotherapy’s reach.