OBJECTIVE In selected rectal cancer patients with residual local disease following neoadjuvant chemoradiation (CRT) and the preference of an organ preservation pathway, additional treatment with dose escalation by endoluminal radiotherapy (RT) may ultimately result in a clinical complete response. To date, the widespread introduction of selective endoluminal radiation techniques is hampered by a lack of evidence-based guidelines that describe the radiation treatment volume in relation to the residual tumor mass. In order to convert an incomplete response into a complete one with additional treatment such as dose-escalation with endoluminal RT from a theoretical perspective, it seems important to treat all remaining microscopic tumor cells after CRT. In this setting, residual tumor extension beneath normal appearing mucosa (microscopic intramural spread - MIS) becomes relevant for accurate tumor volume and margin estimation. With the goal of providing evidence-based guidelines that define an appropriate treatment volume and patient selection, we present results from a meta-analysis based on individual patient data of studies that have assessed the extent or range of MIS of rectal cancers after neoadjuvant CRT. This meta-analysis should provide an estimate of the residual tumor volume/extension that needs to be targeted by any additional radiation therapy boost in order to achieve complete tumor eradication after initial incomplete or near-complete response following standard CRT. METHODS AND MATERIALS A PubMed search was performed. Additional articles were selected based on identification from reference lists. Papers were eligible when reporting MIS in patients who were treated by total mesorectal excision or local excision/transanal endoscopic microsurgery (TEM) after neo-adjuvant long-course CRT. The mean MIS was calculated for the entire group along with the 70th until 95th percentiles. Additional exploratory subgroup analyses were performed. RESULTS Individual patient data from 349 patients with residual disease from five studies were analyzed. 80% of tumors showed no MIS. In order to appropriately treat MIS in 95% of rectal cancer patients after CRT, a margin of 5.5 mm around the macroscopic tumor would suffice. An exploratory subgroup analysis showed that T-stage after CRT (ypT) and time interval between neoadjuvant CRT and surgery are significant factors predicting the extent of MIS (p < 0.001.) The group of ypT1 had the smallest MIS, followed by the ypT3-4 group, while the ypT2 group had the largest MIS (p < 0.001). Regarding time interval between CRT and surgery, a statistically significant difference was seen when comparing the three time-interval groups (less than 8 weeks, 8-12 weeks, and more than 12 weeks), where waiting more than 12 weeks after CRT resulted in the largest MIS (p < 0.0001). CONCLUSION Based on this meta-analysis, in order to treat the MIS for 95% of rectal cancer patients after CRT, a Clinical Target Volume (CTV) margin of 5.5 mm from the lateral most edge of the macroscopic tumor would suffice. 80% of tumors showed no MIS and would not require an extra CTV margin for treatment. These findings support the feasibility of localized radiotherapy boosts for dose-escalation to improve response among patients with incomplete response after standard CRT and can also be applied in the surgical setting.

中文翻译：

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新辅助放化疗后直肠癌壁内显微扩展：基于个体患者数据的荟萃分析

目的 在新辅助放化疗 (CRT) 后有局部残留病灶且偏好器官保存途径的特定直肠癌患者中，通过腔内放疗 (RT) 进行剂量递增的额外治疗可能最终导致临床完全缓解。迄今为止，由于缺乏循证指南来描述与残留肿瘤块相关的放射治疗量，选择性腔内放射技术的广泛引入受到阻碍。为了将不完全的反应转化为完全的反应，从理论角度进行额外的治疗，例如腔内放疗的剂量递增，在 CRT 后治疗所有剩余的微观肿瘤细胞似乎很重要。在这个设定中，正常出现的粘膜下的残留肿瘤扩展（显微壁内扩散 - MIS）与准确的肿瘤体积和边缘估计相关。为了提供定义适当治疗量和患者选择的循证指南，我们提供了基于个体患者数据的荟萃分析结果，这些研究评估了新辅助 CRT 后直肠癌 MIS 的程度或范围。该荟萃分析应提供对任何额外放射治疗增强所需的残留肿瘤体积/扩展的估计，以便在标准 CRT 后初始不完全或接近完全反应后实现完全根除肿瘤。方法和材料 进行了 PubMed 搜索。其他文章是根据参考列表中的识别选择的。在新辅助长程 CRT 后接受全直肠系膜切除或局部切除/经肛门内镜显微手术 (TEM) 治疗的患者中报告 MIS 时，论文符合条件。计算整个组以及第 70 至第 95 个百分位数的平均 MIS。进行了额外的探索性亚组分析。结果 分析了来自五项研究的 349 名残留疾病患者的个体患者数据。80% 的肿瘤没有显示 MIS。为了在 CRT 后 95% 的直肠癌患者中正确治疗 MIS，宏观肿瘤周围 5.5 毫米的边缘就足够了。探索性亚组分析显示，CRT 后的 T 分期（ypT）和新辅助 CRT 与手术之间的时间间隔是预测 MIS 程度的重要因素（p < 0.001）。ypT1 组的 MIS 最小，其次是 ypT3-4 组，而 ypT2 组的 MIS 最大（p < 0.001）。关于 CRT 和手术之间的时间间隔，当比较三个时间间隔组（小于 8 周、8-12 周和大于 12 周）时，可以看到统计学上的显着差异，其中 CRT 后等待超过 12 周导致最大的 MIS (p < 0.0001)。结论 根据这项荟萃分析，为了治疗 95% 的 CRT 后直肠癌患者的 MIS，距离肉眼可见肿瘤最外侧边缘 5.5 mm 的临床靶区 (CTV) 边缘就足够了。80% 的肿瘤没有显示 MIS，并且不需要额外的 CTV 边缘进行治疗。