Approximately 60–80% of cancer patients treated with abdominopelvic radiotherapy suffer post-radiotherapy toxicities including radiation enteropathy and myelosuppression. Effective preventive and therapeutic strategies are lacking for such radiation injury. The gut microbiota holds high investigational value for deepening our understanding of the pathogenesis of radiation injury, especially radiation enteropathy which resembles inflammatory bowel disease pathophysiology and for facilitating personalized medicine by providing safer therapies tailored for cancer patients. Preclinical and clinical data consistently support that gut microbiota components including lactate-producers, SCFA-producers, indole compound-producers and Akkermansia impose intestinal and hematopoietic radio-protection. These features serve as potential predictive biomarkers for radiation injury, together with the microbial diversity which robustly predicts milder post-radiotherapy toxicities in multiple types of cancer. The accordingly developed manipulation strategies including selective microbiota transplantation, probiotics, purified functional metabolites and ligands to microbe-host interactive pathways are promising radio-protectors and radio-mitigators that merit extensive validation in clinical trials. With massive mechanistic investigations and pilot clinical trials reinforcing its translational value the gut microbiota may boost the prediction, prevention and mitigation of radiation injury. In this review, we summarize the state-of-the-art landmark researches related with radio-protection to provide illuminating insights for oncologists, gastroenterologists and laboratory scientists interested in this overlooked complexed disorder.

Diagnostic and Interventional Radiology

Currently, the prognosis for metastatic colorectal cancer (mCRC) still remains poor. The management of mCRC has become manifold because of the varied advances in the systemic and topical treatment approaches. For patients with limited number of metastases, radical local therapy plus systemic therapy can be a good choice to achieve long-term tumor control. In this study, we aimed to explore the efficacy and safety of the combination of fruquintinib, tislelizumab, and stereotactic ablative radiotherapy (SABR) in mCRC (RIFLE study). RIFLE was designed as a single-center, single-arm, prospective Phase II clinical trial. A total of 68 mCRC patients who have failed the first-line standard treatment will be recruited in the safety run-in phase (n = 6) and the expansion phase (n = 62), respectively. Eligible patients will receive SABR followed by fruquintinib (5 mg, d1–14, once every day) and tislelizumab (200 mg, d1, once every 3 weeks) within 2 weeks from completion of radiation. The expansion phase starts when the safety of the treatment is determined (dose limiting toxicity occur in no more than one-sixth of patients in the run-in phase). The primary end point is the objective response rate. The secondary end points include the disease control rate, duration of response, 3-year progression-free survival rate, 3-year overall survival rate, and toxicity. The results of this trial will provide a novel insight into SABR in combination with PD-1 antibody and vascular endothelial growth factor receptor inhibitor in the systematic treatment of metastatic colorectal cancer, which is expected to provide new therapeutic strategies and improve the prognosis for mCRC patients. NCT04948034 (ClinicalTrials.gov).

Purpose: Organ preservation (OP) can be preferred in low-lying rectal cancer to reduce morbidity from radical surgery. Immunotherapy-based total neoadjuvant therapy (iTNT) showed remarkable tumor regression and facilitated OP in locally advanced rectal cancer. This study evaluated the efficacy and safety of iTNT, comprising short-course radiotherapy followed by CAPOX and toripalimab, in enabling OP for early low rectal cancer. Patients and Methods: TORCH-E was a multicenter, single-arm phase II trial enrolling patients with T2–3bN0 rectal adenocarcinoma ≤5 cm from the anal verge. Patients received short-course radiotherapy (25 Gy/5 Fx) followed by four cycles of CAPOX plus toripalimab. Good responders were eligible for watch-and-wait (WW) or local excision (LE), and total mesorectal excision was recommended for poor responders or those with high-risk features after LE. The primary endpoint was complete response (CR), including clinical CR with WW and pathologic CR. Secondary endpoints included OP rate, adverse effects, and quality of life. Results: From December 2022 to March 2024, 33 patients were enrolled, with 75.8% staged as T3. After iTNT, 16 patients achieved clinical CR and adopted WW. Pathologic CR was observed in eight of eight LE and five of nine patients who underwent total mesorectal excision. The most common grade 3 to 4 adverse event was thrombocytopenia (27.3%). After a median follow-up of 24.1 months, four local regrowths and one metastatic recurrence occurred. The total CR rate was 72.7%, and the OP rate was 60.6%. Conclusions: As an exploratory trial, TORCH-E demonstrated a promising iTNT approach achieving a high CR rate, enabling OP through WW and selective LE in early low rectal cancer, warranting subsequent randomized validation.

Objective: To evaluate the feasibility of the EMD (extramural depth)/mesorectum ratio as a marker for T3 rectal cancer and its ability to predict tumour response to neoadjuvant chemoradiation and survival. Methods: From 2010 to 2016, 284 T3 rectal cancer patients who underwent high resolution MRI before neoadjuvant chemoradiation were enrolled. The EMD was defined as the distance from the outer edge of the muscularis propria to the outermost edge of the tumour. The measurement of the tumour EMD and mesorectum was in the same layer and their ratio was calculated. Receiver operating characteristic analysis and relative area under the curve statistics were used to choose the cut-off value. The association of the EMD/mesorectum ratio and other MRI or clinical factors with the tumour regression grade (TRG) was analysed. Cox regression analysis was used to estimate independent risk factors for disease-free survival (DFS) and overall survival (OS). Results: The mean EMD/mesorectum ratio was 0.47 ± 0.3. We chose an EMD/mesorectum ratio of 0.5 in further analyses after receiver operating characteristic analysis. Of 284 patients, 177 (62.3%) had an EMD/mesorectum ratio ≤ 0.5. Patients with an EMD/mesorectum ratio ≤ 0.5 had a higher TRG 0–1 rate than patients with a ratio >0.5 (53.1% vs 36.4%, p = 0.006). A multivariate analysis identified that an EMD/mesorectum ratio >0.5 [hazard ratio (HR) 2.020; p = 0.028] and ypTNM II-III (HR 3.550; p = 0.017) were independent prognostic factors to indicate decreased DFS. For OS, only patients with TRG 2–3 had decreased OS compared with patients with TRG 0–1 (HR 2.959; p = 0.035). Conclusion: When the EMD/mesorectum ratio was applied to categorize T3 rectal cancer patients, the ratio of 0.5 can be used as a cut-off value for T3 rectal cancer. Patients with a ratio ≤ 0.5 had a higher response rate and better DFS. However, further validation is needed in a larger sample of patients. Advances in knowledge: The EMD/mesorectum ratio may serve to predict tumour response to neoadjuvant chemoradiation and survival in T3 rectal cancer patients.

Background: The watch-and-wait (W&W) strategy is a novel treatment option for patients with rectal cancer who have a strong desire for organ preservation. The study aimed to explore the long-term outcomes of the W&W strategy in a large cohort of rectal cancer patients who achieved a clinical complete response (cCR) after consolidation total neoadjuvant therapy (TNT), and to compare with patients who achieved a pathological complete response (pCR) after radical surgery. Methods: The W&W group comprised patients who were assessed as having a cCR after consolidation TNT and adopted the W&W strategy. Patients who underwent standard resection and achieved a pCR were compared as a reference. Inverse probability of treatment weighting (IPTW)-adjusted Kaplan–Meier analysis with log-rank test was used to compare survival outcomes. Results: We included 89 and 171 patients in the W&W and pCR groups, respectively. The median follow-up period was 45 and 58 months for the W&W and pCR groups, respectively. After IPTW adjustment, the 2-year local regrowth/recurrence rate for the W&W and pCR groups were 9.9% and 2.0%, respectively ( p < 0.001). The W&W and pCR groups had similar 5-year outcomes, including overall survival, disease-free survival, and distant metastasis-free survival (all p > 0.05). No significant difference was observed in the rates of distant metastasis between patients in the W&W group with local regrowth and those without local regrowth (25% versus 6.2%, p = 0.119). Conclusion: Patients who were managed with a W&W strategy after consolidation TNT had favorable survival outcomes, which were similar to those of patients with a pCR. The rate of local regrowth in W&W patients was lower in our study than in other studies as a result of the implementation of consolidation TNT.