Letter to the Editor: From hemostasis to healing – rethinking the therapeutic paradigm for chronic radiation proctitis

Abstract

Chronic radiation proctitis (CRP) is a complication of pelvic radiotherapy. Its pathogenesis is driven by microvascular injury, which leads to chronic ischaemia, inflammation, and progressive fibrosis. A recent phase II clinical trial by Huang et al, published in the recent issue of the World Journal of Gastroenterology, showed that thalidomide may reduce bleeding in patients with CRP by controlling local inflammation, inducing vasoconstriction, or improving coagulation, although its immediate effect on structural lesion repair appeared less pronounced. We propose integrating thalidomide with microbiota-based therapy, including fecal microbiota transplantation and washed microbiota transplantation, as a complementary therapeutic strategy that may promote intestinal microbial restoration and mucosal recovery in patients with CRP.

Key Words: Chronic radiation proctitis; Microbiota transplantation; Mucosal healing; Thalidomide; Combination therapy

Core Tip: Thalidomide can effectively reduce bleeding in patients with chronic radiation proctitis, but improvement in mucosal structure appears less pronounced. Microbiota-based therapy, including fecal microbiota transplantation and washed microbiota transplantation, may complement thalidomide by restoring the intestinal microbial ecosystem and promoting mucosal recovery. Integrating haemostatic treatment with microbiota-based therapy may shift the therapeutic goal for chronic radiation proctitis from bleeding control toward mucosal healing.

TO THE EDITOR

We read with great interest the phase II clinical trial by Huang et al[1], published in the recent issue of the World Journal of Gastroenterology, which evaluated the efficacy and safety of thalidomide for refractory haemorrhagic chronic radiation proctitis (CRP). The study showed an overall efficacy rate of 83.9% for thalidomide in improving the Subjective Objective Management Analysis system score. A study of argon plasma coagulation reported a treatment success rate of 68.9%[2]. Although these two studies are not directly comparable, the findings suggest that thalidomide may be promising for bleeding control in patients with CRP. Although rectal bleeding improved substantially, the efficacy rate for improvement in the Vienna Rectoscopy Score among patients with haemorrhagic CRP was only 17.1%. Some endoscopic findings improved, but the degree of endoscopic improvement differed from that of clinical symptom improvement, suggesting that clinical response may not be synchronized with endoscopic mucosal recovery. This observation indicates that treatment for CRP should extend beyond haemostasis and place greater emphasis on mucosal therapy.

MECHANISM OF ACTION OF THALIDOMIDE

The mechanism of action of thalidomide is therefore clinically relevant. In Crohn’s disease, which is characterized by Th1/Th17-driven inflammation[3], thalidomide can achieve a clinical remission rate of approximately 85% when administered at a dose of > 50 mg/day[4]. In small-intestinal angiodysplasia, which is caused by abnormal vascular regulation[5], a 50-mg dose can achieve a remission rate of 51.0%[6]. In CRP, the same agent achieved an 83.9% response rate. CRP develops through chronic ischaemia, inflammation, and fibrosis caused by microvascular injury[7,8]. Therefore, the antiangiogenic and immunomodulatory effects of thalidomide may contribute to its therapeutic effect in CRP. Its antiangiogenic effect may reduce bleeding, whereas regulation of inflammatory mediators, including tumor necrosis factor-α and interleukin-12, may help attenuate inflammation[9,10]. However, mucosal structural improvement with thalidomide appeared less pronounced, and microbiota-based therapy may serve as a complementary treatment to promote mucosal recovery.

Radiotherapy can lead to cause gut dysbiosis and may contribute to chronic radiation-induced intestinal injury through inflammation and impaired mucosal barrier function. A small-sample study by Ding et al[11] in 2020 provided early clinical evidence supporting fecal microbiota transplantation (FMT) for chronic radiation enteritis, with symptom improvement observed in 3 of 5 patients. Washed microbiota transplantation (WMT), a newer method derived from FMT, uses automated purification and washing procedures. In patients with radiation enteritis, the clinical remission rate at week 12 after WMT reached 64.7%, which was higher than the 27.5% rate in the conventional treatment group. Endoscopic evaluation also showed improvement in mucosal lesions. Further research identified Holdemanella biformis as a potential candidate strain that may enhance the efficacy of WMT. This strain may upregulate the PPAR-γ signalling pathway, restore intestinal mucosal barrier function, downregulate tumor necrosis factor-α and interleukin-1β, and regulate Treg/Th17 immune balance, thereby enhancing the therapeutic effect of WMT. In these studies of radiation enteritis, both FMT and WMT showed favourable safety profiles, with no reported serious adverse events[11,12]. Although radiation enteritis and radiation proctitis involve different intestinal segments and differ in microbiota composition, mucosal barrier characteristics, and immune microenvironment, they share important pathological features, including dysbiosis, inflammation, and mucosal injury. These shared features provide a possible basis for extending microbiota-based therapy from radiation enteritis to CRP. Zheng et al[13] reported that FMT relieved bloody stool, abdominal pain, and diarrhea and reduced endoscopic mucosal congestion in a patient with chronic hemorrhagic radiation proctitis. Overall, the limited clinical evidence in CRP, together with the more systematic mechanistic evidence in radiation enteritis, supports further exploration of FMT, especially WMT, for promoting mucosal repair in patients with CRP.

These two treatments may have complementary effects in CRP. Thalidomide can effectively control bleeding, whereas WMT may promote intestinal microbiota restoration and mucosal repair. Because angiogenesis contributes to tissue repair, the antiangiogenic effect of thalidomide may interfere with mucosal regeneration; thalidomide may therefore be used first to control bleeding, with WMT initiated once the patient’s condition has stabilized. This staged approach may expand the therapeutic goal for CRP from haemostasis to mucosal recovery and, ultimately, mucosal healing.

CONCLUSION

The therapeutic target for CRP may need to expand beyond haemostasis toward mucosal healing. The inconsistency between clinical and endoscopic responses observed by Huang et al[1] should not be regarded as a limitation of thalidomide alone, but rather as an important direction for future therapeutic research. With advances in intestinal microbiome research, integrating thalidomide with microbiota-based therapy may help move treatment from haemostasis toward healing, providing a promising option for patients with refractory CRP.