Thalidomide for refractory hemorrhagic chronic radiation proctitis: Bridging the gap between symptom control and disease-modifying therapy

Abstract

Hemorrhagic chronic radiation proctitis (CRP) represents a persistent and debilitating complication in survivors of pelvic radiotherapy, often leading to recurrent bleeding, chronic anemia, and diminished quality of life. As oncology shifts toward long-term survivorship care, effective management of CRP has emerged as a critical unmet need. A recent phase II trial demonstrated that low-dose thalidomide achieved an 83.9% clinical response rate in refractory hemorrhagic CRP, with a favorable safety profile, suggesting its potential as a systemic therapeutic option between local interventions and invasive surgery, pending further validation. Notably, the dissociation between symptomatic improvement and endoscopic findings underscores the importance of incorporating patient-reported outcomes alongside traditional objective metrics. Emerging evidence suggests that CRP pathophysiology involves sustained microvascular dysfunction, chronic inflammation, and possibly gut microbiome alterations-factors that may inform future targeted therapies. In this context, Huang et al recently published a study in World Journal of Gastroenterology, which reviews the pathogenesis, pathological features, and current treatment landscape of CRP. It then discusses the implications of thalidomide’s efficacy, highlights the study’s limitations (including its single-arm design and short follow-up), and considers the potential for a paradigm shift in CRP management: From reactive hemostasis to integrated, long-term strategies that address both symptoms and underlying disease mechanisms within a comprehensive survivorship care framework.

Key Words: Chronic radiation proctitis; Thalidomide; Pathogenesis; Drug therapy; Survivorship care

Core Tip: Low-dose thalidomide demonstrated an 83.9% clinical remission rate and favorable safety profile in refractory hemorrhagic chronic radiation proctitis (CRP) during a phase II trial, suggesting its potential as a systemic therapeutic option based on preliminary evidence. The observed discrepancy between symptom improvement and endoscopic findings underscores the necessity of including patient-reported outcomes alongside traditional objective metrics. This article reviews the pathogenesis and treatment options for CRP, interprets thalidomide’s clinical significance, evaluates the limitations of the study, and advocates for mechanism-based comprehensive management strategies during cancer survivorship.

This editorial refers to “Thalidomide for refractory hemorrhagic chronic radiation proctitis secondary to pelvic malignancy radiotherapy: A phase II clinical trial” by Huang et al, 2026; https://dx.doi.org/10.3748/wjg.v32.i14.116529.

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INTRODUCTION

Chronic radiation proctitis (CRP) is a prevalent and challenging late complication following radiotherapy for pelvic malignancies, such as cervical, prostate, and rectal cancers. It is characterized by persistent hematochezia, chronic anemia, and, in severe cases, dependence on blood transfusions. This condition not only severely impacts physical health but also imposes a significant psychological burden, consequently diminishing the overall quality of life for affected individuals[1-3]. As treatment outcomes for malignancies improve and patient survival rates extend, the effective management of CRP has emerged as a critical unmet need in cancer survivorship care.

Currently, there are no specific oral therapies available for refractory hemorrhagic CRP, and traditional local interventions and surgical approaches exhibit limitations concerning long-term efficacy and safety[4]. Beyond the direct clinical implications, the recent phase II trial of low-dose thalidomide prompts deeper conceptual inquiries regarding treatment success definitions, disease activity measurement, and a reevaluation of CRP’s pathophysiology within the modern context of cancer survivorship[5].

This article aims to synthesize existing research on the mechanisms and pathological manifestations of CRP, evaluate the current status of drug prevention and treatment options, discuss the significance of thalidomide’s efficacy, analyze the limitations of the aforementioned trial, and propose a transformative approach to CRP management. Specifically, it explores the possibility of moving beyond reactive hemostasis toward a more comprehensive management approach that may ultimately include disease modification, while acknowledging that such a paradigm shift remains to be validated by further research.

THE PATHOGENESIS AND PATHOLOGICAL MANIFESTATIONS OF CRP

Pelvic radiotherapy, while effective against malignancies, frequently causes collateral damage to the rectum due to anatomical proximity, leading to CRP[6]. CRP pathogenesis involves persistent microvascular dysfunction, chronic inflammation, and tissue fibrosis[7]. Radiation directly damages submucosal endothelial cells, causing obliterative small arteritis, ischemia, and compensatory telangiectasia-the direct pathological basis for persistent hematochezia[8]. Concurrently, radiation activates local immune responses, with inflammatory cell infiltration and pro-inflammatory cytokine release creating a self-perpetuating inflammatory microenvironment[9,10]. This process promotes fibroblast proliferation and extracellular matrix deposition, culminating in submucosal fibrosis and, in severe cases, rectal stenosis[11,12]. Intestinal microbiome imbalance may also contribute to disease progression[13].

Endoscopically, CRP manifests as mucosal congestion, edema, telangiectasia, and ulceration[14]. Pathological hallmarks include occlusive arteritis, abnormal capillary proliferation, and inflammatory infiltration[7]. These changes are progressive; even minor mucosal damage may evolve into refractory disease if not effectively addressed[15].

THE CURRENT STATUS OF DRUG PREVENTION AND TREATMENT OF CRP

Current CRP management remains symptom-focused, lacking agents that reverse underlying pathology[16]. Prevention primarily relies on optimizing radiotherapy techniques to reduce rectal radiation exposure[4]. Once CRP develops, its course is unpredictable; about one-third of patients eventually require surgery[17].

Therapeutic options include medical, endoscopic, and surgical approaches. Topical agents (sucralfate, formalin) and endoscopic argon plasma coagulation (APC) can control bleeding but have limited effect on deep pathology, with recurrence being common[12,18]. Surgery (stoma or resection) is reserved for severe complications but carries high morbidity and anastomotic leakage rates (40%-65%)[4]. Systemic drug therapy has long been the greatest unmet need. Prior oral medications-sulfasalazine, corticosteroids, aminosalicylates, and antibiotics-have shown limited efficacy[12,16]. This therapeutic void forces patients into a binary choice: Repeated local interventions or invasive surgery. Thalidomide, with its anti-angiogenic and immunomodulatory properties, offers a potential new path from symptomatic hemostasis toward disease modification[19,20].

CLINICAL SIGNIFICANCE OF THALIDOMIDE IN THE TREATMENT OF REFRACTORY HEMORRHAGIC CRP

The phase II clinical trial conducted by Huang et al[5] recently published in World Journal of Gastroenterology, provided instructive clinical evidence for refractory hemorrhagic CRP. Low-dose thalidomide (50 mg/day) achieved an overall response rate of 83.9% in patients who had failed previous treatments, with 95.7% completing treatment for more than 3 months, and it was well tolerated. Although the evidence remains preliminary due to the single-arm design, these findings suggest that low-dose thalidomide may represent a potential oral systemic option positioned between repeated local therapy and invasive surgery, indicating that CRP management may be able to move toward “disease modification” beyond mere “hemostasis”.

Its significance lies not only in the therapeutic effect but also in the mechanism. Thalidomide has multiple effects such as immune regulation, anti-inflammation and anti-angiogenesis. It can inhibit the TNF-α, IL-6 and VEGF pathways and down-regulate the expression of ICAM-1 and MMP-9, thereby intervening in the core pathological process of radiation-induced microvascular injury[21]. This distinguishes it from local ablation or coagulation therapy, which primarily manages superficial bleeding and have limited capacity to modify the underlying persistent microvascular lesions and chronic inflammation. Previous studies on vascular dysplasia have suggested its hemostatic potential, but radiation-induced vascular injury has a different biological background. Therefore, this study provides disease-specific preliminary clinical evidence. It is worth noting that symptomatic improvement does not occur simultaneously with endoscopic changes, suggesting that clinical benefits may precede structural repair. This dissociation has important implications for trial design and clinical practice. In future studies, validated patient-reported outcome measures-such as bleeding frequency, transfusion independence, fatigue, and functional status-should be incorporated as co-primary endpoints alongside endoscopic scoring systems. In clinical follow-up, regular assessment of these patient-centered metrics can complement periodic endoscopy, providing a more comprehensive picture of treatment response and guiding decisions on continuing or adjusting therapy. This phenomenon underscores that patient-reported outcomes and objective indicators should be given equal weight to more truly reflect disease activity. More importantly, the low dose of 50 mg significantly reduces toxicity while preserving efficacy, providing support for its potential suitability for long-term use in tumor survivors with multiple disease burdens[5].

Overall, this study provides preliminary evidence that may support a conceptual advancement in CRP treatment-moving beyond the passive strategy of repeated local hemostasis toward a more systematic intervention targeting microvascular pathology, though this concept awaits confirmation in larger, controlled studies.

RESEARCH LIMITATIONS AND FUTURE RESEARCH PROSPECTS

Although this study provides important clinical signals, its limitations also need to be interpreted with caution. Firstly, the single-arm and open-label design means that the results are still in the exploratory stage, and selection bias and placebo effects cannot be ruled out. The absence of a control arm precludes direct comparison with established local treatments such as APC, limiting the ability to assess the relative efficacy and safety of thalidomide. Secondly, the study was conducted in a single center with a small sample size (n = 62), with the majority of the participants being cervical cancer patients (87.1%). Therefore, the applicability of the conclusion among survivors of other pelvic tumors such as prostate cancer or rectal cancer still needs to be verified. Furthermore, the follow-up period of the study was relatively short (with a median follow-up period of less than 12 months), making it difficult to evaluate long-term efficacy, drug persistence, and delayed toxicity (such as neuropathy). And neurotoxicity is one of the major long-term side effects of thalidomide[22] and requires close monitoring over a longer follow-up period.

The research also revealed a practical phenomenon: About a quarter of the patients did not complete treatment for ≥ 3 months, mostly discontinuing the medication due to insufficient perception of early efficacy. Unlike endoscopic treatments that produce immediate hemostatic effects, the benefits of thalidomide are delayed, which suggests that in real-world applications, the management of treatment expectations and compliance guidance need to be strengthened[5].

These issues do not diminish the research value; instead, they define the research direction for the next stage. Future research should verify the efficacy through a multicenter randomized controlled design under different primary tumor backgrounds and previous local treatment exposures, and attach equal importance to patient-reported outcomes and objective endoscopic indicators to clarify their position in the CRP treatment sequence. Meanwhile, long-term follow-up remains crucial for determining the optimal treatment course, recurrence risk and potential delayed toxicity. While these limitations highlight the need for further evidence, they also prompt consideration of how thalidomide may be positioned in current clinical practice. Based on current evidence, thalidomide may be most relevant in patients with refractory hemorrhagic CRP who have failed repeated endoscopic therapy or are not suitable candidates for invasive surgical interventions. Its broader role remains to be defined in future comparative studies.

CONCLUSION

Refractory hemorrhagic CRP remains a major challenge in long-term management of pelvic cancer survivors, with few effective systemic therapies available. In a phase II study, Huang et al[5] demonstrated that low-dose thalidomide achieved favorable clinical remission and tolerability, potentially addressing radiation-induced vascular lesions and bridging the gap between local hemostatic measures and invasive surgical interventions. This provides preliminary support for a potential shift CRP treatment from symptomatic control to pathological intervention. Notably, the dissociation between symptomatic improvement and endoscopic findings indicates that patient-reported outcomes should be integral to efficacy assessment, challenging conventional evaluation models. Although phase III validation is required, thalidomide may be considered in patients unsuitable for or refractory to endoscopic management. This phase II study highlights a conceptual direction toward disease modification and patient-centered care in CRP management, providing a foundation for future research to confirm whether such a shift is achievable.