Thalidomide for refractory hemorrhagic chronic radiation proctitis secondary to pelvic malignancy radiotherapy: A phase II clinical trial

Abstract

BACKGROUND

Radiotherapy, a cornerstone for the treatment of pelvic malignancies, often causes pelvic-abdominal organ damage, with chronic radiation proctitis (CRP) as the primary toxicity. Over 90% of CRP patients experience persistent, irreversible hematochezia, and its management is challenging due to the limited availability of effective drugs.

AIM

To evaluate the efficacy and safety of thalidomide in CRP patients suffering from intractable bleeding.

METHODS

A single-arm, open-label, phase II clinical trial was implemented to evaluate the therapeutic efficacy and safety of thalidomide in treating hemorrhagic CRP. Patients who had a diagnosis of hemorrhagic CRP with a Subjective Objective Management Analysis system (SOMA) score for hematochezia ≥ 2, or a transfusion history resulting from CRP, were given 50 mg thalidomide orally for 4 months. The primary endpoint was assessment of the therapeutic efficacy of thalidomide.

RESULTS

From October 2020 to February 2024, 62 individuals were enrolled, of whom the median SOMA score was 3 (interquartile range 3-4), and 8 (12.9%) patients were transfusion-dependent due to hematochezia resulting from CRP. The overall efficacy rate of thalidomide in improving the SOMA score was 83.9% (52 of 62), with rates of 58.3% (7 of 12, ≤ 2 months), 95.1% (39 of 41, 3-6 months), and 100% (6 of 6, > 6 months). Significant improvements in endoscopic manifestations were visually observed in 60% (21 of 35) of patients. Adverse events occurred in 37.1% (23 of 62) of the study patients, all categorized as the National Cancer Institute’s Common Terminology Criteria for Adverse Events grade 1-2 manifestations.

CONCLUSION

Thalidomide is effective and well-tolerated for the treatment of hemorrhagic CRP. Further prospective multicenter research is warranted to verify these findings.

Key Words: Bleeding; Chronic radiation proctitis; Thalidomide; Efficacy; Safety

Core Tip: Chronic radiation proctitis (CRP) is a common complication of pelvic radiotherapy. Its most frequent symptom is hematochezia, which is often persistent and irreversible. However, the availability of oral drug treatments for hemorrhagic CRP are still extremely limited. This single-arm, open-label, phase II clinical trial investigated the therapeutic efficacy and safety of thalidomide for refractory hemorrhagic CRP. The results demonstrated that thalidomide achieved a hematochezia remission rate of up to 83.9%, with only mild or moderate adverse events. In summary, thalidomide appears to be an effective and well-tolerated treatment option for hemorrhagic CRP.

INTRODUCTION

Radiotherapy, the cornerstone treatment for pelvic malignancies, induces pelvic-abdominal organ damage despite survival benefits[1,2]. Chronic radiation proctitis (CRP) is the primary secondary associated toxicity after treatment and a significant adverse effect of radiotherapy. It is a challenging condition characterized by persistent and progressive lesions that often lead to irreversible damage[3]. Patients frequently experience prolonged hematochezia, severe anemia requiring blood transfusions, and significant physical and psychological distress. The severity and intractability of bleeding makes CRP management particularly difficult, significantly impacting patient health and their quality of life.

Clinically, the management of hematochezia in CRP is hampered by the absence of fundamental preventive and curative strategies. Current management mainly includes topical agents (e.g., sucralfate, sulfasalazine, formalin), endoscopic argon plasma coagulation (APC), stoma surgery, surgical resection of the diseased intestinal tract, etc.[4,5]. Given the priority of non-invasive management for hemorrhagic CRP, finding an oral drug with an optimal efficacy-safety profile and improved adherence is a crucial unmet need.

CRP is characterized by obliterative arteriolitis within the submucosa, submucosal fibrosis, intestinal ischemia, abnormal hyperplasia and dilation of capillaries, inflammatory cells infiltration, and so on[6,7]. Given this pathophysiology, thalidomide has emerged as a candidate therapy due to its known anti-inflammatory effects, immune regulation functions and its ability to suppress angiogenesis[8-11]. Thalidomide can stimulate intestinal mucosal repair and enhance vascular structure and blood perfusion[12]. Recent research has confirmed that thalidomide is effective in treating intestinal bleeding caused by vascular dysplasia[13-16]. A case study published in Gut reported a significant improvement of refractory bleeding due to CRP in a 78-year-old woman after thalidomide treatment[17]. Currently, published clinical data on the use of thalidomide for hemorrhagic CRP are limited to case reports. Therefore, a single-arm clinical study was conducted to assess the efficacy and safety of thalidomide for the treatment of hemorrhagic CRP.

MATERIALS AND METHODS

Study design and patients

The present research was a single-arm, open-label, single-center, phase II clinical trial, which received approval from the Ethical Committee of the Sixth Affiliated Hospital of Sun Yat-sen University, No. 2020ZSLYEC-207. The present study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. All study patients provided written informed consent prior to the commencement of their treatment. Only patients who had a diagnosis of hemorrhagic CRP were enrolled in the present study.

Inclusion criteria: (1) Age between 18 to 75 years; (2) An Eastern Cooperative Oncology Group physical condition score of 0 to 2; (3) A previous pathological diagnosis of pelvic tumors; (4) Completion of pelvic radiotherapy at least 3 months prior to enrollment; (5) No evidence of recurrence of primary tumor and metastasis; and (6) Diagnosis of refractory hemorrhagic CRP, defined as recurrent bleeding after at least one conventional treatment[4,5], characterized by either hematochezia with a Subjective Objective Management Analysis system (SOMA) score[18] ≥ 2, or a history of requiring blood transfusion due to CRP. The SOMA score was graded using various descriptive terms and ranged from 1 to 4, with higher scores indicating more severe bleeding. Grade 0 was defined as no bleeding; grade 1 was occult, grade 2 was occasionally > 2/week, grade 3 was persistent/daily and grade 4 was gross hemorrhage.

Exclusion criteria: (1) Active bleeding necessitating immediate intervention; (2) Severe complications of CRP (e.g., rectal ulcer with a Vienna Rectoscopy Score (VRS) > grade 3; fistula; perforation; stenosis; necrosis; perianal intractable pain); (3) Previous rectal resection; (4) Concurrent other hemorrhagic disorders, such as grade III or IV hemorrhoids, coagulation dysfunction, etc.; (5) Long-term anticoagulant use due to other circumstances; (6) Concurrent intestinal obstruction requiring surgery; (7) Absolute neutrophil counts < 750/mm³; (8) Known allergic to thalidomide; pregnancy or lactation; (9) Neurological or psychiatric disorders; (10) Active cardiovascular disease or a high thromboembolic risk; (11) Non-adherence to the study medication or follow-up assessments; (12) Unwillingness to use contraception (for patients and their partners) during and for 3 months after the study; and (13) Enrollment in any other clinical trials within 3 months prior to screening.

Procedures

Eligible patients received thalidomide capsules (25 mg each) orally at a daily dose of 50 mg before bedtime for 4 months. Patients who could not tolerate 50 mg/day were withdrawn from the study. Drugs that may cause drowsiness or have a potential link to peripheral neuropathy were also used with caution and closely monitored. Following the completion of treatment, each patient underwent at least 10 months of follow-up. Clinical assessments and laboratory tests were conducted at baseline, every 1 month during treatment and at 1 month post-treatment. Throughout this period, the severity of hematochezia, hemoglobin, frequency of blood transfusions, endoscopy results of the lesion, symptoms, patient complaints and adverse events were closely monitored.

Patients were interviewed in-person before treatment to gather information on the severity, frequency and duration of hematochezia during the previous month. Follow-up assessments were conducted monthly, either in person or by telephone. Laboratory testing, physical examinations and physician interviews were used to assess toxicity. The National Cancer Institute’s Common Terminology Criteria for Adverse Events (version 5.0) was used as the basis for documenting adverse events. Medical interviews were also carried out to assess treatment adherence.

Outcomes

The primary outcome was the evaluation of the therapeutic efficacy of thalidomide, defined as the proportion of patients achieving at least one grade reduction in their SOMA score. Secondary outcomes included the hemoglobin level and endoscopic score, and adverse events throughout thalidomide therapy. Endoscopic scores were evaluated using VRS, using a range of 1 to 5, with higher scores indicating more severe lesions[19,20]. The efficacy of thalidomide on hemorrhagic CRP was determined by comparing SOMA and VRS scores before and after treatment. Thalidomide treatment was deemed effective if SOMA or VRS indicated complete remission or improvement, and ineffective if the scores remained unchanged or worsened.

Statistical analysis

The sample size of the present study was determined using PASS version 11.0 software. Based on the data from our center, the remission rate of APC treatment for hemorrhagic CRP was 68.9%[21]. For refractory hemorrhagic CRP, the estimated remission rate of APC treatment was approximately 40%-50%. Assuming a target remission rate of 50% for APC, it was hypothesized that treatment with thalidomide would achieve a response rate of 70%. With α set at 0.05 and power (1-β) at 80%, and anticipating a 20% dropout rate, it was estimated that 62 patients would need to be enrolled. Data were collected and carefully monitored. All statistical analyses were performed on the intention-to-treat population using SPSS software version 19.0.

RESULTS

Demographics of enrolled patients

From October 2020 to February 2024, 75 patients were screened, and 62 were identified to be eligible for inclusion in the present study (Figure 1). Table 1 summarizes the demographic and clinical characteristics of those enrolled. As shown in Table 1, the study cohort was comprised 58 females (93.5%) and 4 males (6.5%), with a mean age of 61.8 ± 9.1 years. In terms of primary cancer types, cervical cancer was the most frequent, accounting for 87.1% of cases (n = 54). Other types of cancer included endometrial (3.2%, n = 2), prostate (6.5%, n = 4), rectal (1.6%, n = 1) and anal (1.6%, n = 1). The median time from the end of radiotherapy to enrollment was 16.2 months [interquartile range (IQR) 10.3-23.7], and the median time from the end of radiotherapy to the onset of bleeding was 8.2 months (IQR 6.1-13.2). The median duration of bleeding was 5.3 months (IQR 2.4-13.1) and 8 (12.9%) patients were transfusion-dependent. The median pre-enrollment SOMA score and hemoglobin concentration were 3 (IQR 3-4) and 117 g/L (IQR 100-127), respectively. The pre-enrollment VRS of the patients was 3 (IQR 3-3), with the median mucosal congestion and telangiectasia scores being 2 (IQR 2-2) and 3 (IQR 2-3), respectively.

Figure 1  Flow chart of patient selection.

Table 1 Clinical characteristics and demographic information on the study patients, n (%)/median (interquartile range).

Characteristic	Patients (n = 62)
Age, years	61.8 (9.1)
Sex
Male	4 (6.5)
Female	58 (93.5)
Primary cancer
Cervical	54 (87.1)
Endometrium	2 (3.2)
Prostatic	4 (6.5)
Rectal	1 (1.6)
Anal	1 (1.6)
Comorbidities
Coronary artery heart disease	1 (1.6)
Hypertension	5 (8.1)
Diabetes mellitus	2 (3.2)
History of abdominopelvic operation	13 (21.0)
Time from the end of radiotherapy to enrollment, months	16.2 (10.3, 23.7)
Time from ceasing radiotherapy to bleeding, months	8.2 (6.1, 13.2)
Duration of bleeding, months	5.3 (2.4, 13.1)
Transfusion dependent	8 (12.9)
Grade of bleeding (SOMA)	3 (3, 4)
Pre-enrollment hemoglobin, g/L	117 (100, 127)
Pre-enrollment VRS	3 (3, 3)
Mucosal congestion	2 (2, 2)
Telangiectasia	3 (2, 3)
Ulceration	0 (0, 1.5)
Stenosis	0 (0, 0)
Necrosis	0 (0, 0)

SOMA: Subjective Objective Management Analysis system; VRS: Vienna Rectoscopy Score.

Efficacy

Table 2 and Figure 2 show the efficacy of thalidomide on hemorrhagic CRP as measured by the SOMA score. The thalidomide treatment course was 3.5 (IQR 2.8-4.3), with a maximum duration of intermittent administration of up to two years. In the present study, relatively poor adherence or lack of initial efficacy led to only 47 patients (75.8% of the total cohort) completing at least 3 months of thalidomide treatment. The median time to treatment discontinuation at the last follow-up was 16.1 (IQR 10.0-21.8), with a maximum duration of 37 months.

Figure 2 The efficacy of thalidomide on hemorrhagic chronic radiation proctitis as measured by the Subjective Objective Management Analysis system score. SOMA: Subjective Objective Management Analysis system.

Table 2 The efficacy of thalidomide on hemorrhagic chronic radiation proctitis as measured by the Subjective Objective Management Analysis system score.

		Pre-treatment				Post-treatment
SOMA effect	62	1	2	3	4	0	1	2	3	4
Completely remitted	6	0	0	2	4	6	0	0	0	0
Alleviative	46	0	2	25	19	0	27	14	5	0
Unchanged	7	0	2	4	1	0	0	2	4	1
Aggravated	3	0	2	1	0	0	0	0	1	2
Efficacy rate (%)	83.9%

SOMA: Subjective Objective Management Analysis system.

Before thalidomide treatment, the severity of rectal bleeding of the patients evaluated by SOMA was classified thus: Grade 4 in 24; grade 3 in 32; and grade 2 in 6 patients. After thalidomide treatment, rectal bleeding of patients exhibited a significant improvement. The overall efficacy rate of thalidomide on SOMA of the hemorrhagic CRP was 83.9% (52 of 62), with 6 completely remitted, 46 alleviated, while symptoms remained unchanged in 7 patients and were aggravated in 3. In addition, among the 46 patients with improved symptoms, 4 still received APC and 3 received a retention enema based on sucralfate due to persistent minor bleeding. Of the 10 patients who did not respond to treatment, the SOMA score was grade 4 in 1 patient, grade 3 in 5 patients and grade 2 in 4 patients. Among these nonresponders, 8 patients did not achieve the 3-month course of thalidomide medication, but subsequent interventions included bowel resection for bleeding combined with deep rectal ulcers (1 patient), diverting colostomy (2 patients: 1 for bleeding and the other for rectovaginal fistula), APC (2 patients), and retention enema based on sucralfate (2 patients). In our study, 4 patients experienced progression after discontinuing thalidomide, of whom 2 received APC and 2 treated with a retention enema. Additional further analysis revealed that among patients completing at least 3 months of thalidomide treatment, the efficacy rate on SOMA was 95.7% (45 of 47). Specifically, the efficacy rates for thalidomide treatment durations of ≤ 2 months, 3 to 6 months and > 6 months were 58.3% (7 of 12), 95.1% (39 of 41) and 100% (6 of 6), respectively.

Table 3 shows comparisons of SOMA, VRS and hemoglobin for hemorrhagic CRP before and after thalidomide treatment. It was found that thalidomide treatment significantly reduced SOMA and mucosal congestion scores (P < 0.05), with no obvious change in the hemoglobin concentration, VRS or the telangiectasia scores. Figure 3 shows representative endoscopic images before and after thalidomide treatment. It is clearly evident that significant improvement in endoscopic manifestations occurred after thalidomide treatment. The efficacy rates of thalidomide on VRS, mucosal congestion and telangiectasia in patients with hemorrhagic CRP were 17.1%, 28.6% and 14.3%, respectively. Correspondingly, the majority of patients exhibited no significant change in these parameters following treatment. However, as presented in Figure 3, significant improvement in endoscopic manifestations were indeed visually observed in 60% (21 of 35) of patients after treatment, particularly in the extent and severity of the lesions (Figure 3C). Additionally, 6 patients with ulcers before treatment achieved complete remission. However, stenosis occurred after treatment in 1 patient.

Figure 3 Representative endoscopic images before and after thalidomide treatment. A: Vienna Rectoscopy Score (VRS) decreased, telangiectasia score decreased; B: VRS and telangiectasia score unchanged, mucosal congestion score decreased; C: VRS, mucosal congestion score and telangiectasia score unchanged.

Table 3 Before and after thalidomide treatment effects on hemorrhagic chronic radiation proctitis, median (interquartile range).

	Pre-treatment	Post-treatment	P value
SOMA (n = 62)	3 (3, 4)	1 (1, 2)	< 0.001
VRS (n = 35)	3 (3, 3)	3 (2, 3)	0.132
Mucosal congestion	2 (2, 2)	2 (1, 2)	0.007
Telangiectasia	3 (3, 3)	3 (2, 3)	0.257
Ulceration	0 (0, 3)	0 (0, 0)	0.177
Stenosis	0 (0, 0)	0 (0, 0)	0.317
Necrosis	0 (0, 0)	0 (0, 0)	1.000
Hemoglobin, g/L (n = 32)	117.5 (103, 125.5)	108.5 (103, 125.25)	0.199

SOMA: Subjective Objective Management Analysis system; VRS: Vienna Rectoscopy Score.

Adverse events

In the present study, given the previously reported adverse reactions associated with thalidomide, including constipation and limb numbness, nearly all patients given thalidomide were co-administered mecobalamin, Ma Ren capsules and probiotics. The adverse events found during thalidomide therapy are shown in Table 4. Adverse events were found in 37.1% (23 of 62) of the enrolled patients. Dizziness (14.5%) and somnolence (12.9%) were the most common adverse events. The other adverse events were nausea (4.8%), constipation (6.5%), rash (4.8%), limb numbness (1.6%), peripheral edema (1.6%), blurred vision (1.6%) and deep venous thrombosis (DVT) of the lower extremity (1.6%). All the adverse events were generally mild to moderate in their severity (grade 1-2), and tolerable in nearly all of the enrolled patients, except for 1 who discontinued the medication due to an intolerable rash on both feet and dizziness. In the patient who developed DVT, thalidomide was continued due to ongoing hematochezia. Given the contraindication to anticoagulation, a prophylactic inferior vena cava filter was placed and retrieved six months later, with no significant change in the thrombus burden. Notably, even in patients who received thalidomide therapy for nearly 1 year (n = 3) or 2 years (n = 1), no adverse events occurred except for 1 case of constipation.

Table 4 Adverse events, n (%).

Event	Thalidomide treatment (n = 62)
	Grade 1	Grade 2	Total
Any adverse event	17 (27.4)	7 (11.3)	23 (37.1)
Nausea	3 (4.8)	0	3 (4.8)
Constipation	0	5 (6.5)	4 (6.5)
Dizziness	9 (14.5)	0	9 (14.5)
Somnolence	8 (12.9)	0	8 (12.9)
Blurred vision	1 (1.6)	0	1 (1.6)
Rash	3 (4.8)	0	3 (4.8)
Limb numbness	0	1 (1.6)	1 (1.6)
Peripheral edema	1 (1.6)	0	1 (1.6)
DVT of lower extremity	0	1 (1.6)	1 (1.6)

DVT: Deep venous thrombosis.

DISCUSSION

CRP is a common complication of pelvic radiotherapy. Most CRP occur within three years after radiotherapy, although latent presentations beyond ten years are fairly common[22,23]. The natural history of the condition remains largely unpredictable[24] Clinically, bleeding ranges from intermittent minor spotting that may cause chronic anemia to recurrent, severe hematochezia[25]. Patients with mild symptoms often have a favorable outcome. Around 35% achieve spontaneous resolution within six months[26-28], while others may respond to conservative treatments[29]. In contrast, refractory cases that persist despite escalating interventions are associated with poorer outcomes. These include a need for frequent transfusions and a progressively rising mortality rate over time[27,30]. Pathologically, submucosal fibrosis and obliteration of small vessels characterize CRP, which is generally progressive and irreversible[24]. Therefore, even apparently minor bleeding should not be overlooked, as it may indicate underlying progressive vasculopathy. In the present study, the enrolled patients had recurrent bleeding and a median SOMA grade of 3 (IQR 3-4), with 12.9% being transfusion-dependent. Endoscopic evaluation using the VRS revealed notable mucosal changes, scoring 2 (IQR 2-2) for congestion and 3 (IQR 2-3) for telangiectasia. These features indicated that the studied population represented a clinically challenging subgroup.

The severity of CRP is closely associated with radiation dose, fractionation regimen, treatment field, and individual tissue radiosensitivity[31]. In our cohort, the majority of cases (87%) occurred following radiotherapy for cervical cancer. This finding can be largely explained by the standard definitive radiotherapy protocol for cervical cancer, which combines external beam radiation therapy with intracavitary brachytherapy[32]. To achieve curative radiation doses, high-dose exposure to adjacent pelvic organs, especially the anterior rectal wall, is often unavoidable[33]. The steep dose gradient produced by brachytherapy results in an extremely high localized dose to the rectal mucosa, substantially increasing the risk of mucosal injury and delayed hemorrhagic complications[34,35].

Currently, the availability of effective oral therapeutic options for hemorrhagic CRP remains scarce[36]. A recent meta-analysis reported that oral sucralfate did not show significant efficacy on CRP-related bleeding[37]. Thalidomide significantly alleviated hematochezia in patients with hemorrhagic CRP. The overall efficacy rate of thalidomide treatment at a dose of 50 mg on SOMA was 83.9%, which increased to 95.7% in patients treated for ≥ 3 month. Only 4 patients experienced progression after discontinuing thalidomide, indicating that the therapeutic effects persisted after at least 3 months treatment. A previous study also reported that bleeding control remained effective after 4 months of thalidomide treatment for patients with vascular malformation[38]. In the present study, some patients received extended treatment courses. Stratified analysis showed that the efficacy rates were 58.3% (7/12) for treatment durations ≤ 2 months, 95.1% (39/41) for 3-6 months, and 100% (6/6) for > 6 months. The extension of treatment was primarily driven by patient-reported outcomes. Although hematochezia had improved significantly, intermittent or mild bleeding persisted, and patients still perceived the treatment as beneficial. Therefore, thalidomide appeared to be effective for hemorrhagic CRP and was capable of maintaining therapeutic efficacy over a relatively long time period. Compared with conventional clinical treatment strategies, thalidomide is a simple and effective treatment option in clinical practice.

In addition, thalidomide has also been reported to be administered to treat intestinal bleeding due to other causes. Previous study found that thalidomide significantly reduced the bleeding episodes in small-intestinal angiodysplasia (SIA) during the year after a 4-month treatment period, with the effective response being 51.0% for 50 mg and 68.6% for 100 mg[16,39]. In this research, no patient with gastrointestinal vascular malformations due to radiotherapy were included. Historically, SIA is marked by dilated and tortuous arterial or venous capillaries between thin-walled and immature veins and capillaries, often associated with age-related vessel degeneration[40]. It has been reported that bleeding episodes due to angiodysplastic lesions stopped spontaneously in 50% to 90% of cases[41,42]. In contrast, the intestinal tissue of CRP patients exhibited chronic and refractory damage due to the effects of radiotherapy. The hematochezia in these patients was different from SIA, which was refractory and would not resolve spontaneously without treatment. It was reported in Gut that a 78-year-old woman with 3-month intermittent rectal bleeding, unresponsive to conventional treatments including APC and requiring frequent transfusions, achieved stable hemoglobin concentrations within 3 weeks and remained well for 3 months after thalidomide treatment at a dose of 50-100 mg/day[17]. In agreement, the present study also found that thalidomide was effective in treating radiation-induced intestinal vascular malformations and lesions.

Endoscopic scoring is considered one of the key visual systems for assessing the severity of intestinal lesions. However, the efficacy of thalidomide was found to be significantly underestimated when assessed using endoscopic scoring. Although many patients exhibited endoscopic remission of lesions, their VRS remained unchanged or increased, as illustrated in Figure 3C. It may be because the commonly used VRS was only a 5-point scale and only 3-grade scales for capillary and mucosal congestion, which may have been insufficient to capture the nuances of the severity of lesions or their extent[4]. Furthermore, despite no significant endoscopic changes in capillary or mucosal congestion, subjective improvement was reported by many patients, with a reduced frequency and volume of rectal bleeding. The improvement in symptoms may precede histological repair, whereas the VRS score may reflect only the latter. The relief of hematochezia may be associated with local inflammation control, vasoconstriction or improved coagulation function, rather than immediate structural repair of the lesions.

With regard to the safety of thalidomide, its use has been reported to be associated with several adverse events, including fatigue, dizziness, constipation, edema, peripheral neuropathy, DVT and so on[16,43]. In the present study, adverse events occurred in 37.1% (23 of 62) of patients, with fatigue, constipation, dizziness and peripheral edema found most often, similar findings to previous studies. In our study, 1 patient developed an asymptomatic DVT following treatment. Of note, it has been reported that radiotherapy and cancer also increased the risk of developing DVT[44,45], with a much higher prevalence of lower extremity DVT observed in CRP patients following pelvic malignancy radiation compared to the general population[46]. In addition, it has been reported that the efficacy and safety of thalidomide were dose-dependent. Chen et al[16] found that the effective responses to 50 mg and 100 mg thalidomide were 51.0% and 68.6%, respectively, with corresponding adverse event rates of 55.1% and 68.6%. The recommended dosage in the manufacturer’s instructions is typically ≤ 200 mg. Adverse events significantly increased when the dose exceeded 400 mg[47]. In the present study, a 50 mg dose of thalidomide was found to be both a safe and effective. Furthermore, we observed a favorable tolerance in 4 patients who were treated with thalidomide for up to 1-2 years, with only one case of constipation reported. Nevertheless, it must be acknowledged that delayed adverse events such as neuropathy or thrombotic complications might still emerge beyond the follow-up period. This finding is consistent with prior evidence indicating that long-term thalidomide use maintains an acceptable safety profile. As reported by Ali et al[48] thalidomide treatment for up to 30 months at doses of 1-4 mg/kg/day, the adverse events were predominantly mild (e.g., constipation), while complications such as neutropenia (observed after 12-30 months) and thrombosis occurred very infrequently and were often reversible.

However, it should be acknowledged that the present study had a number of limitations. First, this was a single-arm study lacking a randomized control group, consequently limiting the interpretability of the results. Second, the sample size was relatively small, and the observation period remained relatively brief. Third, some patients failed to complete the prescribed treatment course and the required tests within the specified time-frame. Therefore, a long-term, randomized and controlled trial with a larger cohort of patients is warranted to establish unequivocally the efficacy and safety of thalidomide for the treatment of hemorrhagic CRP.

CONCLUSION

In conclusion, thalidomide was effective and well-tolerated when used for the treatment of hemorrhagic CRP. A dose of 50 mg nightly achieved an 83.9% clinical response rate for hematochezia, with no serious adverse events reported. These findings provide robust evidence for thalidomide as a viable treatment option for hemorrhagic CRP. To validate further these findings, a prospective, large-scale, randomized controlled trial with long-term follow-up is warranted.

ACKNOWLEDGEMENTS

We would like to extend our sincere gratitude to every researcher and the participants who contributed to this study.