Efficacy of Thalidomide for Refractory Gastrointestinal Bleeding From Vascular Malformation

1. Efficacy of Thalidomide for Refractory Gastrointestinal Bleeding From Vascular Malformation Zhi–ZhengGe et al GASTROENTEROLOGY 2011;141:1629–1637

2. Editor: DrmohammadSadrkabir

3. Gastrointestinal vascular malformation (GIVM), such as angiodysplasia and gastric antral vascular ectasia (GAVE), became an increasingly recognized cause of obscure gastrointestinal bleeding and iron-deficiency anemia, particularly in the elderly. • Approximately 20% of patients present with iron-deficiency anemia and/or stools that are intermittently positive for occult blood. • Massive bleeding occurs in about 12%−27% of patients. • At present, conventional therapies including angiographic embolization, local endoscopic ablation, and surgical resection for GIVM are often ineffective in preventing recurrent gastrointestinal (GI) bleeding, and may occasionally be associated with severe complications such as ischemic bowel necrosis or even mortality.

4. The inefficacy is partially because the exact locations of lesions are usually hard to determine, especially for multicentral small bowel lesions. Therefore, an effective and relatively safe pharmaceutical agent is urgently needed. • Although hormonal therapy using estrogen and progestagenwas previously considered promising, a recent randomized study found that such a treatment was ineffective. Somatostatin and its analog, octreotide, have been reported to reduce blood loss from intestinal angiodysplasias; however, a final conclusion on its efficacy has not been drawn.

5. There have been several case reports demonstrating encouraging clinical outcomes of thalidomide in the prevention of recurrent GI bleeding from angiodysplasia or GAVE. • Thalidomide has been reported to exhibit an inhibitory effect against neoangiogenesis by suppressing the expression of vascular endothelial growth factor (VEGF). VEGF is strongly expressed within colonic angiodysplasias and may be involved in the pathogenesis of GIVM. • Thus, it has been proposed that the therapeutic efficacy of thalidomide for angiodysplasia might be attributed to the inhibition of VEGF • We performed an exploratory study to determine the long-term efficacy and safety of thalidomide in the prevention of recurrent bleeding due to GIVM and possible role of VEGF.

6. Methods • Consecutive patients who were diagnosed with GIVM at the Department of Gastroenterology, Renji Hospital, from November 2003 to November 2007 were eligible for the screening for the study.

7. Inclusion criteria : • (1) patients were between 40 and 85 years old; • (2) female patients were postmenopausal, with post-tubal ligation, or females with childbearing potential using some form of birth control (eg, contraceptive ring or latex condoms); • (3) patients had recurrent or refractory bleeding due to GIVM. • (4) all patients had been confirmed as having GIVM (angiodysplasia and/or GAVE) without obvious infectious, neoplastic, or other specific lesions by endoscopic examination including EGD, colonoscopy, and capsule endoscope (CE) or double-balloon endoscope (which was performed only when CE was negative).

8. Refractory bleeding was defined as bleeding either unresponsive to (ie, recurrent bleeding after at least 3 sessions of EGD or coloscopic therapies, or at least 1 session of double-balloon endoscope therapy or primary medical approaches, such as hormonal or/and somatostatin therapies) or unsuitable for (ie, in the presence of multiple lesions, lesions inaccessible by endoscopic therapy or surgical ectomy, or patients unwilling or unable to undergo surgery due to poor health condition) conventional therapies.

9. Exclusion critera: • (1) cirrhotic or portal hypertension gastropathy; • (2) severe comorbidities of cardiac, pulmonary, renal, liver, hematological, rheumatologic disorders, or uncontrollable diabetes mellitus or hypertension; • (3), a history of severe bilateral peripheral neuropathy or seizure activity, thromboembolic disease, known thalidomide or iron allergy, or prior treatment of gastrointestinal bleeding with thalidomide; • (4) treatment with any dose of systemic or oral topical corticosteroids or aspirin, NSAIDs, antiplatelet drugs, anticoagulants, or Chinese medications (with salicylates), gingko, or echinacea, or other putative immunomodulators or antiangiogenic agents; • (5) currently pregnant or lactating; and • (6) currently undergoing systemic cancer chemotherapy or receiving radiation.

10. We performed an open-label, randomized, parallel controlled study that consisted of 3 major periods: a 1-year observation period before randomization, a 4-month treatment period, and a subsequent at least 1-year follow-up period. • Recruited patients were entered into the treatment period and randomized only when they had 6 or more bleeding episodes defined by a positive immunoassay fecal occult blood test (iFOBT) in the observation period. • Eligible patients were consecutively assigned a random number in chronological order that allocated him or her to receive either thalidomide or iron.

11. Patients in the thalidomide group received 25 mg thalidomide orally 4 times daily for 4 months, and those in the iron-controlled group received 100 mg iron (ferrous succinate tablets) orally 4 times daily at the same time points. • Patients assigned to the thalidomide group were refrained from iron ingestion during the 4-month course of treatment, regardless of the hemoglobin levels. • During the treatment period, patients were hospitalized and closely monitored for the first week or a few days longer when required.

12. Concomitant therapies, such as blood transfusions and other symptomatic treatments, were performed in both groups as necessary. During the whole period of the study, blood transfusion (ie, packed red cell transfusion) was indicated and recorded when the hemoglobin level fell below 7.0 g/dL (2 U were administered for 6.1 g/dL ≤ hemoglobin ≤ 7.0 g/dL, 3 U for 5.1 g/dL ≤ hemoglobin ≤ 6.0 g/dL, and 4 U for hemoglobin < 5.0 g/dL). • Iron supplementation (100 mg, 4 times per day) was allowed for patients in both groups when the hemoglobin levels fell between 7.1 g/dL and 11.0 g/dL during the 1-year observation period and subsequent follow-up periods.

13. During the whole period of study, patients were asked to record the characteristics of their feces (ie, color, volumes, frequency of defecation, and softness) daily in a planned diary. • All patients were requested to visit the hospital monthly during the observation and follow-up periods and biweekly during the treatment period for data collection. • At each scheduled visit, a physical examination, complete blood counts, and routine iFOBT(using monoclonal colloidal gold color technology) were performed. In patients positive for a routine iFOBT, with or without any signs of overt bleeding, iFOBT was performed daily until there were 3 consecutive days of a negative test. • In addition, during the whole study period, iFOBT was performed daily in the same way in patients with any signs of overt bleeding (such as hematemesis, melena, hematochezia, or a dramatic drop in hemoglobin).

14. The primaryobjective of the present study was to determine the effective response rate that was defined as the proportion of patients in whom bleeding episodes decreased by ≥50% within the first-year of follow-up after treatment, compared with the bleeding episodes in the observation year prior to treatment. • The secondary end points included the rates of cessation of bleeding, blood transfusion, overall hospitalization, and hospitalization for bleeding.

15. In cases with GAVE or angiodysplasiain the duodenum or colon, EGD or colonoscopy was repeated 12 months after the treatment period by the same experienced endoscopist to evaluate the lesion. • Finally, plasma VEGF was measured before and after the 4-month treatment course in the thalidomide group by a technician who was blinded to the study.

16. Results • There were 46 (83.6%) female patients; 16 had childbearing potential and were on birth control, and the remaining were either postmenopausal (n = 24) or received post-tubal ligation (n = 6). • Multiple lesions were present in 27 (49.1%) patients, which were found in the jejunum (n = 7) or ileum (n = 5) or both (n = 15). • Angiodysplasia was identified in 52 (94.6%) patients by CE (n = 48) or subsequent double-balloon endoscope after a negative CE (n = 4). • GAVE was identified in 3 (5.5%) . • Median follow-up period was 39 months (range, 8–52 months). • The demographic baselines were similar .

19. During the observation year, 85.7% (24 of 28) patients in the thalidomide group and 92.6% (25 of 27) in the control group presented with both occult and overt bleeding, whereas 14.3% (4 of 28) of patients and 7.4% (2 of 27) of patients, respectively, in the 2 groups presented only occult bleeding. • There was no significant difference in the bleeding episodes, average bleeding duration (days), hospitalization rate for bleeding, hospitalization number for bleeding, average hospital stay (days), blood transfusion rate, transfused red cell requirements, and average hemoglobin levels between the 2 groups .

21. According to the intention-to-treat principle, the effective response rate was 71.4% (20 of 28) in the thalidomide group and 3.7% (1 of 27) in the iron-controlled group (P < .001) . • Per-protocol analysis revealed the effective response rate of 76.9% (20 of 26) in the thalidomide group and 3.8% (1 of 26) in the iron-controlled group (P < .001)

23. During the follow-up period, 4-month interval bleeding episodes progressively decreased from 4.90 ± 0.62 to 2.30 ± 0.45 after treatment until month 8, and then remained low afterward in the thalidomide group.

25. Adverse events were observed in 20 (71.4%) and 9 (33.3%) patients in thalidomide and the iron-controlled groups, respectively (P = .007). • Two patients in the thalidomide group discontinued treatment due to leukopenia and somnolence, as described. • Fatigue was the most common adverse event in both the thalidomide (32.1%) and iron-controlled groups (11.1%). • Constipation (25.0% vs 11.1%), dizziness (21.4% vs 7.4%), and abdominal distension (3.6% vs 3.7%) were observed in both thalidomide and the iron-controlled groups. • Peripheral edema (n = 4), bitter taste (n = 2), leukopenia (n = 1), thrombopenia (n = 1), numb limb (n = 1), bradycardia (n = 1), somnolence (n = 1), headache (n = 1), hands tremble (n = 1), tinnitus (n = 1), rash (n = 1), pruritus (n = 1), dry eye (n = 1), blurred vision (n = 1), increased vaginal discharge (n = 1), and herpes zoster (n = 1) were reported in the thalidomide group only. • Stomach upset (n = 3), diarrhea (n = 1), nausea (n = 1), and vomiting (n = 1) were reported in the iron-controlled group only.

27. Discussion • It has been reported that bleeding due to angiodysplastic lesions stops spontaneously in approximately 50%–90% of cases. However, spontaneous cessation of bleeding due to GIVM did not occur in any of the patients in the iron-controlled group. This might be attributed to our strict inclusion criterion requiring at least 6 bleeding episodes a year, which could minimize the possible bias caused by spontaneous cessation of bleeding. • Additionally, most of our patients had a long-term bleeding history and previous bleeding episodes from angiodysplasia, which is a risk factor for recurrent bleeding. Thus, bleeding in these patients is less likely to be stopped spontaneously without therapies. Thalidomide may serve as a reasonable option for these patients.

28. No randomized controlled trial assessing the long-term efficacy and safety of thalidomide in treating recurrent bleeding due to GIVM has been reported. • The natural history of bleeding due to GIVM is known to be variable, usually episodic with remissions and recurrences, which makes it difficult to evaluate the efficacy of any therapy in short-term. • In some studies, the increase in hemoglobin level and decrease in transfusion requirement were used to represent the improvement of bleeding status.However, the hemoglobin level usually represents the instantaneous degree of acute bleeding, as it can be easily influenced by blood transfusion, iron supplementation, or recurrent bleeding. Transfusion is not always required in patients with bleeding due to GIVM. In our study, only 50.9% (28 of 55) of patients were transfusion-dependent. Therefore, we included the hemoglobin level or transfusion dependency as the secondary end points instead of the primary end point.

29. Bleeding episode, which directly reflects the status of GI bleeding and the response to medications and is thus reliable, was used as the primary end point in this long-term study. • The optimal dosage of thalidomide for antiangiogenic treatment is unclear. Previous studies used thalidomide dosages of 100–400 mg per day. Considering the older age of our study population, we chose a low dosage (100 mg daily) to achieve hemostasis while minimizing toxicity and consequent residual effects. Thalidomide carries the risk of serious adverse events, such as deep vein thrombosis. • A new thalidomide analogue (lenalidomide), which is reported to be a more potent immunoregulator with possibly fewer side effects,may be evaluated for the prevention of GI bleeding due to GIVM.

30. The precise pathogenesis of GIVM has not been fully clarified. Age-related vessel degeneration is a known causative or associated factor. High intestinal wall tension may precipitate local vascular ectasia, with chronic obstruction of the submucosalveins leading to capillary dilatation and precapillary sphincter incompetence. • More importantly, abnormalities or disorders of angiogenesis or angiogenic regulation are believed to play a major role. This is particularly true for abnormalities related to VEGF signal transduction, because VEGF is the strongest angiogenic factor expressed in the vascular wall. • Evidence of VEGF and its messenger RNA has been found in colonic angiodysplasia patients.

31. The major limitation of the present study is that we failed to carry out a double-blinded placebo design. • The primary and most secondary outcomes were objective; therefore, the findings were minimally susceptible to reporting bias. • We acknowledge that iron supplementation as a control could most likely favorably impact some of our secondary end point variables, such as the hemoglobin and transfusion requirement, so that it can be regarded as a positive control agent rather than blank (placebo) control agent.

32. Conclusions • Thalidomide is effective and relatively safe for refractory bleeding from GIVM. • Mechanisms of thalidomide activity might involve VEGF.

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