Thalidomide for the Management of Gastrointestinal Bleeding in a Palliative Care Setting

Background: Palliative care patients frequently present with clinically significant gastrointestinal bleeding. Due to the existence of confounding comorbidities and a remarkably reduced state of general health in many cases, the management of gastrointestinal bleeding in this population is often challenging. Summary: This review summarizes and discusses the role of thalidomide in gastrointestinal bleeding with a special focus on palliative care patients. In addition, an illustrative case report is presented. Thalidomide may be beneficial in gastrointestinal bleeding by exerting antiangiogenic effects. The drug has an acceptable safety profile. Side effects like neurotoxicity may limit its use but can be monitored safely. Due to thalidomide’s thrombin generation potential, patients managed with thalidomide-containing regimes should be closely monitored for deep venous thrombosis. Given its teratogenicity, thalidomide should not be administered to women of childbearing potential who are not using adequate contraception. Key Message: Physicians caring for patients in a palliative care setting should be aware of thalidomide as an effective therapeutic option when endoscopy fails to find a bleeding source or for those patients who cannot or refuse to undergo endoscopy but present with recurrent or obscure gastrointestinal bleeding.


Introduction
The following case illustrates the clinical challenge in palliative care patients with obscure gastrointestinal bleeding.Eight months prior to admission, this 66-year-old female patient (body weight 50 kg, height 163 cm, body mass index 19 kg/m 2 ) complained of loss of appetite, nausea, bloating, diarrhea, and a reduced general health.Computed tomography of the abdomen showed a mass (4.4 × 4.0 cm) in the tail of the pancreas, multiple adjacent enlarged lymph nodes, and several masses in the liver with the largest 5.5 cm in diameter.There was evidence of substantial ascites.Histology of the endosonography-guided biopsy of the pancreatic mass revealed pancreatic adenocarcinoma.Laboratory data showed significantly elevated levels of the tumor marker CA 19-9 (23,181 kU/L, normal: 0-27 kU/L); in addition, cytologic investigation of the ascites suggested peritoneal carcinomatosis.Chemotherapy with gemcitabine/paclitaxel and nal-irinotecan/5-fluorouracil was initiated and continued for 7 months.Exocrine pancreatic insufficiency was well managed with pancreatic enzyme replacement.For nausea, the patient received metoclopramide, ondansetron, and dronabinol.With this palliative management, the condition of the patient was stable for 6 months and she was cared for at home assisted by a mobile palliative care team.Despite initial clinical stability, 5 months after the diagnosis of pancreatic cancer, the patient developed deep venous thrombosis in the left lower limb and therefore, received anticoagulation with edoxaban (60 mg, once daily).
After receiving two units of packed red blood cells, her hemoglobin level increased to 8.8 g/dL but could not be stabilized on intravenous therapy with somatostatin (6 mg/50 mL NaCl 0.9%, continuous flow 4.2 mL/h for 3 days), even though oral anticoagulation with edoxaban had been terminated.Subsequently, the patient needed repeated blood transfusions (four additional units of packed red blood cells) over a period of 8 days.Esophagogastro-duodenoscopy was unremarkable; colonoscopy was not carried out because of increasing deterioration of the patient's general health and her wish not to undergo further endoscopy.Capsule endoscopy may have been helpful to identify a potential bleeding source but was not performed in this case because it was deemed to be too cumbersome for the patient.Further, results of capsule endoscopy would have taken at least 2 weeks to obtain in our institution.When she additionally developed massive hematochezia, and there was no response to somatostatin and tranexamic acid (1.5 g/day for 2 days as an attempt to manage her gastrointestinal bleeding although not primarily recommended any more), an off-label, 7-day therapeutic trial with thalidomide 100 mg at bedtime was initiated after the patient's informed consent had been obtained.While on this therapy, the patient's gastrointestinal bleeding completely ceased within 2 days and the hemoglobin level remained stable at about 10 g/ dL without the need for additional blood transfusions.
As the patient had a history of deep venous thrombosis, the thrombin generation potential (expressed as peak thrombin and endogenous thrombin generation potential) was measured before and after administration of thalidomide using a commercially available in vitro fluorogenic assay (Technothrombin TGA, Technoclone, Vienna, Austria).Due to the urgent need of managing the gastrointestinal bleeding, there was, however, no wash-out phase after discontinuing tranexamic acid and initiating thalidomide.The analysis revealed a slight increase in both peak thrombin (6.2%) and the endogenous thrombin generation potential (9.3%) while on therapy with thalidomide.There was no thromboembolic event during follow-up.

Discussion and Review of the Literature
The number of admitted patients who meet the criteria for palliative care has been rising over the last years [1].Of these, it is estimated that about one-third is within their last year of life [2].Palliative care patients are defined as patients suffering from at least one chronic lifelong medical condition; hospice care patients are patients who have a life expectancy of less than 6 months [3].Clinically significant bleeding occurs in 6-10% of palliative care patients [4].In homebound palliative care patients, about 56% of gastrointestinal bleedings are fatal within 48 h [5].Due to the existence of confounding comorbidities, an often remarkably reduced state of general health and the necessity to always consider the patients' attitude, the availability of resources and cost-related factors, the management of gastrointestinal bleeding in this population is often challenging.

Gastrointestinal Bleeding
Gastrointestinal bleeding is a common condition, classified into upper and lower gastrointestinal bleeding, depending on the localization.Upper gastrointestinal bleeding occurs proximally to the ligament of Treitz and lower gastrointestinal bleeding distally, encompassing the small and large intestine [6].
Causes of upper gastrointestinal bleeding include, among others, peptic ulcer, gastritis, esophagitis, variceal bleeding, Mallory-Weiss tear, malignancy [7] and druginduced or chemically induced duodenal erosions and ulcers [8].In the lower gastrointestinal tract, enteropathy and colonopathy due to non-steroidal anti-inflammatory drugs (NSAIDs) are also important.Regular intake of NSAIDs promotes gastrointestinal bleeding and increases fecal blood loss 2-to 4-fold as compared to patients who are not on such medications [9].Diverticular disease of the colon is one of the most common causes of acute lower gastrointestinal tract bleeding (30-50%) [10] and can also be responsible for chronic occult blood loss, leading to anemia in about 25% of affected patients [11].
Further, vascular abnormalities such as angiodysplasia, gastric antral vascular ectasia (GAVE), Dieulafoy's lesions, and portal hypertensive gastropathy give rise to gastrointestinal bleeding.Despite different macroscopic appearance and etiology, vascular lesions are basically characterized by fragility of vessels due to an abnormal wall structure, and short circuits between the arterial and the venous system [12].The pathogenesis of vascular malformations remains unclear but is thought to be due to an imbalance of proangiogenic factors, such as vascular endothelial growth factor (VEGF) and anti-angiogenic properties leading to neovascularisation [13].Based on in vitro studies that have demonstrated upregulation of VEGF due to increased expression of hypoxia-inducible factor α1 and α2 under hypoxic conditions, local hypoxia within the gastrointestinal wall is suggested to be pivotal in the genesis of gastrointestinal vascular malformation [14].
Angiodysplasias are abnormal, dilated, ectatic, tortuous, small blood vessels, visualized within the mucosal and submucosal layers of the gut; they contain no or only little smooth muscle and are lined by endothelium only [15,16].Since they are predominantly found in elderly patients they are also known as "senile angiodysplasia" [12].Angiodysplasias are seen throughout the whole gastrointestinal tract and are thought to be one of the most common gastrointestinal vascular malformations in adults, accounting for 4-7% of non-variceal upper gastrointestinal bleeding, 35-50% of small bowel bleeding found at capsule endoscopy, and 3-40% of lower gastrointestinal hemorrhage [17].Several chronic conditions have been associated with gastrointestinal angiodysplasias.For example, in patients with aortic stenosis, the increased shear stress in stenotic valves activates vWF multimers which undergo conformational change from a globular to a flexible chain-like shape of varying length.Further proteolytic degradation of vWF multimers by ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type 1 motif 13) results in decreased circulating high molecular weight vWF multimers [18] and subsequently predisposes to gastrointestinal bleeding from angiodysplasias, known as Heyde's syndrome [19].In addition, it is suggested that the decreased pulse pressure in aortic stenosis can lead to reduced gastrointestinal tract perfusion and mucosal ischemia, promoting the formation of angiodysplasias [20].Angiodysplasias have also been shown to increase the risk of gastrointestinal bleeding in patients with left ventricular assist devices and in those with chronic renal failure [21], who are additionally predisposed to gastrointestinal bleeding due to an increased incidence of gastritis, peptic ulcer disease, mucosal ulcerations at any level of the gastrointestinal tract and diverticula of the colon.With a prevalence of 10-30%, gastrointestinal bleeding is also common in patients with acute renal failure [22].Since blood is absorbed as it passes through the small bowel and patients may have decreased renal perfusion, patients with acute upper gastrointestinal bleeding typically have an elevated BUN-to-creatinine or urea-to-creatinine ratio.Values of >30: 1 or >100:1 suggest upper gastrointestinal bleeding; the higher the ratio, the more likely the bleeding is from an upper gastrointestinal source [23].In the presented patient, the BUN-to-creatinine ratio was 48 on admission, but decreased to 17 after 2 days of therapy with thalidomide, indicating cessation of gastrointestinal bleeding.
Hereditary hemorrhagic telangiectasia (Osler's disease) is a vascular malformation due to different mutations within the angiogenic-signaling cascade, causing overproduction of VEGF and stimulation of neoangiogenesis [24].In contrast to sporadic angiodysplasias, such lesions are not flat but present as enlarged ectatic vessels on the mucosal surface [12].
Gastric antral vascular ectasia (GAVE) is frequently found in patients with chronic diseases such as liver disease, connective tissue diseases, and chronic renal failure.Bleeding from GAVE accounts for 4% of upper gastrointestinal bleeding and predominantly occurs in women.Endoscopically, GAVE appears as either punctate lesions throughout the stomach or as red lesions radiating from the pylorus in stripes ("watermelon stomach") [21].Increased plasma levels of VEGF and basic fibroblast growth factor may thereby reflect a nonspecific generalized activation of angiogenesis [25].
Besides vascular malformation and neoplasia-related bleedings which can occur throughout the whole gastrointestinal tract, also radiotherapy-induced proctitis may lead to bleeding in the colon and rectum.About 70% of all patients with cancer receive some radiation therapy.Despite significant improvements in the delivery of radiotherapy, about 15% of patients undergoing radiotherapy will suffer from the complication of radiation proctitis [26], which is characterized by endothelial cell damage with increased chemotaxis and thrombogenesis in the damaged vessels [27,28] and enhanced levels of VEGF [29].

Management of Gastrointestinal Bleeding
Basic measures in patients with gastrointestinal bleeding include discontinuation of anticoagulants, antiplatelet agents and drugs, which are known to trigger or aggravate bleeding as a side effect (e.g., NSAIDs, metamizol, selective serotonin reuptake inhibitors) [30,31], administration of a bolus of normal saline or lactated Ringer solution to correct hypovolemia and to maintain blood pressure, optimization of the coagulation system, and transfusion of platelets and red blood cells if indicated.
For bleeding originating proximally to the ligament of Treitz, initial management additionally requires high-dose proton pump inhibitors (esomeprazole or pantoprazole, 80 mg intravenously) [23].Therapy should be started upon presentation with upper gastrointestinal bleeding and should be continued for the first 72 h post-endoscopy because this is when the rebleeding risk is highest [32].There is no difference in the efficacy of oral or intravenous proton pump inhibitors in regard to recurrent bleeding, need for surgery, or mortality [33].Administration of antibiotic prophylaxis is not recommended routinely in patients with gastrointestinal bleeding but should be given to patients with known or suspected esophagogastric variceal bleeding to minimize the risk of bleeding-related mortality [34].Endoscopy (esophago-gastro-duodenoscopy, colonoscopy, capsule endoscopy, enteroscopy) constitutes the gold standard of diagnostic and therapeutic management of gastrointestinal bleeding and should be performed urgently (within 24 h).For an established bleeding, various treatment options are available such as argon plasma coagulation, electrocoagulation, photocoagulation, endoscopic clips or endoscopic ligations [35], as well as specific obliteration techniques for variceal bleeding [34].
In cases in which no bleeding source can be identified on endoscopy or intervention is not possible because of a significantly reduced general health as found in many multimorbid elderly patients or palliative care patients, or in terminally ill patients, limited medical therapies are available for the management of gastrointestinal bleeding [36] (Table 1).Palliative hemostatic radiotherapy, angiography, embolization, or surgery are further therapeutic options when endoscopic and medical treatment fail; however, discussion of these strategies should always take into account the individual situation and the patient's preference [37], and should correspond to the overall goals of palliative care.Catastrophic gastrointestinal bleeding, which results in imminent death (within minutes), advocates the use of sedatives to reduce awareness and distress.Midazolam 5 mg by intravenous or intranasal route is the drug most commonly used in clinical practice [43,52].Opioids should only be administered in the case of overt pain or dyspnea [3].

Red Blood Cell and Platelet Transfusion
Current guidelines recommend a restrictive strategy of blood transfusion with a hemoglobin threshold of ≤7 g/dL prompting administration of packed red cells in hemodynamically stable patients with gastrointestinal bleeding.After transfusion, a target hemoglobin level between 7 g/dL and 9 g/dL is desired.A higher target hemoglobin (≥10 g/dL) should be considered in patients with significant comorbidity (e.g., ischemic cardiovascular disease); in these patients, a hemoglobin threshold of ≤8 g/dL should be taken as a cut-off value prompting blood transfusion [32].In patients with esophageal varices, transfusion policy is more restrictive because data suggest that under this condition, overtransfusion may be as harmful as undertransfusion.Thus, in hemodynamically stable patients, red blood cell transfusion should aim at a hemoglobin level between 7 g/dL and 8 g/dL [53].
Specific guidelines for platelet transfusion in palliative care patients are currently not available [3].It is estimated that about 28% of platelet transfusions are used in a gray zone of proper indication [54].Platelet count alone provides no qualitative information about the risk of hemorrhage [3].In gastrointestinal bleeding, therapeutic platelet transfusion is only indicated in thrombocytopenia with a threshold of 30 G/L (target range 30-50 G/L) [3,55].In end-of-life patients, the decision of platelet transfusion should be individualized but should be the exception rather than the rule [3].

Antifibrinolytic Agents
In patients with gastrointestinal bleeding and inadequate coagulation, individual optimization should be considered.Oral administration of antifibrinolytic agents was long discussed as a therapeutic option in the management of gastrointestinal bleeding [39].However, recent data from a large randomized, double-blind, placebo-controlled trial including 12,009 patients with upper or lower gastrointestinal bleeding found that tranexamic acid is not effective to reduce death from gastrointestinal bleeding and is associated with a higher rate of venous thromboembolic events (deep venous thrombosis or pulmonary embolism) as compared to the placebo group (48 [0.8%] of 5,952 vs. 26 [0.4%] of 5,977; RR 1.85; 95% CI: 1.15-2.98).Thus, the authors concluded that tranexamic acid should not be used for the treatment of gastrointestinal bleeding [50].Furthermore, the limited therapeutic benefit of tranexamic acid in patients with thrombocytopenia should be taken into account [51].

Hormonal Therapy
Since the 1950s, gastrointestinal bleeding from a vascular malformation has been treated with hormonal therapy based on anecdotal reports of use for nasal bleeding in patients with hereditary hemorrhagic telangiectasia.Only five studies investigated the efficacy of hormonal therapy in gastrointestinal angiodysplasia.Three of these studies showed beneficial results but lacked a control group [56][57][58].Data from the first study comparing hormonal therapy (norethynodrel either with mestranol or with conjuncted estrogen) with placebo did not show a significant difference in terms of the occurrence of gastrointestinal bleeding and transfusion requirements with a mean follow-up of 16 months [59].These findings were confirmed by a second randomized clinical trial (n = 72) which investigated the efficacy of hormonal therapy (ethinylestradiol and norethisterone) for treatment of gastrointestinal angiodysplasia [60].Based on these data, hormonal therapy is no longer recommended for overt or occult bleeding secondary to gastrointestinal angiodysplastic lesions.

Somatostatin and Somatostatin Analogs
Somatostatin and somatostatin analogs such as octreotide have been evaluated for the treatment of gastrointestinal bleeding from angiodysplasia in numerous case reports and retrospective studies [61].The mechanisms involved include improved platelet aggregation, decreased splanchnic blood flow, increased vascular resistance, and inhibition of angiogenesis by reduced VEGF synthesis [62].Efficacy of somatostatin has been documented in 40-77% of patients [63,64].In a metaanalysis using the cessation of bleeding as the primary outcome measure, a significant effect of somatostatin analogs was shown, with a pooled odds ratio of 14.5 (95% CI: 5.9-36) [65].Evaluation of long-acting, extendedrelease (LAR) octreotide for the treatment of patients with refractory small bowel angiodysplasia revealed a complete response in 70% of patients, and failure of therapy in 10% [66].Management of chronic gastroin-testinal bleeding from angiodysplasia in patients in whom endoscopic treatment has failed appears to be well-tolerated without serious adverse effects.Moreover, it significantly reduces the length of hospitalization per year (from 22 to 2 days; p < 0.0001) and the number of required blood transfusions (from 11 to 2; p < 0.002) [67].The new long-acting somatostatin analog, pasireotide-LAR, binds with high affinity to four of the five somatostatin receptors with a specific 40-fold increase in the affinity for subtype five compared with other analogs.Pasireotide-LAR is mainly used in the therapy of acromegaly and Cushing's disease but has also been shown to be an effective and safe option for the treatment of refractory bleeding caused by gastrointestinal angiodysplasia.Data of a noncomparative prospective double-blind randomized trial revealed a 50-83% success rate and a significant reduction in transfusion requirement under therapy with pasireotide-LAR (3 vs. 11.5 units of packed red blood cells in the control group within 6 months) [42].Since the use of LAR somatostatin analogs every 28 days is more convenient and could be advantageous in terms of compliance, it could also be considered as an effective therapeutic option in palliative care patients who present with recurrent or obscure gastrointestinal bleeding but cannot or refuse to undergo endoscopic treatment.

Pressins
The efficacy of intra-arterial vasopressin infusion in the management of variceal hemorrhage was first described by Nusbaum et al. [68].The agent directly constricts arterioles and capillaries [69] and reduces portal pressure [3].Previous studies suggested that vasopressin is an effective treatment in neoplasia-related gastrointestinal bleeding [43].Likewise terlipressin has also been shown to be effective in variceal and ulcer bleeding.However, due to its adverse effects (Table 1) intravenous pressins are less used today.
Desmopressin (1-deamio-8-D-arginine vasopressin) is the synthetic analog of vasopressin.The substance is approved by the Food and Drug Administration for control of bleeding in patients with either hemophilia A or mild-to-moderate von Willebrand disease (type I), both with factor VIII levels greater than 5% [45].Off-label management of a patient with refractory gastrointestinal bleeding with inhaled desmopressin (150 μg/spray, one spray in one nostril 3 days a week) has been reported to result in a significant reduction in hospital admissions and transfusion requirements along with an improved quality of life [46].Nasal administration of desmopressin increases levels of vWF to 150-250% shortly after administration.Potential adverse effects include hyponatremia and fluid overload (because of antidiuretic effects), hypertension, and acute thrombosis [45].Although data about the management of gastrointestinal bleeding with desmopressin are limited, it could be considered as a therapeutic option in patients with intractable gastrointestinal bleeding.

Thalidomide
Thalidomide, a synthetic derivative of glutamic acid, was initially developed in the 1950s as a sedative prior to the availability of benzodiazepines [12].Besides its anxiolytic effect, the drug soon became recommended for the treatment of morning sickness due to observed antiemetic effects in pregnant women [70].Despite a lack of systemic evaluation of safety in humans (which was not routinely performed in the 1950s), thalidomide became widely available without prescription.In Germany, it was the most commonly used sedative with more than 140 million tablets sold in 1960 [71].Because of concerns about drug safety, thalidomide had not been approved by the Food and Drug Administration.After realization of its teratogenicity, leading to congenital anomalies, such as phocomelia, dysmelia, amelia, bone dysplasticity and internal organ abnormalities, the drug was withdrawn from the market [12,71].

Mechanism of Action
Thalidomide has immunomodulatory, antiinflammatory, anti-angiogenic, and anti-proliferative properties (Table 2) and so is capable to control biological features that are highly relevant in the context of tumor development and secondary spread as well as autoimmune conditions [72].Inhibition of angiogenesis by thalidomide is not only effective in cancer treatment but also in the management of gastrointestinal bleeding.Effects are suggested to be mediated by the parent molecule thalidomide and its speciesspecific hepatic metabolites [73,74].Although the exact molecular mechanisms are not fully elucidated, studies have revealed disruption of angiogenesis by inhibitory effects of thalidomide on VEGF, a key signaling molecule in vessel development, and on basic fibroblast growth factor [70,75].Thalidomide alters VEGF expression and influences cell proliferation via NOTCH1/DELTA4 and phosphoinositide-3 kinase (PI3K)/protein kinase B (AKT) pathways [72,76].Nuclear factor kappa B (NFκB) is another pathway implicated in thalidomide action and targets genes such as for interleukin 8, interleukin signal transducer tumor necrosis factor receptor-associated factor 1, and cellular inhibitor of apoptosis protein 2 (IAP2) [77].The inhibition of NFκB is triggered by downregulation of TNF-α via thalidomide (by targeting cereblon) and also leads to downregulation of other cytokines that promote induction of angiogenesis [72,78].Thalidomide further facilitates cross talk between pathways of angiogenic signaling (VEGF, PI3/AKT, and NFκB) by mammalian target of rapamycin (mTOR) [72].In addition, it inhibits the production of nitric oxide, which is required for endothelial cell function and blood vessel formation and was found to cause blood vessel defects through VEGF receptor depletion [79].Moreover, thalidomide promotes formation of reactive oxygen species that are pivotal in orchestrating cell signaling and so mediate immunomodulatory and anti-inflammatory effects and also inhibit vessel formation via loss of expression of fibroblast growth factor 8 and promote cell death by causing damage to the DNA and other cellular marcomolecules [78,79].In embryonic zebrafish and chicks binding of thalidomide to the protein cereblon has been shown to directly or indirectly regulate fibroblast growth factor 8 and to inhibit limb outgrowth [80], suggesting disruption of angiogenesis to be an important mechanism underlying teratogenicity of thalidomide.Angiogenesis is further influenced by effects of thalidomide on the actin cytoskeleton of rapidly proliferating endothelial cells (by binding to tubulin) [79].In summary, the effects of thalidomide on angiogenesis are complex.Further research is needed to better understand the mechanisms of how thalidomide exerts antiangiogenic effects in humans and on the other hand is teratogenic.Present Therapeutic Use Thalidomide and its analogs lenalidomide and pomaidolone resurfaced and are now used in the management of patients with specific clinical entities under tight regulations.Among others, these include erythema nodosum leprosum, infectious diseases (HIV-1-associated Kaposi sarcoma and proctitis), multiple myeloma, prostate cancer, neuroendocrine tumors, and Waldenström's macroglobulinemia as well as autoimmune conditions such as graft-versus-host disease [12,71,72,81].In clinical trials, thalidomide has also been found to be effective in the treatment of advanced renal cancer, esophageal cancer, chemotherapy-refractory endometrial cancer, and pancreatic cancer, which suggests its therapeutic potential in cancer treatment in the future [78].

Thalidomide in Gastrointestinal Bleeding
Thalidomide was first reported as an effective agent for bleeding from gastrointestinal angiodysplasia in 2002 [82].After several case series [83][84][85], a randomized study finally proved the efficacy of thalidomide in 2011 [86].In this study, 55 patients with recurrent bleeding from gastrointestinal vascular malformations (angiodysplasia and GAVE; at least six bleeding episodes in 1 year) that were unsuitable or unresponsive to endoscopic or medical approaches received either 100 mg thalidomide (n = 28) or 400 mg iron (n = 27) daily for 4 months.An effective response rate, defined as at least a 50% decrease in bleeding episodes within 1 year, was found in 71% of patients on thalidomide, but in only 4% of patients in the control group.Reduced transfusion requirements and complete cessation of bleeding was observed in 46% of patients on thalidomide, but not in the patients treated with iron.The most common adverse effects reported were fatigue (32%), constipation (25%), and dizziness (21%) [86].In another study investigating thalidomide for refractory gastrointestinal bleeding from vascular malformation in patients (n = 15) with significant comorbidities, 40% of patients had no recurrent gastrointestinal bleeding or transfusion requirement after treatment with thalidomide at the 6-month follow-up.Furthermore, 85% of patients had a reduction in transfusion requirements and hospitalization for gastrointestinal bleeding [21].Using video capsule endoscopy, small bowel angiodysplastic lesions were shown to decrease in number, size, and color intensity when patients were on thalidomide [84].
Evaluation of long-term treatment with thalidomide in 80 patients (median follow-up of 42.6 months) showed bleeding cessation in 39% and decreased bleeding in 32% of patients; 20% of patients did not respond [87].Data showed an overall response rate of 60% (1-year response rate: 77%) and a significantly reduced number of bleeding episodes, hospitalizations, requirement of blood transfusions, and higher hemoglobin levels.Although there was a recurrence rate of 21%, a response to retreatment was reported in 100% [87].Indeed, it has been found that a relatively short treatment with thalidomide (3-4 months) exerts a lasting effect on bleeding from sporadic angiodysplasia.In many patients, clinically relevant bleeding does not recur for several years [88].Thalidomide is also effective in reducing transfusion requirements in patients with radiation proctitis refractory to endoscopic or medical treatment [89,90].However, the post-treatment effect was variable with one case remaining without need for transfusion for 3 months [89], while the others experienced an early relapse of symptoms [90].
Evidence for the use of thalidomide in gastrointestinal cancer-related bleeding is limited.There is only one case report on the management of bleeding from gastric cancer with thalidomide, in which endoscopy was not successful and the patient had failed to respond to other therapeutic options such as tranexamic acid, sucralfate, and etamsylate.Bleeding ceased within 4 days after initiation of thalidomide and did not recur upon of thalidomide due to side effects [91].
Thalidomide has also been successfully used in cases with obscure bleeding [88].In previous studies, the dose of thalidomide associated with lower frequency and intensity of bleeding, reduction of transfusion requirements and improvement of quality of life [92] ranged from 50 to 400 mg per day [21].Due to reports of liver toxicity and even acute liver failure at higher doses, it is recommended that a daily dose of 100 mg thalidomide should not be exceeded [12].However, it is well documented that doses of up to 200 mg/day are usually well tolerated [93].Some data suggest that the dosing and efficacy of thalidomide is related to a patient's body mass index [21,94].

Adverse Effects
The most common adverse effects of thalidomide are sedation and peripheral neuropathy; less frequently, rash, constipation, dizziness, headache, mood changes, and tremor have been reported [12,17,71].The underlying mechanism of thalidomide-related neurotoxicity has yet to be established; however, reduction of VEGF by thalidomide is considered pivotal as VEGF mediates both the neurotropic and neuroprotective effects [95].Moreover, neural cells express neuropilin-1, which is an additional VEGF receptor involved in axonal regeneration [96].Since neuropathy is reversible after dose reduction or discontinuation of thalidomide, this potential side effect should not be considered a general contraindication for treatment [12].
Given the teratogenicity of thalidomide, this drug should not be administered to women of childbearing potential who are not using adequate contraception.However, the majority of patients with gastrointestinal bleeding in a palliative care setting tend to be elderly, so teratogenicity is unlikely to be an important consideration in these cases [12].Indeed, the necessity to be able to swallow the drug (because of lacking thalidomide for intravenous administration) may be a limiting factor in this patient group.
Many of the studies on thalidomide promote its short-term use over concerns of its side effects caused by drug accumulation.It is well documented, however, that vascular lesions recurred throughout the gastrointestinal tract and according to several case reports and series, bleeding restarted after discontinuation of thalidomide, necessitating its reintroduction [6].In addition, repeated courses of thalidomide lead to higher rates of adverse effects than drug accumulation due to long-term use [87].
The risk of venous thromboembolism is increased in cancer patients, and numerous specific cancer-related, patient-related, and treatment-related risk factors have been identified [97].Hematologic malignancies have been shown to be generally associated with higher rates of thrombotic events compared to solid tumors, with multiple myeloma having the highest risk [98].Thalidomide is a known treatment-related risk factor for venous thromboembolism in patients with multiple myeloma and clinical practice guidelines recommend prophylactic antithrombotic treatment in patients managed with thalidomide-containing regimens [99].The importance of thalidomides for the treatment of multiple myeloma and some B-cell malignancies cannot be over-emphasized.Treatment efficacy in solid tumors is, however, uncertain.Since data are scarce and there is a varying response rate among tumor entities with some not showing any response at all [72], data about the risk of venous thromboembolism associated with the use of thalidomide in solid tumors are likewise lacking.In vitro thrombin generation is a biomarker associated with the risk of venous thromboembolism in cancer patients [100].Evaluation of coagulability by a thrombin generation assay in patients receiving combined therapy with melphalan, prednisone and thalidomide, or bortezomib, dexamethasone and thalidomide revealed an increase in the peak thrombin (8%) and the endogenous thrombin generation potential (9%) before cycles 2 and 3 but not during the entire follow-up period.These alterations were comparable to those found in the discussed patient when she was on therapy with thalidomide.Although thalidomide-containing therapy resulted in changes of peak thrombin and endogenous thrombin generation potential, these alterations did not promote thromboembolic events in Thalidomide for Gastrointestinal Bleeding Dig Dis 2024;42:113-125 DOI: 10.1159/000533437 patients with multiple myeloma [101].Studies and case series reporting the use of thalidomide in gastrointestinal bleeding have never found an increased risk of thromboembolic events [6,86].

Pharmacology and Drug Interactions
After oral administration and absorption, thalidomide undergoes mainly spontaneous non-enzymatic hydrolytic cleavage by serum albumin and different metabolites are formed [78].Cytochrome P450 2C19 is the major enzymatic pathway involved in the oxidative metabolism of the drug [102].Polymorphism of this enzyme promotes toxicity and unexpected drug interactions through drug metabolism [102,103].Furthermore, interaction with vincristine, platinumcontaining agents, and bortezomib can increase thalidomide's neurotoxicity [104].It enhances the effect of barbiturates, alcohol, chlorpromazine, and reserpine [105] and increases midazolam metabolism and cyclosporine A clearance in a dose-dependent manner [102].
Thalidomide is a chiral drug and its R and S enantiomers differ in their pharmacological effects.The R enantiomer is a safe and efficacious molecule, whereas the S enantiomer is highly toxic and responsible for the teratogenic effects of thalidomide.In vivo, there is a racemization of the drug [72].Nonracemizing derivatives of thalidomide have been shown to exert various effects concerning teratogenicity, cytotoxicity, and TNF-α inhibitory activity [106,107].Hence, further studies are needed to enhance the efficacy and reduce adverse effects of thalidomide in the future.

Financial Aspects
Finally, it may be of interest that a 1-day therapy with somatostatin costs about EUR 800, whereas 1 day of thalidomide costs only EUR 40 according to current drug prices, i.e., a 20-fold difference.

Conclusion
Thalidomide (Table 3) appears to offer an effective treatment option for gastrointestinal bleeding in the elderly, particularly in the palliative care setting when endoscopy is not possible due to a reduced general condition or when no bleeding source can be identified.Gastrointestinal vascular malformations such as angiodysplasias are a likely source of bleeding in this patient group and may lead to refractory gastrointestinal bleeding.Besides the frequent requirement of blood transfusions, patients with chronic or recurrent gastrointestinal bleeding are often deeply concerned and have a severely impaired quality of life.Our case report illustrates the benefit of thalidomide in this situation.The drug has an acceptable safety profile.Since the majority of patients with gastrointestinal bleeding in a palliative care setting are usually elderly, teratogenicity is not an important issue in these cases.Other side effects of thalidomide like neurotoxicity may limit its use but can be monitored safely.As the substance may increase thrombin generation potential, patients receiving this therapy should be closely observed for venous thromboembolism.A limiting factor for the use of thalidomide may be the necessity to swallow the drug.Physicians caring for patients with gastrointestinal bleeding in the palliative care setting should be aware of thalidomide as an effective therapeutic option.