High-dose Thalidomide Research Articles

A real-world study of low-dose thalidomide in severe erythema nodosum leprosum highlighting its mechanistic rationale in a resource-constrained target population.

Corticosteroids remain the main therapy in erythema nodosum leprosum (ENL), and long-term usage in chronic or recurrent ENL is a cause of significant morbidity and mortality. Thalidomide exerts dramatic effect in controlling ENL and helps reduce the dose of steroids, but the cost is a hindrance to its usage. Patients of ENL (steroid naïve and steroid-dependent) were recruited over a 1-year period. An escalating dose of low-dose thalidomide with a reducing dose of prednisolone was titrated depending on the control of disease activity. The primary aim was to reduce the dose of steroids to the lowest effective dose, and the secondary aim was to stop. Sixteen patients of ENL were studied (mean duration of ENL 22.1 months, 15 severe ENL), and a majority (11/16, 68%) were on steroids with a mean duration of 11.27 months. All patients had steroid-related side effects (cushingoid habitus 81.8%, weight gain 54.5%, diabetes mellitus 9%, hyperlipidemia 18.18%, cataract 18.1%, osteoporosis 36.3%, striae 36.3%, acneiform eruptions 18.1%, and myopathy 9%). Steroids could be tapered in a majority of patients (n = 9) within 3 months (mean 2.44 months) with a low dose of thalidomide (25-150 mg/day, mean 78.3 mg) achieving a significant reduction in prednisolone dose (33.16 mg at baseline; 4.28 mg at 3 months, P < 0.05). Steroids could be stopped in 92% of patients by 3.03 months, and both drugs could be stopped in 80% of cases by 5.83 months. The rapid and effective control of ENL with low-dose thalidomide in our series is comparable to the historical efficacy of high-dose thalidomide regimens, making it an affordable therapy in resource-constrained settings and an excellent steroid-sparing agent. The rapid onset of disease control is likely attributable to its action via neutrophils.

Efficacy and Safety of Thalidomide in Patients with Complicated Central Nervous System Tuberculosis: A Systematic Review and Meta-Analysis.

Thalidomide, an anti-inflammatory and immunomodulatory agent, has a potential role in cases with central nervous system tuberculosis (CNS-TB) with paradoxical reactions. Although several articles have described the use of thalidomide in CNS-TB, no systematic review has been performed in this regard. Different electronic databases were searched for articles describing the use of thalidomide in patients with CNS-TB. For determining pooled estimates in the quantitative review, studies with a minimum sample size of 5 were only considered, whereas for qualitative synthesis even single case reports were included. Fixed or random effect models were used suitably depending on the degree of heterogeneity. Fourteen articles describing a total of 107 patients (98 children and 9 adults) were selected from 156 records. A favorable clinical response was observed in 89% of patients with CNS-TB who had paradoxical reactions refractory to corticosteroids. Majority of the studies used a dose of 2-6 mg/kg/day and around 24% suffered from at least one adverse effect, with a mortality of 5%. Predominant adverse effects were rash (9.5%), neuropathy (6%), and elevated liver transaminases (9.5%). Only one placebo-controlled trial has been performed till now, which showed that high-dose thalidomide has numerous adverse effects, without any clinically significant improvement as compared with placebo. While in HIV-positive patients with TB-immune reconstitution inflammatory syndrome thalidomide was helpful in around 82% of cases. Low-dose thalidomide is helpful in patients with CNS-TB who had a paradoxical reaction and unresponsive to corticosteroids. Large, randomized trials are needed to provide more concrete information regarding the safety and efficacy of thalidomide.

Protective Effect of Thalidomide on 2,4,6-Trinitrobenzenesulfonic Acid-Induced Experimental Colitis in Rats via the Inhibition of T Helper 17 Cells

Objective To observe the effects of thalidomide on 2,4,6-trinitrobenzenesulfonic acid- (TNBS-) induced experimental colitis in rats and to explore the possible mechanism of thalidomide in the treatment of CD. Methods Forty SD rats were randomly assigned into a healthy control group and TNBS-induced colitis groups, including an untreated TNBS-induced colitis group, a low-dose thalidomide group, and a high-dose thalidomide group, with 10 rats in each. After 7 days, the disease activity index (DAI), colon macroscopic damage index (CMDI), and tissue damage index (TDI) were evaluated. The colonic protein and mRNA expression levels of interleukin-6 (IL-6), IL-17, IL-23, and retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt) were determined using immunohistochemistry, western blot, and qRT-PCR. Results Relative to the untreated TNBS-induced colitis group, the DAI, CMDI, and TDI were all reduced following the administration of thalidomide. Analytical testing (immunohistochemistry, western blot, and qRT-PCR) shows that IL-6, IL-17, IL-23, and RORγt protein and mRNA expression levels were significantly reduced by thalidomide (p < 0.05 for all) and that these levels were significantly lower in the high-dose thalidomide group than in the low-dose thalidomide group (p < 0.05 for all). Conclusions Thalidomide effectively alleviated the symptoms and intestinal inflammatory injury induced by TNBS in rats, the effect of which was dose-dependent. The underlying mechanism may be a reduction in the expression levels of IL-6, IL-17, IL-23, and RORγt in colonic tissue and then subsequent inhibition of the differentiation and function of Th17 cells, thus further alleviating the intestinal inflammatory response.

Higher single dose of bortezomib plus thalidomide and dexamethasone is a promising therapy for newly diagnosed multiple myeloma

Background: Bortezomib in combination with thalidomide and dexamethasone (VTD) has been widely used for newly diagnosed multiple myeloma (MM). The aim of this study was to evaluate the efficacy and safety of a new high-dose bortezomib plus thalidomide and dexamethasone as an induction and consolidation therapy regimen for MM. Methods: A total of 93 patients with previously untreated symptomatic MM were enrolled in this single-center study. In group-1, 40 patients received bortezomib 1.6 mg/m 2 and dexamethasone 40 mg on days 1, 6 and 11, plus thalidomide 100 mg on days 1–21 (VTD-1). In group-2, 53 patients received bortezomib 1.3 mg/m 2 and dexamethasone 40 mg on days 1, 4, 8 and 11 in combination with thalidomide 100 mg on days 1–21 (VTD-2). Results: The odds ratio rates after 2 cycles of VTD and the best response during this study were 95% vs . 81.1% (P=0.044), and 95% vs . 90.6% (P=0.349) in group-1 and group-2, respectively. The best CR rate in group-1 was higher than that in group-2 [52.5% vs . 45.3% (P=0.316)]. In group-1, only 2 of 21 patients who achieved CR relapsed from the disease, as did 9 of 24 patients in group-2 (P=0.031). The median PFS in group-1 and group-2 were 34 and 28.8 months (P=0.969), and the median OS in group-1 and group-2 were 33.5 and 46.4 months (P=0.987). In group-1 and group-2, the median CD34 + cells of stem cell collection were 3.68×10 6 vs . 5.84×10 6 cells/kg (P=0.179). Patients in group-1 had a lower incidence of peripheral neuropathy than group-2 [32.5% vs . 41.5% (P=0.371)]. Conclusions: High-dose bortezomib at a dose of 1.6 mg/m 2 in combination with thalidomide and dexamethasone was well tolerated and highly efficient as an induction and consolidation therapy for MM.

High-dose thalidomide increases the risk of peripheral neuropathy in the treatment of ankylosing spondylitis.

Thalidomide is an effective drug for the treatment of ankylosing spondylitis but might induce peripheral neuropathy. This major adverse reaction has attracted much concern. The current study aimed to observe the incidence of thalidomide-induced peripheral neuropathy among ankylosing spondylitis patients for 1 year after treatment. In this study, 207 ankylosing spondylitis cases received thalidomide treatment, while 116 ankylosing spondylitis cases received other treatments. Results showed that the incidence of thalidomide-induced peripheral neuropathy in the thalidomide group was higher than that in the non-thalidomide group. There was no significant difference in the incidence of neuropathy between the < 6 months medication and ≥ 6 months medication groups. There were no differences in the mean age, gender, or daily dose between the two groups. The incidence of peripheral neuropathy among patients receiving 25, 50, 75, or 100 mg thalidomide per day was 4.6%, 8.5%, 17.1%, 21.7%, respectively. The incidence was significantly different between the groups receiving 25 mg and 100 mg thalidomide. In conclusion, thalidomide can induce peripheral neuropathy within 1 year after treatment of ankylosing spondylitis; however, age and gender have no obvious impact on the incidence of peripheral neuropathy. The incidence of peripheral neuropathy is associated with increasing daily doses of thalidomide.

Quantitative evaluation of viable tissue perfusion changes with contrast-enhanced greyscale ultrasound in a mouse hepatoma model following treatment with different doses of thalidomide.

This study aimed to quantify intratumoural viable tissue perfusion with contrast-enhanced greyscale ultrasound to evaluate tumour response to anti-angiogenic treatment. H22 hepatoma-bearing mice were treated with low-dose thalidomide (Group B), high-dose thalidomide (Group C) or 0.5% carboxylmethylcellulose (Group A). Contrast-enhanced greyscale ultrasound was performed after 7 days of treatments to evaluate the percentage of non-enhanced area for each tumour; regions of interest within the enhanced area were analysed offline to determine the area under the curve (AUC), maximum intensity (IMAX), perfusion index (PI), mean transit time (MTT), time to peak (TTP) and quality of fit (QOF). Immunohistochemical analysis was performed for evaluation of microvascular density (MVD). The percentage of non-enhanced area was significantly larger in Group C than in Groups A and B (p<0.05); however, there was no significant difference between Groups A and B. Treatment with thalidomide resulted in a significant decrease in AUC, PI and IMAX compared with Group A (p<0.05). Immunohistochemistry showed significant decreases in MVD in Groups B and C compared with Group A (p<0.05); however, there was no significant difference in MVD between Groups B and C. MVD was positively correlated with IMAX (r = 0.419, p = 0.023) and PI (r = 0.455, p = 0.013). Quantitatively analysing intratumoural viable tissue perfusion enables early evaluation of tumour response to anti-angiogenic therapy before apparent changes in tumour necrosis.

Interventions for erythema nodosum leprosum. A Cochrane review

Treatment for erythema nodosum leprosum (ENL), an immunological complication of leprosy, is diverse. We undertook a systematic review as it was not clear which treatments were most beneficial. We did a systematic search to identify randomised controlled trials (RCTs) comparing treatment with placebo, no treatment or another therapy. Two authors assessed quality and checked data. We included 13 studies involving 445 participants. These trials assessed: betamethasone, thalidomide, pentoxifylline, clofazimine, indomethacin and levamisole. The quality of the trials was generally poor and no results could be pooled due to the treatments being so heterogeneous. Treatment with thalidomide showed a significant benefit compared to aspirin (RR 2.43; 95% CI 1.28 to 4.59). Clofazimine treatment was superior to prednisolone (more treatment successes; RR 3.67; 95% CI 136 to 9.91) and thalidomide (fewer recurrences; RR 0.08; 95% CI 0.01, 0-56). Minor adverse events were significantly lower in participants on a low dose thalidomide regimen compared to a high dose thalidomide regimen (RR 0.46; 95% CI 0.23 to 0.93). Significantly more minor adverse events were reported in participants taking clofazimine compared with prednisolone (RR 1.92; 95% CI 1.10 to 3.35). None of the studies assessed quality of life or economic outcomes. There is some evidence of benefit for thalidomide and clofazimine, but generally we did not find clear benefits for interventions in the management of ENL. This does not mean they do not work because the studies were small and poorly reported. Larger studies using clear definitions and internationally recognised scales are urgently required.

A Pharmacokinetic Study Evaluating the Relationship Between Treatment Efficacy and Incidence of Adverse Events with Thalidomide Plasma Concentrations in Patients with Refractory Multiple Myeloma

BackgroundMultiple myeloma (MM) is a clonal disorder of plasma cells, accounting for 10% of hematologic malignancies. Relapsed or refractory MM has a poor prsognosis. Thalidomide has been reported to be effective for these patients; however, high-dose thalidomide has induced many adverse events, including in the nervous, gastrointestinal, and hematopoietic systems in approximately 20%-50% of patients. Recently, low-dose thalidomide therapy has been used in many countries in order to reduce these adverse events. The objective of this study was to determine whether plasma concentration of thalidomide is related to the efficacy and the development of adverse events in patients with refractory MM treated with low-dose thalidomide plus low-dose dexamethasone. Patients and MethodsA total of 66 patients (age range, 40-74 years) presenting with progressive disease after previous treatments were treated with low-dose thalidomide and low-dose dexamethasone. Thalidomide was administered orally at 100 mg/day for the first week. When severe adverse events did not develop, the dose was increased to 200 mg/day in the second week and was continued until progression. Dexamethasone was administered at a dose of 4 mg/day for the first 4 weeks, then decreased by 1 mg every week, and finally maintained at 1 mg/day. Plasma trough concentration of thalidomide 3 days after thalidomide treatment was analyzed by high-performance liquid chromatography in 45 patients (age range, 42-74 years) who agreed to participate in this study of thalidomide concentration analysis. ResultsThe mean concentrations at 100 mg/day and 200 mg/day were 0.343 μg/mL (range, 0.05-1.45 μg/mL) and 0.875 μg/mL (range, 0.19-2.09 μg/mL), respectively. The overall response rate (near-complete response + partial response + minimal response) of this treatment was 73%. Five had stable disease, and 3 patients experienced progressive disease. There was no relationship between the concentration of thalidomide in the plasma and the efficacy (P > .8). Severe adverse events, including grade > 2 nonhematologic and grade > 3 hematologic adverse events, were observed in 21 patients (46.6%). There was no significant difference in the concentration of thalidomide between the patients with and without severe adverse events (P > .843). ConclusionThe thalidomide concentration in the plasma does not predict treatment efficacy and the development of adverse events.

Sclerodermatous Chronic Graft‐Versus‐Host Disease—A Report of Four Pediatric Cases

The sclerodermatous variant of chronic graft-versus-host disease postallogeneic bone marrow transplantation is rare. We present four pediatric cases of sclerodermatous variant of chronic graft-versus-host disease describing their clinical appearance, management, and outcomes. We compare the pharmacologic and supportive therapies administered to these patients with the management suggested in the current literature. Several key findings were noted. There was a significantly higher mortality rate observed in this series compared with previous reports, with three of the four patients dying ultimately as a result of sclerodermatous variant of chronic graft-versus-host disease. The development of widespread ulceration, in two of the four patients, appeared to be associated with an overall deterioration in the clinical condition. In two patients high-dose thalidomide at 12 mg/kg/day seemed to halt the progression of cutaneous disease. Optimal care of sclerodermatous variant of chronic graft-versus-host disease patients required a multidisciplinary team. A lack of community services observed in this case series led to the need for unnecessarily prolonged inpatient admissions.

Cutaneous Rosai-Dorfman disease

A 63-year-old woman developed multiple nodules at the site of a recently biopsied proliferation of CD 68+ histiocytes. Clinical lymphadenopathy was not present on physical examinaton or on computed tomography scans. A subsequent skin biopsy specimen showed changes consistent with Rosai-Dorfman disease. Rosai-Dorfman disease is a benign, histiocytic proliferative disorder also known as sinus histiocytosis with massive lymphadenopthy. A particularly rare, extranodal, purely cutaneous form has been described. Spontaneous regression tends to occur over months to years, with surgical intervention remaining the most effective treatment. Documented success with a number of other therapies has been reported, which include systemic high-dose thalidomide in extensive cutaneous disease.

Nonsecretory Primary Plasma Cell Leukemia with Good Response to Thalidomide-Based Treatment

Primary plasma cell leukemia (PCL) is a rare hematologic disorder with distinct features. The criterion for the diagnosis of PCL is based on the finding of malignant plasma cells in the peripheral blood (more than 2 x 10(9)/L or more than 20% of white blood cells). We report a case of a 74-year-old patient with primary nonsecretory PCL. Examination of blood smears led to the diagnosis of PCL, which was confirmed by bone marrow biopsy. Due to the patient's impaired general condition, intensive chemotherapy could not be administered. After an oral induction chemotherapy consisting of cyclophosphamide and high dose dexamethasone followed by one cycle of high-dose dexamethasone and thalidomide no evidence of the disease in the peripheral blood was detectable. Consequently, the patient was put on a thalidomide maintenance therapy. Six months after first diagnosis, the patient was found to have bone marrow and peripheral blood relapse with anemia and neutropenia in the clinical context of acute on chronic renal failure. After a limited response to further chemotherapy, the patient died 14 months after the first diagnosis while on dexamethasone maintenance. We conclude that monotherapy with thalidomide might be an alternative maintenance strategy with limited response duration for patients with primary PCL in impaired general condition.

Low‐dose thalidomide plus low‐dose dexamethasone therapy in patients with refractory multiple myeloma

We report the results of a non-randomized phase II study of low-dose thalidomide plus low-dose dexamethasone therapy in 66 patients with refractory multiple myeloma. The overall response rate (near complete, partial and minimal response) was 63.6%, and progression-free and overall survival periods were 6.2 and 25.4 months. In adverse events, the incidence of peripheral neuropathy and deep vein thrombosis was lower than the data reported in USA and Europe. On the other hand, leukopenia was observed in 41% of patients, including 11% of those with Grade 3. Leukopenia was closely related to pretreatment pancytopenia, especially thrombocytopenia. The incidence of adverse events related to dexamethasone was low. In conclusion, low-dose thalidomide plus low-dose dexamethasone therapy was as effective as high-dose thalidomide plus high-dose dexamethasone therapy in patients with refractory multiple myeloma. Leukopenia is one of the most serious adverse events in Japanese patients, especially in patients with pretreatment pancytopenia.

Long term use of thalidomide: Safe and effective

To assess the efficacy and safety of high dose thalidomide therapy for longer duration of time in relapsed or refractory Multiple Myeloma (MM) patients. Twelve relapsed/refractory MM patients (7 Males, 5 Females), who received thalidomide for more than 2 years were selected from the Out Patient Department of Institute Rotary Cancer Hospital (IRCH), AIIMS, India. Patients received thalidomide beginning at a dose of 200 mg/day with fortnightly increment to a maximum dose of 800 mg/day. Patients were assessed for response on the basis of M proteins (MP), bone marrow biopsy with touch preparation and skeletal X-rays. Nine patients tolerated a maximum dose of 800 mg/day whereas three patients were given 600 mg/day. All patients showed > or = 25-50% decline in serum /urine M proteins. Complete response/ near complete response was seen in 50%, partial response in 17% and minimal response (SD) in 34% patients. Median duration of thalidomide therapy was 47 months (range 29-60 months). Currently 11 patients are alive. Varying degree of constipation and sedation were seen universally. One patient had DVT, which responded to anti-coagulant therapy. Other toxic effects included infections, skin reactions. There was no toxic death. Long-term use of thalidomide is safe, effective and feasible. We feel that this is one of few reports describing safety and efficacy of long-term thalidomide in relapsed and refractory MM.

Pegylated Liposomal Doxorubicin (Doxil®), Dexamethasone and Low Dose Thalidomide (DDt) as Therapy for Newly Diagnosed Multiple Myeloma.

Background: Thalidomide with dexamethasone is considered the current standard induction therapy for multiple myeloma. Previously, treatment consisted mainly of infusional vincristine, adrimaycin and dexamethasone (VAD). High dose thalidomide is associated with significant toxicity. We conducted a study to evaluate efficacy and toxicity of adding liposomal adriamycin (Doxil®) to dexamethasone and low dose thalidomide. Stem cell harvest yield was also assessed.Methods: Patients were treated with Doxil® 40mg/m2 IV d1, thalidomide 100 mg PO Q HS, and dexamethasone 40 mg PO d1–4 and 15–18 Q 28 days for 4 cycles. After 4 cycles, eligible patients underwent autologous stem cell transplant. Patients received prophylactic Amoxicillin 250 mg PO Q day and Acyclovir 200 mg PO BID. Erythropoietin and biphosphonates were administered. Aspirin was changed to full dose coumadin anticoagulation after one death from pulmonary embolism.Results: Between 3/03 and 5/05, 11 out of planned 25 patients were enrolled on the study; 1 patient excluded for wrong diagnosis. Median age 61.5 (51–81yrs); 7 males; 7 IgG, 2 IgA and 1λ-light chain subtypes; Stage IB-1, Stage IIA-4, Stage IIIA-5; median albumin 3.75 (range:1.6–5.1 g/dL), creatinine 0.95 (range: 0.7 – 2.7 mg/dL) and B2M 1.95 (range: 1.1–10.1 mg/L). Four patients completed 4 cycles; one is undergoing treatment; three patients taken off study-one after 2 cycles per patient's request, one secondary to grade 4 toxicity after cycle 1, and another after greater than 3 weeks treatment delay after cycle 3 secondary to pneumonia. Three patients (30%) developed grade 3–4 toxicities- two due to pneumonia (after cycles 2 and 3, respectively); and one with dehydration and renal failure after cycle 1. There were 2 deaths-one secondary to pulmonary embolism after cycle 1; another due to myocardial infarction after cycle 2. Two patients developed VTE- one after cycle 1 while on low dose coumadin; another died of pulmonary embolism after cycle 1, while on aspirin, requiring amendment to full dose coumadin anticoagulation. No further thrombotic episodes were encountered. Five patients underwent stem cell harvest with cyclophosphamide mobilization. The median harvest yield was 9.76 x106 CD34/kg (range: 5.27 – 31.94) with a median of 1 day (range: 1–7) to achieve at least 5 x 106 CD34/kg. Of the ten patients who received at least one cycle and assessable for response, the ORR was 80% (near complete remission(nCR)-10%; PR-70%), 1 MR, 1 SD. The M-spike response after first cycle of therapy ranged from 8% to 71%, with six patients (60%) having greater than 50% reduction in M-protein level. One patient achieved nCR after 2 cycles. Responses after the 3rd and 4th cycles were minimal.Conclusions: Doxil®, dexamethasone and low dose thalidomide represents an active induction therapy for patients with untreated multiple myeloma. Major responses were achieved rapidly, arguing for early stem cell harvest and autologous transplant after two cycles of therapy. Treatment related complications occurred early in the course of treatment. Full dose anticoagulation to prevent deep venous thromboembolism is essential when using this combination regimen. No adverse impact on stem cell harvest is associated with this therapy.

550 ORAL Population based mammography screening results in substantial savings in treatment costs by reducing the number of breast cancer deaths

Multiple myeloma (MM) is a clonal disorder of plasma cells, accounting for 10% of hematologic malignancies. Relapsed or refractory MM has a poor prsognosis. Thalidomide has been reported to be effective for these patients; however, high-dose thalidomide has induced many adverse events, including in the nervous, gastrointestinal, and hematopoietic systems in approximately 20%-50% of patients. Recently, low-dose thalidomide therapy has been used in many countries in order to reduce these adverse events. The objective of this study was to determine whether plasma concentration of thalidomide is related to the efficacy and the development of adverse events in patients with refractory MM treated with low-dose thalidomide plus low-dose dexamethasone.A total of 66 patients (age range, 40-74 years) presenting with progressive disease after previous treatments were treated with low-dose thalidomide and low-dose dexamethasone. Thalidomide was administered orally at 100 mg/day for the first week. When severe adverse events did not develop, the dose was increased to 200 mg/day in the second week and was continued until progression. Dexamethasone was administered at a dose of 4 mg/day for the first 4 weeks, then decreased by 1 mg every week, and finally maintained at 1 mg/day. Plasma trough concentration of thalidomide 3 days after thalidomide treatment was analyzed by high-performance liquid chromatography in 45 patients (age range, 42-74 years) who agreed to participate in this study of thalidomide concentration analysis.The mean concentrations at 100 mg/day and 200 mg/day were 0.343 μg/mL (range, 0.05-1.45 μg/mL) and 0.875 μg/mL (range, 0.19-2.09 μg/mL), respectively. The overall response rate (near-complete response + partial response + minimal response) of this treatment was 73%. Five had stable disease, and 3 patients experienced progressive disease. There was no relationship between the concentration of thalidomide in the plasma and the efficacy (P > .8). Severe adverse events, including grade > 2 nonhematologic and grade > 3 hematologic adverse events, were observed in 21 patients (46.6%). There was no significant difference in the concentration of thalidomide between the patients with and without severe adverse events (P > .843).The thalidomide concentration in the plasma does not predict treatment efficacy and the development of adverse events.

A lower dose of thalidomide is better than a high dose in metastatic renal cell carcinoma

To conduct a dose-finding trial using a single low dose and dose escalation of a higher dose of thalidomide in patients with metastatic renal cell carcinoma (RCC), and to evaluate the antineoplastic effectiveness of thalidomide as an anti-angiogenic agent on RCC. The 14 patients enrolled in the study had progressive measurable metastatic RCC and consented to participate. Patients were randomized to either a fixed low dose of 200 mg of thalidomide or to a high dose of 800 mg that was increased to a maximum dose of 1200 mg daily. Patients were evaluated for response after 8 weeks of therapy. Stable disease was achieved in six patients and was seen in both the low-dose and high-dose thalidomide groups. The median overall survival was 9 months. The low-dose thalidomide regimen was better tolerated and patients survived longer than those on the high-dose regimen (16 vs 6 months, P = 0.04) The use of low-dose thalidomide in patients with metastatic RCC was well tolerated and they survived for longer than those on the high-dose regimen.

Clinical and histopathologic spectrum of cutaneous Rosai-Dorfman disease in Taiwan

Background Cutaneous Rosai-Dorfman disease (RDD) is a rare entity of unknown origin and is not well documented, especially in Asian populations. Objective The purpose of this study was to evaluate the clinical manifestation, diagnostic histopathology, clinical course, and response to treatment of cutaneous RDD in Taiwan. Materials and methods This study included 21 patients with cutaneous RDD who presented at our institution from 1995 to 2003. Pathologic examinations with both hematoxylin-eosin and immunohistochemical stains were reviewed, as were associated clinical features and therapeutic methods. Results None of the 21 patients with cutaneous RDD had nodal lesions. The clinical manifestation was variable, but most commonly involved a central noduloplaque with satellite papules. One patient manifested as an ulcerated nodule, something not reported previously. Multifocal involvement only occurred in 4 patients. Concurrent involvement of uvea or vocal cord occurred in two patients. The most prominent histologic feature was a florid and mixed inflammatory infiltration. The phagocytosis of inflammatory cells into the cytoplasm of histiocytes, a process called “emperipolesis,” is a characteristic finding of nodular RDD but usually only focally presented in cutaneous ones. Positivity for S-100 protein helped to confirm the diagnosis. The most effective treatment was surgical excision of solitary lesions. High-dose thalidomide (300 mg/d), but not low-dose, was effective to control the extensive cutaneous diseases in two patients. A total of 3 patients experienced spontaneous remission 1 to 2 years after diagnosis. Conclusions Cutaneous RDD appeared more frequently in Asian populations than in reports from Western countries. The incidence of multifocal involvement in this series is much lower than in other literature. Although treatment of disseminated cutaneous RDD is difficult, high-dose thalidomide (300 mg/d), which was effective in two patients in this series, may be helpful.

Poor tolerance to high doses of thalidomide in patients with primary systemic amyloidosis

Treatments effective against multiple myeloma may be useful in primary systemic amyloidosis (AL). Thalidomide is active in myeloma. Results of the first 12 patients enrolled on a phase II trial of thalidomide for AL are presented. Progressive edema, cognitive difficulties, and constipation occurred in approximately 75%; dyspnea, dizziness and rash in 50%. Five developed progressive renal insufficiency. Deep venous thrombosis and syncope each occurred in two. Median time on the study was 72 days, range was 25 to 333 days. All 12 have withdrawn from the study (side-effects, 6; progression, 4; and death, 2 patients). AL patients do not tolerate high dose thalidomide.

Phase II trial of thalidomide in renal-cell carcinoma

BackgroundThalidomide has been reported to yield anti-tumor activity in cancer. We performed a phase II trial of this drug in patients with metastatic renal cell carcinoma to determine its efficacy. Patients and methodsPatients with proven metastatic renal cell cancer, measurable progressive disease and a performance status of 0–2 were enrolled in this study. Thalidomide was given daily at a starting dose of 400 mg, followed by a 400 mg increment to 800 mg and then to 1200 mg with6–12 weeks at each dose level. The response rate at 6 months was the primary end point. Toxicity, overall survival, tumor vascularization depicted on color Doppler ultrasonography and serum vascular endothelial growth factor, basic fibroblast growth factor, interleukin-12 and tumor necrosis factor-α levels were secondary end points. ResultsForty patients were enrolled. Two partial responses were observed (5%) and disease remained stable in nine patients after 6 months. Median survival was 10 months. Toxicity was high, with frequent manifestations of fatigue, constipation and lethargy. The incidence of neuropathy detected on electromyography (EMG) attained 70% at 6 months, and 100% in patients on thalidomide for 12 months. Nine patients developed venous thromboembolism during the first 12 weeks of treatment, and three of them experienced pulmonary embolism. One unexpected (and unexplained) death occurred. ConclusionsDespite undisputed, albeit marginal, activity in renal cell cancer, high-dose thalidomide cannot be recommended using this schedule since the level of toxicity is high.

Thalidomide in gastrointestinal disorders.

Thalidomide was originally marketed as a sedative, but was removed from the market in 1961 after it was associated with an epidemic of severe birth defects. Subsequently, it has been shown to have therapeutic efficacy in a number of the gastrointestinal tract conditions characterised by immune dysregulation. The exact mechanism of the immunosuppressive effects of thalidomide is unknown; proposed mechanisms include inhibition of tumour necrosis factor alpha release and inhibition of angiogenesis. In chronic graft versus host disease, use of high dose thalidomide (1200 mg/day) may bring about a response in 20% of patients with refractory disease. Thalidomide 200 mg/day helps eradicate ulcers in 50% of patients with HIV-associated oral aphthous ulceration. In Behçet's disease, thalidomide 100 to 300 mg/day can decrease the number of mucocutaneous ulcers, although full remission occurs in less than 20% of patients. In Crohn's disease, thalidomide 50 to 300 mg/day may decrease the severity of mucosal disease and prompt closure of fistulae. Patients to be placed on thalidomide therapy must practice either abstinence or strict birth control; women must undergo regular pregnancy testing and utilise 2 forms of contraception. Other adverse effects include sedation (present in nearly all patients), symptomatic neuropathy (present in approximately 20%), and skin rashes. Given the potential toxicity, thalidomide use should generally be limited to clinical protocols with institutional review board oversight.