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PubMed2003

An open-label phase II study of low-dose thalidomide in androgen-independent prostate cancer.

The antiangiogenic effects of thalidomide have been assessed in clinical trials in patients with various solid and haematological malignancies. Thalidomide blocks the activity of angiogenic agents including bFGF, VEGF and IL-6. We undertook an open-label study using thalidomide 100 mg once daily for up to 6 months in 20 men with androgen-independent prostate cancer. The mean time of study was 109 days (median 107, range 4-184 days). Patients underwent regular measurement of prostate-specific antigen (PSA), urea and electrolytes, serum bFGF and VEGF. Three men (15%) showed a decline in serum PSA of at least 50%, sustained throughout treatment. Of 16 men treated for at least 2 months, six (37.5%) showed a fall in absolute PSA by a median of 48%. Increasing levels of serum bFGF and VEGF were associated with progressive disease; five of six men who demonstrated a fall in PSA also showed a decline in bFGF and VEGF levels, and three of four men with a rising PSA showed an increase in both growth factors. Adverse effects included constipation, morning drowsiness, dizziness and rash, and resulted in withdrawal from the study by three men. Evidence of peripheral sensory neuropathy was found in nine of 13 men before treatment. In the seven men who completed six months on thalidomide, subclinical evidence of peripheral neuropathy was found in four before treatment, but in all seven at repeat testing. The findings indicate that thalidomide may be an option for patients who have failed other forms of therapy, provided close follow-up is maintained for development of peripheral neuropathy.

Aged↗
PubMed1999

Combination oral antiangiogenic therapy with thalidomide and sulindac inhibits tumour growth in rabbits.

Neovascularization facilitates tumour growth and metastasis formation. In our laboratory, we attempt to identify clinically available oral efficacious drugs for antiangiogenic activity. Here, we report which non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit corneal neovascularization, induced by basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF). This antiangiogenic activity may contribute to the known effects of NSAIDs on gastric ulcers, polyps and tumours. We found that sulindac was one of the most potent antiangiogenic NSAIDs, inhibiting bFGF-induced neovascularization by 50% and VEGF-induced neovascularization by 55%. Previously, we reported that thalidomide inhibited growth factor-induced corneal neovascularization. When we combined sulindac with thalidomide, we found a significantly increased inhibition of bFGF- or VEGF-induced corneal neovascularization (by 63% or 74% respectively) compared with either agent alone (P < 0.01). Because of this strong antiangiogenic effect, we tested the oral combination of thalidomide and sulindac for its ability to inhibit the growth of V2 carcinoma in rabbits. Oral treatment of thalidomide or sulindac alone inhibited tumour growth by 55% and 35% respectively. When given together, the growth of the V2 carcinoma was inhibited by 75%. Our results indicated that oral antiangiogenic combination therapy with thalidomide and sulindac may be a useful non-toxic treatment for cancer.

Administration, Oral↗
PubMed2001

Efficacy of thalidomide therapy for extramedullary relapse of myeloma following allogeneic transplantation.

Treatment options for patients with myeloma who relapse after allogeneic stem cell transplantation are limited. Thalidomide, an antineoplastic agent, has been shown to be effective in multiple myeloma through proposed mechanisms that may include angiogenesis inhibition. Herein we report successful thalidomide treatment of four patients who relapsed following allogeneic transplantation, three of whom had predominantly extramedullary relapse. Thalidomide was well tolerated in all patients; in two patients interferon-alpha was subsequently added to thalidomide as maintenance therapy without worsening graft-versus-host disease. We suggest that extramedullary myeloma is particularly sensitive to thalidomide, speculating that growth biology may in part be dependent on angiogenesis.

Adult↗
PubMed2003

Effect of thalidomide on stem cell collection and engraftment in patients with multiple myeloma.

The purpose of this study was to determine the effect of thalidomide on stem cell collection and engraftment in patients with multiple myeloma. We performed a retrospective review of 67 patients newly diagnosed with multiple myeloma at Mayo Clinic and treated with a single regimen prior to stem cell transplantation between January of 2000 and September of 2001. Stem cells were collected from 24 patients who received thalidomide, 200 mg/day, with dexamethasone as initial therapy before stem cell collection. These patients were compared with 43 control patients seen during the same period who had received only one previous regimen before stem cell collection and transplantation. The cumulative thalidomide dose before stem cell collection was 17 000 mg over a median of four cycles (range, 2-7 cycles). The thalidomide and control groups were not significantly different in their baseline characteristics, number of stem cells collected, time to collection, or time to engraftment of neutrophils or platelet count of 50 000/microl. Time to platelet count of 20 000/microl was delayed by a median of 4 days (P=0.008), but platelet transfusion requirements did not differ (P=0.95). We concluded that thalidomide does not substantially affect peripheral cell mobilization or engraftment.

Adult↗
PubMed2001

Thalidomide for previously untreated indolent or smoldering multiple myeloma.

We conducted a clinical trial of thalidomide as initial therapy for asymptomatic smoldering (SMM) or indolent multiple myeloma (IMM). Sixteen patients were studied. Thalidomide was given orally at a dose of 200 mg/day for 2 weeks, and then increased as tolerated by 200 mg/day every 2 weeks to a maximum dose of 800 mg/day. Bone marrow microvessel density (MVD) and angiogenesis grading were estimated using CD34 immunostaining. Six patients had a confirmed response to therapy with at least 50% or greater reduction in serum and urine monoclonal (M) protein. When minor responses (25-49%) decrease in M protein concentration) were included, 11 of 16 patients (69%) responded to therapy. Major grade 3-4 toxicities included two patients with somnolence, and one patient each with syncope and neutropenia. Pre-treatment MVD was not a significant predictor of response to therapy, median MVD 4 and 12 in responders and non-responders respectively, P = 0.09. We conclude that thalidomide has significant activity in the treatment of newly diagnosed SMM/IMM. However, we do not recommend treatment with thalidomide at this stage since some patients with SMM/IMM can be stable for several months or years without any therapy. Additional randomized trials are needed to determine if thalidomide will delay progression to active multiple myeloma.

Administration, Oral↗
PubMed2003

Immunomodulatory analogs of thalidomide inhibit growth of Hs Sultan cells and angiogenesis in vivo.

We have previously shown that thalidomide and its potent immunomodulatory derivatives (IMiDs) inhibit the in vitro growth of multiple myeloma (MM) cell lines and patient MM cells that are resistant to conventional therapy. In this study, we further characterize the effect of these drugs on growth of B cell malignancies and angiogenesis. We established a beige-nude-xid (BNX) mouse model to allow for simultaneous in vivo measurement of both anti-tumor and anti-angiogenic effects of thalidomide and its analogs. Daily treatment (50 mg/kg/d) with thalidomide or IMiDs was nontoxic. The IMiDs were significantly more potent than thalidomide in vivo in suppressing tumor growth, evidenced by decreased tumor volume and prolonged survival, as well as mediating anti-angiogenic effects, as determined by decreased microvessel density. Our results therefore show that the IMiDs have more potent direct anti-tumor and anti-angiogenic effects than thalidomide in vivo, providing the framework for clinical protocols evaluating these agents in MM and other B cell neoplasms.

Angiogenesis Inhibitors↗
PubMed2005

Therapeutic renaissance of thalidomide in the treatment of haematological malignancies.

Very few drugs had a history similar to that of thalidomide (alpha-N-[phthalimido] gluramide). First introduced in the late 1950s in Germany, in 1961 thalidomide was withdrawn due to its teratogenic effects. More than three decades after, it is attracting growing interest because of its reported immunomodulatory and anti-inflammatory properties. The discovery that thalidomide inhibits angiogenesis led to preclinical and clinical trials as an anticancer agent in the treatment of solid tumours and haematological malignancies, as summarized in this review article. More recently, structural analogues of thalidomide have been synthesized in order to explore potential molecular targets of thalidomide, as well as to identify new agents with improved therapeutic efficacy.

Angiogenesis Inhibitors↗
PubMed2000

Thalidomide in patients with advanced multiple myeloma.

INTRODUCTION: Recently, a report has suggested the efficacy and safety of thalidomide in refractory multiple myeloma. In an attempt to assess the efficacy and tolerance of thalidomide in advanced multiple myeloma (on behalf of the Intergroupe Franchophone dy Myelome (IFM)), we report the preliminary experience of the IFM with this drug. MATERIALS AND METHODS: Patients with advanced multiple myeloma (n=27) were treated with an oral dose of thalidomide (median 400 mg/day). At the start of treatment, all patients had active disease and 20 patients had received at least one autologous transplantation. RESULTS: Median follow-up was 105 days from the first administration. The serum and/or urine levels of the M-component were reduced by at least 75% in four patients including one patient with a >90% reduction, by at least 50% in five patients and by at least 25% in three patients, giving a total response rate of 45% (12 out of 27 patients). Nine patients had stable disease and six patients had progressed disease. Short-term side-effects of thalidomide were generally moderate. CONCLUSION: This study confirms that thalidomide is an effective agent in patients with advanced myeloma.

Agranulocytosis↗
PubMed1967

The fate of[14C]thalidomide in the pregnant rabbit.

1. The fate of [(14)C]thalidomide orally administered to pregnant rabbits at the beginning of the sensitive phase of pregnancy has been studied. 2. After the oral administration of [(14)C]thalidomide on the 192nd hour of pregnancy about 68% of the radioactivity appears in the urine and 22% in the faeces. 3. The urinary (14)C is made up as follows (% of dose): thalidomide (2); alpha-(o-carboxybenzamido)glutarimide (16); 2- and 4-phthalimidoglutaramic acids (11); 2-phthalimidoglutaric acid (0.2); 2- and 4-(o-carboxybenzamido)glutaramic acids and 2-(o-carboxybenzamido)-glutaric acid (29). 4. The plasma (14)C concentration is maximal at 12hr. after dosing and the radioactivity persists for more than 58hr. At 4hr. the main compound in the plasma is thalidomide, but its concentration steadily declines while the concentration of its hydrolysis products increases. 5. At 12, 24 and 58hr. after dosing radioactivity is present in the embryo and the maternal tissues examined. The (14)C concentration in the embryo is at nearly all times higher than that in the plasma, brain, skeletal muscle and fat but lower than that in the liver and kidney. 6. At 4hr. after dosing the mother on the tenth day of pregnancy the specific activities of the embryo and the yolk-sac fluid are similar. 7. Thalidomide is found in the embryo together with seven of its hydrolysis products for more than 24hr. after dosing. The accumulation of radioactivity in the embryo is due to retention of the polar hydrolysis products.

Adipose Tissue↗
PubMed2004

Thalidomide for the treatment of idiopathic myelofibrosis.

Except rare instances of allogeneic stem cell transplantation, treatment of idiopathic myelofibrosis (IMF) is only palliative and based on cytostatic treatment (hydroxyurea and anagrelide), androgen therapy, steroids and splenectomy. Thalidomide is an anti-angiogenic and immunomodulatory drug with a wide spectrum of activities, which are not clearly understood. Current data suggest that the action of thalidomide is related to several different mechanisms, including suppression of tumor necrosis factor, effects on basic fibroblast growth factor, vascular endothelial growth factor, interleukins and interferons, downregulation of selected cell surface adhesion molecules, and changes in the lymphocyte subsets. We administered thalidomide to 16 patients with IMF (15 men, one women) who had transfusion-dependent anemia, thrombocytopenia or symptomatic splenomegaly. Median age was 59 yr (range: 52-78). Patients received thalidomide at an escalating dose from 100 to 400 mg/d (median 300 mg). The drug was discontinued in four patients because of progressive disease (two) or polyneuropathy (two). Other adverse effects were obstipation (10), fatigue (eight) and edema (two). Clinical response has now been observed for a median duration of 9 months (range: 3-20). Fifteen patients are evaluable. Anemia improved in six of 10 patients who were anemic. Platelet counts improved in five of seven patients with thrombocytopenia. Splenomegaly regressed in three of 13 patients. Lactate dehydrogenase (LDH) decreased in seven of 12 patients, but increased in four patients. LDH levels were not correlated with clinical response. In summary, thalidomide appears useful in the treatment of IMF.

Aged↗
PubMedDate not supplied

Effect of thalidomide in different tumors in rodents.

This study investigated the effects of chronic administration of thalidomide on three different neoplasms of ectodermic origin in rodents: 1) chemically induced tumors of the nervous system of rats by transplacental exposure to ethylnitrosourea; 2) transplanted RPMI-1846 melanoma in hamsters and 3) transplanted C6 glioblastoma in rats. No effects were seen on thalidomide-treated rats on the frequency- and time of tumor development induced by ethylnitrosourea. In contrast, a reduction in tumoral growth and mitotic-index was obtained in animals treated with thalidomide in transplanted tumors, melanoma and glioblastoma, when compared with controls (P < 0.001 and 0.025, respectively). These results suggest that, although thalidomide is not a cytotoxic drug for neoplastic cells, it might partially inhibit the tumoral growth through any of its pharmacological actions; by blockage of cell-surface adhesion receptors induction of DNA oxidation, or inhibition of angiogenesis. Further investigations on the use of thalidomide perhaps associated to cytotoxic drugs, for treatment of ectodermic neoplasms seem guaranteed.

Angiogenesis Inhibitors↗
PubMed2003

Oesophageal cancer and cachexia: the effect of short-term treatment with thalidomide on weight loss and lean body mass.

BACKGROUND: Cachexia is common in patients with advanced cancer and has a direct impact on well-being and mortality. AIM: To test the hypothesis that thalidomide can promote weight gain and lean body mass in patients with advanced oesophageal cancer. METHODS: In an open-label study, 11 patients with non-obstructing and inoperable oesophageal cancer were established on an isocaloric diet for 2 weeks, followed by 2 weeks on thalidomide, 200 mg daily. The primary end-points were weight change and lean body mass. Secondary end-points were quality of life and changes in resting energy expenditure. RESULTS: Ten patients completed the study protocol. The average caloric intake remained the same throughout the study period in all patients. Nine of 10 patients (95% confidence interval, 0.60, 0.98) lost weight on diet alone. The mean weight gain on thalidomide in the following 2 weeks was 1.29 kg (median, 1.25 kg). A similar trend was shown in the lean body mass. Eight of nine patients (95% confidence interval, 0.57, 0.98) initially lost lean body mass on diet alone (missing data in one patient). The mean gain in lean body mass on thalidomide in the following 2 weeks was 1.75 kg (median, 1.33 kg). CONCLUSIONS: Thalidomide treatment appeared to reverse the loss of weight and lean body mass over the 2-week trial period.

Aged↗
PubMed2001

Thalidomide usage in Wales: the need to follow guidelines.

BACKGROUND: Thalidomide is a potentially useful drug for several dermatological disorders. OBJECTIVES: To assess prescribing and monitoring practices for this drug in Wales. METHODS: A questionnaire was completed by 17 of 19 consultant dermatologists concerning thalidomide usage in Wales (population 2.93 million). RESULTS: Eleven of the 17 respondents had used thalidomide in 40 patients. Only two consultants gave information leaflets and only five obtained written consent. Four obtained baseline nerve conduction studies and nine obtained these during therapy. Of seven women of child-bearing age currently taking thalidomide, none had had baseline pregnancy tests. CONCLUSIONS: We describe variability in prescribing practices for thalidomide. Published guidelines are reviewed and suggestions made concerning consent forms, pregnancy testing, nerve conduction studies and patient information.

Dermatologic Agents↗
PubMed2000

Frequent good partial remissions from thalidomide including best response ever in patients with advanced refractory and relapsed myeloma.

Twenty-three patients with advanced and heavily pretreated myeloma were treated with thalidomide. Starting dose was 200 mg/d, and 20 patients had dose escalations up to 400 (n = 5), 600 (n = 12) or 800 mg/d (n = 3), usually in divided doses. Nineteen patients were refractory to recent chemotherapy, and four had untreated relapse after prior intensive therapy. Ten out of 23 patients (43%) achieved partial response (PR; nine with refractory and one with relapsed disease), six patients had minor response or stabilization of the disease and four had disease progression. Another three patients died early from advanced myeloma at less than 3 weeks of thalidomide therapy. Of the 10 patients with PR, seven had a better response than after any prior therapy, despite vincristine-doxorubicin-dexamethasone (VAD)-based treatment in all but one and high-dose melphalan with autologous stem cell support in four. Time to achieve PR was rapid in patients receiving thalidomide in divided doses (median 31 d). Responses also included reduced bone marrow plasma cell infiltration and improved general status. Normalized polyclonal gammaglobulin levels were seen in four cases. Six out of 10 patients with PR remained in remission with a median time on treatment of 23 weeks (range 15-50 weeks). Sedation was common but usually tolerable, and some patients continued full- or part-time work. Four patients had skin problems, three patients had pneumonia, one hypothyrosis, one sinus bradycardia and one minor sensory neuropathy. Thalidomide may induce good partial remissions in advanced refractory myeloma with tolerable toxicity, and should be evaluated in other settings for myeloma patients. Divided thalidomide doses seem to reduce time to achieve remission and may improve response rate.

Adult↗
PubMed1997

Thalidomide: a novel therapy for microsporidiosis.

BACKGROUND & AIMS: Microsporidiosis is a common cause of chronic diarrhea in human immunodeficiency virus (HIV)-seropositive individuals and often does not respond to treatment. Fecal tumor necrosis factor alpha (TNF-alpha) is elevated in microsporidiosis; therefore, thalidomide, an anti-TNF-alpha agent, was used as therapy. METHODS: Eighteen subjects with chronic diarrhea caused by Enterocytozoon bieneusi that had not responded symptomatically to albendazole and 1 untreated subject with Encephalitozoon intestinalis received 1 month of thalidomide, 100 mg nocte. Clinical response was assessed by stool frequency and body weight, histological response by light microscopy with villus height/crypt depth ratios and electron microscopy, and immunologic response by fecal TNF-alpha level. RESULTS: Seven subjects with chronic diarrhea due to E. bieneusi had a complete clinical response, and 3 had a partial response to thalidomide. There was a significant decrease in stool frequency from 5.3 to 3.1 per day (P = 0.001), and weight increased significantly by 1.2 kg (P < 0.02). Thalidomide significantly increased the villus height/crypt depth ratio (1.95 to 2.07; P = 0.045) and number of abnormal forms of microsporidia (P < 0.01). Fecal TNF-alpha level nonsignificantly decreased from 17.9 to 8.9 U/mL. There was apparent disruption of all stages of the life cycle of E. intestinalis. CONCLUSIONS: Thalidomide may be an effective therapy for diarrhea and weight loss from E. bieneusi.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Thalidomide with or without dexamethasone for refractory or relapsing multiple myeloma.

Both thalidomide and intermittent high-dose dexamethasone are agents with established activity against multiple myeloma. We summarized our experience with thalidomide alone, and then in combination with dexamethasone, for groups of patients with myeloma resistant or relapsing despite standard treatments. Criteria of response were based on greater than 50% reduction of serum myeloma protein and/or greater than 75% reduction of Bence Jones protein for patients treated with thalidomide alone and greater than 75% reduction of serum myeloma protein and/or greater than 90% reduction of Bence Jones protein for those who received thalidomide with dexamethasone. Among patients with resistant or relapsing disease treated with a combination of thalidomide and dexamethasone, 47% of patients achieved remission with significant prolongation of survival for responsive patients. Among patients in stable partial remission after intensive therapy who received the same program, myeloma protein was reduced further by greater than 90% in 52% of patients who had not received prior thalidomide/dexamethasone. Side effects were frequent, mild and reversible, and often preventable. Our program of thalidomide/dexamethasone was a safe and effective combination for patients with resistant or relapsing disease, or as consolidation of partial remission after intensive therapy.

Adjuvants, Immunologic↗
PubMed2002

Low-dose thalidomide in myeloma: efficacy and biologic significance.

The efficacy of thalidomide at doses as low as 50 mg every other day was first reported at the VII International Multiple Myeloma Workshop in Stockholm, Sweden, in September 1999. This article discusses the duration of responses with low-dose thalidomide and the subsequent efficacy with thalidomide combination approaches. The median effective dose of thalidomide was 200 mg/d. Thalidomide's mechanism of action, particularly its effects on macrophages, is described. Current approaches to single-agent and combination therapy are presented.

Adjuvants, Immunologic↗
PubMed2000

Continuous low dose Thalidomide: a phase II study in advanced melanoma, renal cell, ovarian and breast cancer.

To grow and metastasize, solid tumours must develop their own blood supply by neo-angiogenesis. Thalidomide inhibits the processing of mRNA encoding peptide molecules including tumour necrosis factor-alpha (TNF-alpha) and the angiogenic factor vascular endothelial growth factor (VEGF). This study investigated the use of continuous low dose Thalidomide in patients with a variety of advanced malignancies. Sixty-six patients (37 women and 29 men; median age, 48 years; range 33-62 years) with advanced measurable cancer (19 ovarian, 18 renal, 17 melanoma, 12 breast cancer) received Thalidomide 100 mg orally every night until disease progression or unacceptable toxicity was encountered. Three of 18 patients with renal cancer showed partial responses and a further three patients experienced stabilization of their disease for up to 6 months. Although no objective responses were seen in the other tumour types, there were significant improvements in patients' sleeping (P < 0.05) and maintained appetite (P < 0.05). Serum and urine concentrations of basic fibroblast growth factor (bFGF), TNF-alpha and VEGF were measured during treatment and higher levels were associated with progressive disease. Thalidomide was well tolerated: Two patients developed WHO Grade 2 peripheral neuropathy and eight patients developed WHO grade 2 lethargy. No patients developed WHO grade 3 or 4 toxicity. Further studies evaluating the use of Thalidomide at higher doses as a single agent for advanced renal cancer and in combination with biochemotherapy regimens are warranted.

Adult↗