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PubMed2005

The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma.

OBJECTIVE: To study the efficacy of daily low-dose aspirin (81 mg orally) in decreasing the incidence of venous thromboembolic events (VTEs) in patients with multiple myeloma receiving pegylated doxorubicin, vincristine, and decreased-frequency dexamethasone, plus thalidomide (DVd-T). PATIENTS AND METHODS: In this phase 2 clinical trial of DVd-T, conducted by the Cleveland Clinic Foundation from August 2001 to October 2003, 105 patients were enrolled. The first 35 patients experienced increased numbers of VTEs. von Willebrand levels and platelet aggregation to ristocetin before and after treatment with DVd-T increased significantly, suggesting a pathophysiology involving platelet-endothelial interaction. Aspirin was added to the regimen, thus generating 3 patient groups: group 1 received aspirin from the start of DVd-T treatment before the study began (58 patients), group 2 received aspirin after the start of DVd-T treatment and after the study began (26 patients), and group 3 did not receive daily low-dose aspirin during the study (19 patients). Two patients being treated with warfarin for other indications were excluded from the study. The primary end point for this study was the incidence of VTE in the form of either deep venous thrombosis or pulmonary embolism. Secondary end points were the time to the first VTE, time to the composite end point of death or first VTE, and incidence of bleeding complications. RESULTS: After a median follow-up of 24 months, on an intent-to-treat basis, 26 posttreatment VTEs occurred after a median of 90 days, with 19% occurring in group 1, 15% in group 2, and 58% in group 3. Following multivariate time-to-event analysis, aspirin use continued to be associated with lower relative risk of VTE (hazard ratio, 0.22; confidence interval, 0.10-0.47; P<.001) and of the composite end point (hazard ratio, 0.28; confidence interval, 0.15-0.51; P<.001). CONCLUSION: Daily low-dose aspirin (81 mg orally) given to patients with newly diagnosed and relapsed/refractory multiple myeloma who were receiving DVd-T reduced the incidence of VTEs without an increase in bleeding complications.

Adult↗
PubMed1990

Thalidomide, pregnancy and renal failure.

A 26-year-old woman with upper limb phocomelia as a result of thalidemide embryopathy developed renal failure that required dialysis during pregnancy. The pregnancy was complicated by dialysis difficulties, uncontrollable hypertension and deteriorating renal function resulting in fetal loss at 26-weeks' gestation. The patient was left with end-stage renal failure and recently has undergone cadaveric renal transplantation. This case highlights the widespread effects, including urinary-tract abnormalities, that thalidomide may have and illustrates the peculiar difficulties in managing such a patient during and after pregnancy.

Adult↗
PubMed1976

[Problems of treating the clubhand in dysmelia syndrome (thalidomide-embryopathy)].

In our follow-up examination of about 500 children suffering from thalidomide embryopathy we have studied the results of conservative and operative treatment of club hand. The results of treatment have not corresponded to the prognosis with regard to function. In our opinion the possibility of operative treatment should not be considered until growth of the ulna ceases.

Abnormalities, Drug-Induced↗
PubMed2000

Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy.

Although thalidomide (Thal) was initially used to treat multiple myeloma (MM) because of its known antiangiogenic effects, the mechanism of its anti-MM activity is unclear. These studies demonstrate clinical activity of Thal against MM that is refractory to conventional therapy and delineate mechanisms of anti-tumor activity of Thal and its potent analogs (immunomodulatory drugs [IMiDs]). Importantly, these agents act directly, by inducing apoptosis or G1 growth arrest, in MM cell lines and in patient MM cells that are resistant to melphalan, doxorubicin, and dexamethasone (Dex). Moreover, Thal and the IMiDs enhance the anti-MM activity of Dex and, conversely, are inhibited by interleukin 6. As for Dex, apoptotic signaling triggered by Thal and the IMiDs is associated with activation of related adhesion focal tyrosine kinase. These studies establish the framework for the development and testing of Thal and the IMiDs in a new treatment paradigm to target both the tumor cell and the microenvironment, overcome classical drug resistance, and achieve improved outcome in this presently incurable disease.

Antineoplastic Agents↗
PubMed2000

Irinotecan and thalidomide in metastatic colorectal cancer.

Fifteen patients with metastatic colorectal cancer were treated with irinotecan (CPT-11, Camptosar) at 300 to 350 mg/m2 every 21 days and thalidomide (Thalomid) at 400 mg/d. Of the 15 patients, 11 were in a pilot study and 4 were in an ongoing phase II protocol. There were 12 men and 3 women, with a median age of 56 years (range: 29 to 79 years). Patients were treated with a median of three cycles (range: one to eight cycles). The four patients enrolled in the formal protocol were not evaluable for response at the time of this report. Of the 11 patients in the pilot study, 10 were evaluable for response; there were two complete responses, two partial responses, and six progressions. Investigators noted a remarkable absence of grade 3/4 gastrointestinal toxicities, and concluded that further testing of the complete response and toxicity profile of the irinotecan/thalidomide regimen was warranted.

Adult↗
PubMed2001

High plasma basic fibroblast growth factor concentration is associated with response to thalidomide in progressive multiple myeloma.

The aim of this study was to define prognostic factors that might be predictive for response to thalidomide (Thal) in progressive multiple myeloma (n = 54). We examined the concentration of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), two potent heparin-binding mediators of angiogenesis in peripheral blood (PB; PB-VEGF and PB-bFGF) and bone marrow (BM; BM-VEGF and BM-bFGF), in combination with well-characterized predictors for response and survival to chemotherapy. After a median follow-up time of 15 months (range, 0.3-20), 29 patients (pts.) showed at least a minimal response to Thal therapy, whereas 25 pts. were nonresponsive. As shown by univariate analysis, responsive pts. had statistically significant higher concentrations of PB-bFGF (P = 0.009) and beta2-microglobulin (P = 0.03) before therapy, as well as lower hemoglobin (P = 0.008) and albumin (P = 0.02) levels, whereas no statistically significant difference was found for PB-VEGF (P = 0.93). When a multiple logistic regression analysis was performed, PB-bFGF was the only statistically significant predictor for response to therapy (P = 0.01). None of these variables was associated with a prolonged progression-free survival. In conclusion, our findings indicate that high pretreatment plasma bFGF levels in pts. with progressive multiple myeloma are associated with unfavorable parameters of response and survival but nevertheless predict for response to Thal therapy.

Adult↗
PubMed1999

[The protective effects of thalidomide on acute liver failure].

OBJECTIVE: To understand whether thalidomide (Thal) has the same protective effects as it does in leprosy reaction type II, immunologic and inflammatory diseases. METHODS: D-Galactosamine (D-GalN, 600 mg/kg body weight, intraperitoneally) and lipopolysaccharide (LPS, 5 microg/rat, hypodermically) were used to produce a model of acute liver failure in Wistar rats. The mortality of the models was counted. The plasma peak levels of various cytokines and transaminases were measured. The pathological alterations of the livers were examined with hematoxylin and eosin stain under light microscopy. The expression of tumor necrosis factor (TNF)alpha mRNA was determined by dot blot hybridization combined with semiquantitative analysis. RESULTS: It was found that Thal could lower the mortality of the models (P < 0.05); reduce the peak levels of plasma cytokines, especially TNFalpha, and transaminases (P < 0.05), alleviate the degree of liver injury and suppress the expression of TNFalpha mRNA (P < 0.05). CONCLUSION: It is fully demonstrated that Thal has definite protective effect on acute liver failure, as it does in other diseases. Even though Thal possesses teratogenic effect in patients with pregnancy, it is still believed that Thal has an important curative significance in the treatment of patients who are not pregnant.

Animals↗
PubMedDate not supplied

Influence of thalidomide on Bcl2 expression and proangiogenic cytokine levels in short-term culture of peripheral blood and bone marrow mononuclear cells of multiple myeloma patients.

Supernatants from short-term culture of peripheral blood and bone marrow mononuclear cells obtained from 22 multiple myeloma patients were used to measure the concentration of TNF-alpha, HGF, IL-6 and its soluble receptor (sIL-6R), VEGF and bFGF. Cells were cultured with or without thalidomide (THAL). We observed statistically significant decrease in TNF-alpha, HGF, IL-6, sIL-6R in supernatants from THAL cultures compared to cells cultured without THAL. Flow cytometry technique was applied to study the Bcl2 expression on CD 4, CD 8 and CD 138 positive cells. The statistically significant decrease in Bcl2 expression on myeloma cells (CD 138+) was observed both in PB and BM cultures. THAL could inhibit the plasma cell growth both by diminishing proangiogenic cytokines production and enhancing myeloma cell apoptosis.

Angiogenesis Inhibitors↗
PubMed2002

Polymorphisms of the tumor necrosis factor-alpha gene promoter predict for outcome after thalidomide therapy in relapsed and refractory multiple myeloma.

Thalidomide (Thal) is a drug with antiangiogenic, anti-inflammatory, and immunomodulatory properties that was found to inhibit the production of tumor necrosis factor-alpha (TNF-alpha) in vitro. We studied single nucleotide polymorphisms at positions -308 and -238 of the TNF-alpha gene promoter and measured the corresponding TNF-alpha cytokine levels in 81 patients (pts) with refractory and relapsed multiple myeloma (MM) who were treated with Thal. In myeloma pts carrying the TNF-238A allele (n = 8), we found a correlation with higher pretreatment TNF-alpha levels in peripheral blood (P =.047). After Thal administration, this TNF-238A group had a prolonged 12-month progression-free and overall survival of 86% and 100% versus 44% and 84% (P =.003 and P =.07) in pts with the TNF-238G allele, respectively. These findings suggest that regulatory polymorphisms of the TNF-alpha gene can affect TNF-alpha production and predict the outcome after Thal therapy, particularly in those MM pts who are genetically defined as "high producers" of TNF-alpha.

Adult↗
PubMed1975

[World survey on the use of thalidomide in leprosy reaction].

Review of the answers of a questionary sent to 62 different Leprosy Departments. The results indicate that in 99% of lepromatous patients with lepra-reactions, the response to thalidomide was satisfactory. In the tuberculoid and borderline types of lepra, the results were not good.

Drug Evaluation↗
PubMed2002

Dose-dependent effect of thalidomide on overall survival in relapsed multiple myeloma.

PURPOSE: Although thalidomide (Thal) was introduced successfully in the treatment of multiple myeloma (MM), the optimal Thal dosage and schedule are still controversial. The aim of this study was to analyze whether the effect of Thal in MM is dose dependent and whether the outcome might be improved when the Thal dosage is adjusted to parameters reflecting body size. EXPERIMENTAL DESIGN: From December 1998 to March 2001, 83 patients with relapsed MM were enrolled in a clinical Phase II trial and treated with a maximum Thal dosage of 400 mg daily. We performed a retrospective analysis and studied the effect of the cumulative 3-month Thal dosage on progression-free survival and overall survival (OS) together with age and the pretreatment levels of beta2-microglobulin, C-reactive protein, albumin, and hemoglobin in a Cox regression model. RESULTS: After a median follow-up time of 17 months (range, 1-30 months), the estimated 12-month progression-free survival and OS were 45% (SE = 6%) and 86% (SE = 4%) for the whole patient group. After backward selection, hemoglobin (P = 0.002) and the cumulative 3-month Thal dosage (P = 0.002) were the remaining factors for OS. The effect on OS could not be improved when the cumulative 3-month Thal dosage was adjusted to parameters reflecting body size such as height, weight, body surface area, or body mass index in comparison with Thal alone. CONCLUSIONS: Our retrospective analysis demonstrates that the cumulative 3-month Thal dosage is one of the major prognostic factors for OS, supporting the hypothesis of a dose-dependent effect of Thal in relapsed MM.

Adult↗
PubMed2002

Differential regulation of dendritic cell function by the immunomodulatory drug thalidomide.

Thalidomide (Thal) was shown to be a potent immunomodulating agent. Because of their central role in controlling immunity, we investigated the effects of Thal on monocyte-derived dendritic cells (Mo-DC). The addition of 10 micro g/ml or 20 micro g/ml Thal from the beginning of monocyte culture with granulocyte macrophage-colony stimulating factor and interleukin (IL)-4 did not block Mo-DC differentiation. Moreover, Thal alone could not induce Mo-DC maturation. However, Thal exerted a modulation of Mo-DC functional properties. At 10 micro g/ml, Thal modified the allostimulatory capacity of DC little, whereas a dose of 20 micro g/ml up-regulated this capacity (P=.05) and increased IL-12p70 production in a dose-dependent manner between 10 and 20 micro g/ml (P=.001). Mo-DC generated with 10 micro g/ml Thal were poor stimulators of T helper cell type 1 (Th1) responses (P=.01), but 20 micro g/ml was able to strengthen Th1 responses (P=.03). Also, Thal induced a significant reduction of IL-10 production in response to the maturation-inducing stimulus CD40L. Similarly, tumor necrosis factor alpha production was significantly decreased when Mo-DC were exposed to 10 micro g/ml Thal, and a dose of 20 micro g/ml did not induce any significant changes. The effects of Thal in vitro on the secretion of IL-12p70 and strengthening of Th1 responses might contribute to the antitumor effects of Thal. Thus, DC appear to be potential targets for the immunomodulatory capacity of Thal, defining a new mechanism of action of this drug.

Adjuvants, Immunologic↗
PubMed2004

[Report of two cases with pleural effusion and ascites that responded dramatically to the combination of thalidomide, celecoxib, irinotecan, and CDDP infused in thoracic and abdominal cavities].

Malignant pleural effusion (PE) and ascites are associated with highly symptomatic, advanced-stage cancers. These fluid accumulations cause severe symptoms such as abdominal distention, shortness of breath, cachexia, anorexia, and fatigue. Malignant PE and ascites have consistently been shown to indicate a poor prognosis in advanced-stage cancer patients, being associated with high morbidity and mortality. The efficacy of this treatment is variable and does not prolong the survival of cancer patients. Clearly, a more effective therapy for malignant PE and ascites is needed. Vascular permeability factor (VPF) from malignant ascites and PE have been hypothesized to be responsible for the fluid accumulations. In addition, malignant PE and ascites contain high levels of biologically active VEGF. VEGF was discovered as a potent angiogenesis stimulator and recognized to be VPF. Increased amounts of COX-2 have been detected in epithelial and stromal cells and COX-2 in mammary tissue is sufficient to induce cancer. It is suggested that COX-2 stimulates angiogenesis. A combination of molecular target inhibitors (thalidomide and celecoxib) and standard cytotoxic drugs appear to increase efficacy of each drug, decrease the side effects of cytotoxic drugs and prolong life.

Adenocarcinoma↗
PubMedDate not supplied

[Interest of color Doppler ultrasonography to evaluate a new anti-angiogenic treatment with thalidomide in metastatic renal cell carcinoma].

PURPOSE: To assess the effectiveness of Doppler Ultrasonography (DUS) in evaluating the anti-angiogenic effect of thalidomide. MATERIALS AND METHODS: [corrected] Forty patients with metastases of cancer of the kidney were included in a phase II therapeutic trial. Twenty eight had tumor targets which could be evaluated by DUS. Before treatment, the volume was studied in 59 tumors and the vascularity in 54 tumors. During treatment, comparative DUS examinations were performed every 6 weeks. RESULTS: Before treatment, the mean tumor volume was 41 cm3, more than 10 vessels were visible in 57% of them. A correlation was noted between the size of the tumors and the degree of vascularity. A stabilisation of tumor volume correlated with a decrease in the number of vessels and an increase in vascularity preceding an increase in tumor volume were also observed. CONCLUSION: DUS is effective in assessing tumour size and vascularity.

Angiogenesis Inhibitors↗
PubMed2005

The influence of thalidomide therapy on cytokine secretion, immunophenotype, BCL-2 expression and microvessel density in patients with resistant or relapsed multiple myeloma.

Thalidomide (THAL) is currently used as a novel drug in patients with chemotherapy resistant or relapsed multiple myeloma. THAL antitumor activity seems to be very complex, however the precise mechanisms of its action are still not fully understood. The aim of this study was to assess some of possible mechanisms of THAL action both in in vivo analysis of immune cells phenotype and in in vitro cultures with THAL. The study involved 30 patients with relapsed or chemotherapy refractory multiple myeloma who were qualified to THAL treatment. We assessed immunophenotype of malignant plasma cells and T lymphocytes in both peripheral blood (PB) and bone marrow (BM) samples taken before and after 4 and 8 weeks of THAL treatment. Before therapy cytokine secretion (VEGF, HGF, bFGF, TNF, IL-6 an sIL-6R) and Bcl-2 expression in PB and BM cell cultures with THAL were analyzed. We used flow cytometry technique and ELISA method. The clinical response to therapy was assessed after 4 and 8 weeks of treatment. We also investigated microvessel density (MVD) in bone marrow samples before the THAL treatment and after 6 months of therapy in the group of responding patients. In cell cultures with THAL we detected statistically significant lowering of analyzed cytokines concentration and the decrease in Bcl-2 expression by malignant plasma cells in BM and CD8(+) T lymphocytes in BM and PB. In the group of patients responding to therapy we observed the decrease in the number of myeloma cells and significant increase of CD4(+) and CD8(+) cells in both PB and BM samples. There was statistically significant increase of CD3(+)/CD69(+) cells in the course of therapy, while the percentage of CD3+/HLA-DR(+) cells was significantly lower after 8 weeks of therapy. We also detected lowering of MVD after THAL therapy in responders group. The obtained results demonstrate that THAL efficacy in MM is multidirected and included such mechanisms like down-regulation of proangiogenic cytokines, that could lead to lowering of MVD, induction of apoptosis and influence on malignant cells and T lymphocytes immunophenotype.

Administration, Oral↗
PubMed2005

[A case report of chemotherapy with thalidomide, celecoxib and gemcitabine in the treatment of patients with brain metastases from lung cancer].

Chemotherapy for the treatment of brain metastases arising from non-small cell lung cancer (NSCLC) has been limited by poor efficacy and high toxicity. Especially in heavily pretreated patients with brain metastases, further chemotherapy is known to be extraordinarily difficult. Expression of vascular endothelial growth factor is necessary but not sufficient for production and growth of brain metastasis. Most current preclinical experiments evaluate antiangiogenic drugs used singly or in combination with other antiangiogenic drugs and/ or cytotoxic drugs. Cerebral edema is responsible for significant morbidity and mortality in patients harboring malignant gliomas. In preclinical experiments, cyclooxygenase (COX) -2 plays an important role in the formation of brain edema. Glioma-infiltrating microglia are a major source of PGE2 production through the COX-2 pathway and support the use of COX-2 inhibitors as possible alternatives to glucocorticoids in the treatment of peritumoral edema in patients with malignant brain tumors. Here we report a case of lung cancer patient with brain metastases who had been treated with chemotherapy and whole-brain radiation therapy (WBRT). He was treated with thalidomide, celceoxib and gemcitabine, after which brain metastases have almost completely disappeared. He tolerated extremely well. This combination may play an important role for patients with NSCLC and brain metastases.

Adult↗
PubMed2006

Combination treatment with temozolomide and thalidomide inhibits tumor growth and angiogenesis in an orthotopic glioma model.

The chemotherapeutic agent temozolomide (TMZ) and the anti-angiogenic agent thalidomide (THD) have both demonstrated anti-tumor activity in patients with recurrent malignant glioma. Combination treatment with TMZ and THD in patients with glioblastoma multiforme (GBM) appears to be more effective than treatment with either drug alone. To investigate the mechanism of this anti-tumor effect, we examined the combined effects of TMZ and THD in a rat glioma xenograft model. We found that combination treatment markedly inhibited the growth of tumors that were orthotopically implanted into rat brains. Using proliferating cell nuclear antigen (PCNA) staining, we observed a significant decrease in cell proliferation in these tumors. CD31 staining of the microvasculature revealed a significant decrease in angiogenesis. We also found increased apoptosis in treated tumors by terminal deoxynucleotidyl-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay. We further demonstrated that the expression of angiogenic factors, such as vascular endothelial cell growth factor (VEGF) and basic fibroblastic growth factor (bFGF), were inhibited by THD. THD also decreased the number of ED1-positive, activated macrophages or microglial cells, which produce pro-angiogenic molecules around the glioma. Taken together, these results suggest that combination treatment with TMZ and THD inhibits tumor growth via the induction of apoptosis and the inhibition of angiogenesis in a rat model and may be a promising therapy for malignant gliomas.

Angiogenesis Inhibitors↗