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"A piperidinyl isoindole originally introduced as a non-barbiturate hypnotic, but withdrawn from the market due to teratogenic effects. It has been reintroduced and used for a number of immunological and inflammatory disorders. Thalidomide displays immunosuppresive and anti-angiogenic activity. It inhibits release of TUMOR NECROSIS FACTOR-ALPHA from monocytes, and modulates other cytokine action." (MeSH 2013)

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Web Resources: Thalidomide
Latest Research Publications

Web Resources: Thalidomide (6 links)

Latest Research Publications

Kahn JS, Casseres RG, Her MJ, et al.
Treatment of Psoriasis With Biologics and Apremilast in Patients With a History of Malignancy: A Retrospective Chart Review
J Drugs Dermatol. 2019; 18(4) [PubMed] Related Publications
Introduction: Biologics have transformed the management of moderate-to-severe psoriasis. The risk of developing a malignancy during treatment is an important consideration, and many studies have been conducted to determine the magnitude of this risk. However, there is little research on the use of biologic treatment in psoriasis patients with a history of established malignancy. Methods: We preformed a retrospective chart review of patients with psoriasis and a history of malignancy that were treated with biologics or apremilast. A list was created containing the 690 patients with psoriasis who were treated in our clinic with biologics or apremilast between January 1st, 2012 and May 31, 2018. The charts were examined, and 16 patients were found to have a history of malignancy excluding non-melanoma skin cancer. Results: Sixteen patients met criteria to be included in this review. The average time from cancer diagnosis to initiation of biologics or apremilast was 4.7 years, and 9 patients (56%) started treatment within five years. Three patients (19%) received concurrent cancer therapy during biologic treatment. None of the 16 patients had recurrence or progression of their cancer noted clinically or radiographically during biologic or apremilast treatment. Most patients had improvement of their psoriasis. Discussion: The data reviewed here show successful treatment on biologics despite concurrent malignancy, though confirmatory research is needed. J Drugs Dermatol. 2019;18(4):387-390.

DE Campos CB, Lavalle GE, Monteiro LN, et al.
Adjuvant Thalidomide and Metronomic Chemotherapy for the Treatment of Canine Malignant Mammary Gland Neoplasms.
In Vivo. 2018 Nov-Dec; 32(6):1659-1666 [PubMed] Free Access to Full Article Related Publications
BACKGROUND/AIM: The aim of the present study was to evaluate a multimodal approach for the treatment of canine malignant mammary gland neoplasms, including surgery, chemotherapy, thalidomide, and metronomic chemotherapy (MC).
MATERIALS AND METHODS: Fifty-eight female dogs were submitted to four different treatments: surgery; surgery with chemotherapy; surgery with chemotherapy and thalidomide; and surgery with chemotherapy and metronomic chemotherapy and overall survival was evaluated.
RESULTS: No statistical difference was found in the proliferative index and microvessel density of primary neoplasms and distant metastases following thalidomide treatment. Diffuse intense inflammatory infiltrate was predominant in primary tumors and diffuse moderate inflammatory infiltrate in metastatic lesions. No statistically significant difference was observed in median survival time (MST) between treatment groups when including all clinical stages (p=0.3177). However, animals diagnosed with distant metastasis treated with surgery and chemotherapy associated with thalidomide or MC presented longer MST when compared to animals treated only with surgery or surgery and chemotherapy (p<0.0001).
CONCLUSION: The proposed multimodal therapy protocols including antiangiogenic and immunomodulatory therapies demonstrated a clinical benefit for patients in advanced clinical stages.

Tun HW, Johnston PB, DeAngelis LM, et al.
Phase 1 study of pomalidomide and dexamethasone for relapsed/refractory primary CNS or vitreoretinal lymphoma.
Blood. 2018; 132(21):2240-2248 [PubMed] Free Access to Full Article Related Publications
The combination of pomalidomide (POM) and dexamethasone (DEX) was evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL) and primary vitreoretinal lymphoma (PVRL) to determine the maximal tolerated dose (MTD) of POM as the primary objective, and overall response rate (ORR), progression-free survival (PFS), and safety profile as secondary objectives. A cohorts-of-3 study design was used with a dose-escalation schedule consisting of POM (3, 5, 7, or 10 mg) orally daily for 21 days every 28 days and DEX 40 mg orally every week. After 2 cycles, POM was continued alone until disease progression, intolerance, or subject withdrawal. Following MTD determination, the MTD cohort was expanded. Twenty-five of 29 patients with the median of 3 prior treatments were eligible for assessment as per international PCNSL collaborative group criteria. The MTD of POM was 5 mg daily for 21 days every 28 days. Whole-study ORR was 48% (12 of 25; 95% confidence interval [CI], 27.8%, 68.7%) with 6 complete response (CR), 2 complete response, unconfirmed (CRu), and 4 partial response (PR). MTD cohort ORR was 50% (8 of 16; 95% CI, 24.7%, 75.4%) with 5 CR, 1 CRu, and 2 PR. Median PFS was 5.3 months (whole study) and 9 months (for responders). One patient had pseudoprogression. Grade 3/4 hematologic toxicities included neutropenia (21%), anemia (8%), and thrombocytopenia (8%). Grade 3/4 nonhematologic toxicities included lung infection (12%), sepsis (4%), fatigue (8%), syncope (4%), dyspnea (4%), hypoxia (4%), respiratory failure (8%), and rash (4%). POM/DEX treatment is feasible with significant therapeutic activity against relapsed/refractory PCNSL and PVRL. This trial was registered at www.clinicaltrials.gov as #NCT01722305.

Yang W, Wang D, Huang L, et al.
Thalidomide Combined with Transcatheter Arterial Chemoembolization (TACE) for Intermediate or Advanced Hepatocellular Carcinoma: A Systematic Review and GRADE Approach
Asian Pac J Cancer Prev. 2018; 19(8):2043-2055 [PubMed] Free Access to Full Article Related Publications
Objective:According to current guidelines, there is no clear second-line treatment for advanced liver cancer. In practice, clinicians have attempted to use thalidomide(TLD) combined with transcatheter arterial chemoembolization (TACE) for treating liver cancer. This study aims to assess the clinical efficacy and safety of TLD combined with TACE in patients with intermediate or advanced hepatocellular carcinoma. Methods: Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), database of ClinicalTrials.gov, CBM, CNKI, VIP and Wanfang database were searched for eligible studies. Criteria for inclusion in our meta-analysis included a study that patients diagnosed with intermediate or advanced HCC, the use of TACE plus TLD or its derivatives, and the availability of outcome data for survival. A meta-analysis was conducted to summarize the evidences of randomized controlled trials (RCTs). And finally, the GRADE approach was used to assess the quality of these evidences. Results: Twelve RCTs involving 894 Hepatocellular Carcinoma (HCC) patients were included. The meta-analysis results showed that TACE plus TLD was significantly superior than TACE alone in terms of 12-month survival rate (OR=2.55, 95% CI:1.78-3.64, P<0.01), 24-month survival rate (OR=2.95, 95% CI:1.96-4.44, P<0.01), 36-month survival rate (OR=2.95, 95% CI:1.41-6.19, P<0.004), progression-free survival (PFS) (MD=2.23, 95% CI:1.19-3.28 , P<0.001), objective response rate (OR=1.84, 95% CI:1.34-2.52, P<0.0001), and disease control rate (OR=2.68, 95% CI:1.80-3.99). Subgroup analysis demonstrated no differences across related outcomes. Sensitivity analyses showed no important differences in the estimates of effects. Quality of evidence for all outcomes was rated moderate to very low after applying GRADE approach. Conclusions: Current evidence seemed to support the suggestion that TACE plus TLD as the second line treatment for patients with intermediate or advanced HCC. However, this finding is not definitive due to the poor quality of included studies, more carefully designed and conducted RCTs are warranted to confirm above conclusions.

King L, Tsilioni I, Theoharides TC
Time to look past TNF and thalidomide for cachexia - could mast cells and flavonoids be the answer?
J Biol Regul Homeost Agents. 2018 May-Jun; 32(3):443-447 [PubMed] Related Publications
Cachexia is a wasting condition associated with late stages of many chronic illnesses and may be present in up to 80% of patients with advanced cancers. Cachexia is a metabolic derangement resulting in a disturbance to the homeostasis of muscle breakdown and synthesis, favoring catabolism and muscle loss. Despite making strides in treating cancer itself, there have been no major advances in the treatment of cachexia pharmacologically or nutritionally. Clinical trials using anti-TNF biologics and thalidomide have largely failed. A new approach may be to focus on other possible waste-inducing mediators, possibly derived from mast cells, and the beneficial action of select natural flavonoids.

Charlinski G, Grzasko N, Jurczyszyn A, et al.
The efficacy and safety of pomalidomide in relapsed/refractory multiple myeloma in a "real-world" study: Polish Myeloma Group experience.
Eur J Haematol. 2018; 101(3):354-361 [PubMed] Related Publications
BACKGROUND: Patients with relapsed/refractory multiple myeloma (RRMM) have poor prognosis. Pomalidomide is an immunomodulatory compound that has demonstrated activity in MM patients with disease refractory to lenalidomide and bortezomib.
OBJECTIVES: Participants of clinical trials are highly selected populations; therefore, the aim of this study was to present observations from real practice that might provide important information for practitioners.
PATIENTS AND METHODS: We analyzed retrospectively 50 patients treated with pomalidomide in 12 Polish sites between 2014 and 2017. Median age was 63 years, median time since diagnosis 4.5 years and median number of prior regimens 4.
RESULTS: The overall response rate was 39.1%. Median progression-free survival (PFS) and overall survival (OS) were 10.0 and 14.0 months, respectively. Previous treatment with immunomodulatory drugs, bortezomib or stem cell transplant had no impact on PFS and OS. Most frequent grade 3/4 treatment-emergent adverse events were hematologic (neutropenia 24.0%, thrombocytopenia 10.0%, anemia 8.0%). Most common grade 3/4 non-hematologic toxicities were respiratory tract infection (14.0%) and neuropathy (4.0%).
CONCLUSIONS: This real-world data have confirmed that pomalidomide is an active drug in RRMM and support results of published clinical trials and other real-world studies.

Sun X, Xu Y, Wang Y, et al.
Synergistic Inhibition of Thalidomide and Icotinib on Human Non-Small Cell Lung Carcinomas Through ERK and AKT Signaling.
Med Sci Monit. 2018; 24:3193-3203 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been widely used in the treatment of non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations. However, the survival of patients with EGFR-TKI administration is limited by the inevitable development of acquired drug resistance. Recently, multi-targeted drugs combination has been shown to be a promising strategy to improve the efficacy of EGFR-TKI treatment and enable the reduction of drug resistance in NSCLC. MATERIAL AND METHODS Humanized NSCLC cell lines PC9 and A549 were co-cultured with thalidomide and/or icotinib to test for anti-tumor efficiency. Cell proliferation was measured by MTT assay, cell apoptosis by flow cytometry and cell migration by wound healing assay. Western blot was performed to determine the expression of caspase-3, -8, -9, Bax, EGFR, VEGF-R, AKT, ERK, MMP2, MMP9, and NF-κB. The xenograft mouse model was used to explore the effects of thalidomide and icotinib in vivo. Immunohistochemical testing was used to determine the expression of Ki-67 and TUNEL staining in tumor tissues. RESULTS Treatments of thalidomide and/or icotinib reduced cell viability, induced apoptosis, and suppressed migration. Attenuation of pEGFR and pVEGF-R resulted in deactivation of ERK and AKT pathways, which eventually increased the anti-proliferative response. In PC9 xenograft model, combined administration of thalidomide and icotinib restrained tumor growth with remarkable reduced Ki-67 index and increased TUNEL positive cells. CONCLUSIONS Thalidomide sensitizes icotinib to increase apoptosis and prevent migration, and it may be a potentially promising anti-tumor drug in lung cancer multi-modality therapy.

Chen LX, Ni XL, Zhang H, et al.
Preparation, characterization, in vitro and in vivo anti-tumor effect of thalidomide nanoparticles on lung cancer.
Int J Nanomedicine. 2018; 13:2463-2476 [PubMed] Free Access to Full Article Related Publications
Introduction: Thalidomide (THA) is an angiogenesis inhibitor and an efficient inhibitor of the tumor necrosis factor-α (TNF-α). However, the clinical application of THA has been limited due to hydrophobicity of the compound.
Materials and methods: To increase the water solubility of THA and in order to evaluate the anticancer abilities of this material on human lung carcinoma, methoxy poly(ethylene glycol)-poly(ε-caprolactone) nanoparticles loaded with THA (THA-NPs) were prepared. The synthesis of THA-NPs was carried out via a dialysis method with relative satisfactory encapsulation efficiency, loading capacity, size distribution, and zeta potential.
Results: A cytotoxicity assay demonstrated that THA-NPs inhibited the growth of cells in a dose-dependent manner. The evaluation of anti-tumor activity in vivo showed that THA-NPs could inhibit tumor growth and prolong the survival rate of tumor-bearing mice. Immunohistochemical analysis indicated that THA-NPs inhibited cell proliferation (Ki-67 positive rate, 32.8%±4.2%,
Conclusion: In general, the drug delivery system reported herein may shed light on future targeted therapy in lung cancer treatment.

Xie M, Chen X, Qin S, et al.
Clinical study on thalidomide combined with cinobufagin to treat lung cancer cachexia.
J Cancer Res Ther. 2018; 14(1):226-232 [PubMed] Related Publications
Objective: To discuss and assess the clinical value of treating lung cancer cachexia with thalidomide combined with cinobufagin.s.
Methods: A cohort of 54 patients, who were diagnosed with lung carcinoma, was randomly divided into two groups, a trial group and a control group, respectively. The trial group was given 150 mg/day thalidomide and 2700 mg/day cinobufagin; the control group only received 2,700 mg/day cinobufagin. The therapy lasted for 12 weeks, and the nutritional status, quality of life, survival, and side effects in patients in the two groups were recorded.
Results: The nutritional status, quality of life, and survival of patients with lung cancer cachexia in the trial group were significantly improved compared to the control group. The trial group received 150 mg thalidomide, which by contrast reduced the incidence of side effect and increased tolerance.
Conclusion: Using thalidomide combined with cinobufagin to treat patients with lung cancer cachexia will significantly improve their nutritional status and quality of life. This therapy is better than that using cinobufagin alone and is well tolerated.

Ao M, Xiao X, Ao Y
Low density lipoprotein modified silica nanoparticles loaded with docetaxel and thalidomide for effective chemotherapy of liver cancer.
Braz J Med Biol Res. 2018; 51(3):1-10 [PubMed] Free Access to Full Article Related Publications
In the present study, we successfully developed a docetaxel (DTX) and thalidomide (TDD) co-delivery system based on low density lipoprotein (LDL) modified silica nanoparticles (LDL/SLN/DTX/TDD). By employing the tumor homing property of LDL and the drug-loading capability of silica nanoparticles, the prepared LDL/SLN/DTX/TDD was expected to locate and specifically deliver the loaded drugs (DTX and TDD) to achieve effective chemotherapy of liver cancer. In vitro analysis revealed that nano-sized LDL/SLN/DTX/TDD with decent drug loading capabilities was able to increase the delivery efficiency by targeting the low density lipoprotein receptors, which were overexpressed on HepG2 human hepatocellular liver carcinoma cell line, which exerted better cytotoxicity than unmodified silica nanoparticles and free drugs. In vivo imaging and anti-cancer assays also confirmed the preferable tumor-homing and synergetic anti-cancer effects of LDL/SLN/DTX/TDD.

Li Q, Liu Y, Yu Y
Antiangiogenic therapy for primitive neuroectodermal tumor with thalidomide: A case report and review of literature.
Medicine (Baltimore). 2017; 96(51):e9272 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Peripheral primitive neuroectodermal tumor (PNET) is a kind of small round cell tumor derived from primitive neuroectodermal tumor.
PATIENT CONCERNS: PNET is a highly malignant tumor that is subordinated to Ewing sarcoma. It occurs predominantly in soft tissue and bone and rarely in the bronchi and lung. Traditional surgery, radiotherapy, and chemotherapy are used for the treatment of PNET, but are usually ineffective.
DIAGNOSES: There was a rare case of a 17 year-old man diagnoses with primary pulmonary PNET.
INTERVENTIONS: The patient was treated by the remedy treatment with thalidomide after the poor effect of conventional radiotherapy and chemotherapy.
OUTCOMES: The patient survived without disease progression for 15 months and was in stable condition.
LESSONS: Thalidomide provides a choice for maintenance therapy in PNET.

Scharenberg C, Jansson M, Saft L, Hellström-Lindberg E
Megakaryocytes harbour the del(5q) abnormality despite complete clinical and cytogenetic remission induced by lenalidomide treatment.
Br J Haematol. 2018; 180(4):526-533 [PubMed] Related Publications
The mechanisms underlying lenalidomide-resistance of del(5q) MDS stem cells remain to be elucidated and may include cell-intrinsic as well as microenvironmental causes. Abnormal hypolobated megakaryocytes constitute one of the hallmarks of del(5q) MDS. We hypothesized that these cells have potential implications for the regulation of haematopoietic stem cells (HSC) similarly to what has recently been described for megakaryocytes in the murine system. Therefore, we conducted a study to determine the response of abnormal hypolobated megakaryocytes to lenalidomide therapy. We studied lenalidomide-treated patients in the MDS-004 trial as well as a cohort seen at our institution. Morphological evaluation at time of complete cytogenetic remission (CCyR) demonstrated the persistence of hypolobated megakaryocytes in all evaluable patients (n = 9). Furthermore, we provide evidence that the abnormal hypolobated morphology is restricted to del(5q) megakaryocytes, both at diagnosis and during CCyR. Using fluorescence in situ hybridisation analysis on flow-sorted stem- and progenitor populations, we observed a similar degree of clonal involvement in megakaryocyte-erythroid-progenitors as in HSC. Taken together, our findings suggest that megakaryocyte morphology might aid in the evaluation of patients where discontinuation of lenalidomide is considered and offers interesting hypotheses for further investigation of lenalidomide resistance.

Fracchiolla NS, Iurlo A, Ferla V, et al.
Concomitant Occurrence of Blastic Plasmacytoid Dendritic Cell Neoplasm and Acute Myeloid Leukaemia after Lenalidomide Treatment for.
Clin Lab. 2017; 63(9):1513-1517 [PubMed] Related Publications
BACKGROUND: Myelodysplastic syndromes with chromosome 5 long arm deletion (5q-mds) may benefit from lenalidomide treatment. However, unresponsive patients have a high risk for clonal evolution and progression to acute myeloid leukemia. Case: We describe a 5q-patient treated with lenalidomide, who concomitantly developed acute myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm, a rare and highly aggressive lymphoma.
CONCLUSIONS: Evolution of 5q- syndrome to acute myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm may have occurred through various mechanisms, including persistence of neoplastic lenalidomide-resistant stem cells and selection of a more aggressive clone via lenalidomide augmentation of the ARPC1B gene, or because of lenalidomide stimulation on dendritic cells. Further studies are needed to clarify lenalidomide oncogenic potential.

Zhang L, Qu X, Teng Y, et al.
Efficacy of Thalidomide in Preventing Delayed Nausea and Vomiting Induced by Highly Emetogenic Chemotherapy: A Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase III Trial (CLOG1302 study).
J Clin Oncol. 2017; 35(31):3558-3565 [PubMed] Related Publications
Purpose We examined the efficacy and safety of thalidomide (THD) for the prevention of delayed nausea and vomiting in patients who received highly emetogenic chemotherapy (HEC). Patients and Methods In a randomized, double-blind, active-controlled, phase III trial, chemotherapy-naive patients with cancer who were scheduled to receive HEC that contained cisplatin or cyclophosphamide-doxorubicin/epirubincin ≥ 50 mg/m

Shao YY, Chen BB, Ou DL, et al.
Lenalidomide as second-line therapy for advanced hepatocellular carcinoma: exploration of biomarkers for treatment efficacy.
Aliment Pharmacol Ther. 2017; 46(8):722-730 [PubMed] Related Publications
BACKGROUND: Lenalidomide has immunomodulatory and anti-angiogenic effects and showed moderate anti-tumour efficacy in patients with. advanced hepatocellular carcinoma (HCC) AIM: To explore potential biomarkers of lenalidomide efficacy as second-line therapy for HCC.
METHODS: Eligible patients were diagnosed with advanced HCC, documented progression on sorafenib, and Child-Pugh class A liver function. Patients received 25 mg/day lenalidomide orally on days 1-21 every 4 weeks. The primary endpoint was 6 month progression-free survival rate. Early α-fetoprotein response was defined as a > 20% decline of α-fetoprotein levels from baseline within the first 4 weeks of treatment. Vascular response, evaluated using dynamic contrast-enhanced magnetic resonance imaging, was defined as a > 40% decline in K
RESULTS: Fifty-five patients were enrolled. The response rate was 13%, and the disease-control rate was 53%. The 6 month progression-free survival rate was 9.1%. The median progression-free and overall survival was 1.8 months and 8.9 months respectively. Early α-fetoprotein response was significantly associated with higher disease-control rate (76% vs 22%, P = .001) and longer progression-free survival (P = .020). Vascular response was not associated with any treatment outcomes. Patients with a high pre-treatment B cell percentage were more likely to have disease control (70% vs 36%, P = .010) and exhibited longer progression-free survival (P < .001) and overall survival (P = .042).
CONCLUSIONS: Lenalidomide exhibited moderate activity as second-line therapy for advanced HCC. Its immunomodulatory effects should be further explored (www.clinicaltrials.gov NCT01545804).

Nishi K, Luo H, Ishikura S, et al.
Apremilast Induces Apoptosis of Human Colorectal Cancer Cells with Mutant
Anticancer Res. 2017; 37(7):3833-3839 [PubMed] Related Publications
BACKGROUND/AIM: We previously reported the crucial roles of oncogenic Kirsten rat sarcoma viral oncogene homologue (KRAS) in inhibiting apoptosis and disrupting cell polarity via the regulation of phosphodiesterase type 4B2 (PDE4B2) expression in human colorectal cancer (CRC) HCT116 cells in a three-dimensional culture (3DC). Here, we evaluated the effects of apremilast, a selective PDE4 inhibitor, on luminal apoptosis in 3DC and nude mice assay using HKe3 human CRC cells stably expressing wild-type (wt)PDE4B2 (HKe3-wtPDE4B2), mutant (mt)PDE4B2 (kinase dead) (HKe3-wtKRAS), wtKRAS (HKe3-wtKRAS) and mtKRAS (HKe3-mtKRAS).
MATERIALS AND METHODS: Apoptosis was detected by immunofluorescence using confocal laser scanning microscopy or western blot in HKe3-wtPDE4B2, HKe3-mtPDE4B2, HKe3-wtKRAS and mtKRAS cells treated with or without apremilast in 3DC. Tumourigenicity was assessed in nude mice assay using these cells.
RESULTS: Apremilast did not inhibit the proliferation of HKe3-wtPDE4B2 cells or HKe3-mtKRAS in two-dimensional cultures, whereas the number of apoptotic HKe3-wtPDE4B2 cells and HKe3-mtKRAS cells increased after apremilast treatment in 3DC, leading to formation of a luminal cavity. Tumour growth in nude mice was dramatically reduced by intraperitoneal injection of apremilast. Notably, a decreased level of caspase-1 expression was observed in HKe3-wtPDE4B2 and HKe3-mtKRAS cells.
CONCLUSION: Apremilast induces tumour regression in nude mice, possibly by inducing caspase-1 expression.

Li Y, Chu Y, Song R, Xu F
Thalidomide combined with chemotherapy in treating elderly patients with advanced gastric cancer.
Aging Clin Exp Res. 2018; 30(5):499-505 [PubMed] Related Publications
AIM: The current systemic chemotherapy brings toxicity to human body, which elder patients suffer more than young people. The effective and well-tolerated treatment methods are of great importance for elderly advanced GC patients. This paper proposed an effective way of combining thalidomide with chemotherapy to treat elderly advanced GC patients, on the purpose of improving life quality and the treatment efficacy.
METHODS: In the control group, capecitabine was given with 2000 mg/m
RESULTS: No significant differences were observed in the major prognostic factors among 64 eligible patients between the study and control groups. The ORRs and DCRs of the treatment and control groups showed no significant difference (P > 0.05). PFS of the study and control groups were 5.3 months (95% CI 4.5-6.2) and 4.2 months (95% CI 3.4-5.1), respectively. PFS exhibited a significant difference between the two group (P = 0.03), while the overall survivals of the patients between the two groups (10.4 months vs. 9.7 months) resulted as statistically non-significant (P = 0.47). Adverse effects were minimal in the study group, only a few patients suffered the grade 3 toxicity. The rate of drowsiness, fatigue, constipation of the study group was higher than that of the control group, and the rate of anorexia was lower (P < 0.05).
CONCLUSIONS: Our results demonstrated that thalidomide combined with capecitabine was mildly effective and safe for treating elderly patients with advanced GC.

Wang X, Wu L, Shi X, et al.
Extramammary Paget's disease of the oral mucosa and perioral skin.
Oral Surg Oral Med Oral Pathol Oral Radiol. 2017; 124(2):e157-e163 [PubMed] Related Publications
Extramammary Paget's disease (EMPD) is an unusual intraepidermal adenocarcinoma. Only 2 cases of EMPD in the oral mucosa have been reported previously. Here, we present the first report of a rare case of Paget's disease of the oral mucosa and perioral skin with extensive contiguous erythematous and erosive manifestations. Ultimately, the patient was treated with oral thalidomide for 8 weeks. We noticed an improvement with resolution of symptoms. A 3-year follow-up showed no relapse. Thus, this case may provide new insights to clinicians about treatment of EMPD. More importantly, we advise that dentists be vigilant about the possibility of some clinically significant conditions in patients with extensive nonspecific clinical lesions mimicking inflammatory or infectious diseases in the oral and maxillofacial regions, especially lesions that are refractory to long-term treatment. Requesting consultations with relevant clinical departments promptly and obtaining histopathologic confirmation at an early stage are crucial for early therapy and a better prognosis.

Borhani K, Bamdad T, Hashempour T
Lenalidomide acts as an adjuvant for HCV DNA vaccine.
Int Immunopharmacol. 2017; 48:231-240 [PubMed] Related Publications
Hepatitis C virus (HCV) is a blood-borne pathogen which has chronically infected people worldwide. Therefore, it is of utmost importance to design prophylactic and therapeutic vaccine in order to control HCV infection. To date, several researchers have attempted to improve the efficiency of HCV vaccine by using different adjuvants. However, a few studies have focused on the synthetic immunomodulatory drugs as adjuvants for HCV vaccine. Recently, researchers have shown that lenalidomide, which is used to treat the patients with multiple myeloma, is capable of improving the immune system factors. In this paper, two doses of lenalidomide along with pcDNA3.1+NS3 as HCV DNA vaccine were administrated in mice models and the percentage of regulatory T cells (Treg cells) and the cells with PD-1+ expression in spleen of mice model were investigated by flow cytometry method. Additionally, activities of CTL cells and NK cells were evaluated in spleen of prophylactic and therapeutic mice models via LDH method. Results of the Treg and PD-1 analysis showed that low dose of lenalidomide along with pcDNA3.1+NS3 can noticeably decrease the percentage of Treg cells and the cells with PD-1+ expression, while lenalidomide can significantly increase the CTL and NK activity in mice models. Also, results of the therapeutic mice model, in which SP2/0 cells- challenged mice were treated with 5mg/kg lenalidomide in combination with pcDNA3.1+NS3, reasonably agreed with those of the prophylactic model. Finally, it was found that lenalidomide can reduce the level of Treg cells which results in lower the cells with PD-1+ expression and subsequently higher CTL and NK cell activities. This study concluded that lenalidomide possess the characteristics of an ideal adjuvant candidate for use in combination with HCV DNA vaccine in order to promote the immune response and vaccine efficiency.

Bagot M, Hasan B, Whittaker S, et al.
A phase III study of lenalidomide maintenance after debulking therapy in patients with advanced cutaneous T-cell lymphoma - EORTC 21081 (NCT01098656): results and lessons learned for future trial designs.
Eur J Dermatol. 2017; 27(3):286-294 [PubMed] Related Publications
EORTC 21081 was a randomized phase III study of observation alone versus lenalidomide maintenance (25 mg po for 21 days) after debulking therapy in patients with advanced-stage cutaneous T-cell lymphomas (CTCLs). The aim was to investigate whether maintenance treatment with lenalidomide prolonged response after debulking in patients who had not been previously treated with intravenous chemotherapy. A total of 26 centres from 10 different European countries registered 30 patients with advanced CTCL. Twenty-one patients were randomized (20% of the 105 patients initially deemed necessary for the study; the study was terminated early following withdrawal of funding support from Celgene). Of 30 registered patients, nine failed to be randomized, 12 were randomized to observation alone, and nine to lenalidomide maintenance. Median progression-free survival was 5.3 months (95% CI: 1.87-22.54) in the maintenance lenalidomide group and two months (95% CI: 0.92-7.82) in the observation alone group. Although statistical comparison in the study was severely underpowered and would not be meaningful, this study provides useful information, revealing rapid disease progression within four weeks in a third of patients, highlighting the need for maintenance therapy.

Crowley J, Thaçi D, Joly P, et al.
Long-term safety and tolerability of apremilast in patients with psoriasis: Pooled safety analysis for ≥156 weeks from 2 phase 3, randomized, controlled trials (ESTEEM 1 and 2).
J Am Acad Dermatol. 2017; 77(2):310-317.e1 [PubMed] Related Publications
BACKGROUND: Randomized, controlled trials demonstrated efficacy and safety of apremilast for moderate-to-severe plaque psoriasis and psoriatic arthritis.
OBJECTIVE: Assess long-term safety of oral apremilast in psoriasis patients.
METHODS: Safety findings are reported for 0 to ≥156 weeks from the Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis (ESTEEM) 1 and 2.
RESULTS: The 0 to ≥156-week apremilast-exposure period included 1184 patients treated twice daily with apremilast 30 mg (1902.2 patient-years). During 0 to ≤52 weeks, the adverse events (AEs) that occurred in ≥5% of patients included diarrhea, nausea, upper respiratory tract infection, nasopharyngitis, tension headache, and headache. From 0 to ≥156 weeks, no new AEs (affecting ≥5% of the population) were reported. AEs, serious AEs, and study drug discontinuations caused by AEs did not increase with long-term exposure. During the 0 to ≥156-week period, the rates of major cardiac events (exposure-adjusted incidence rate [EAIR] 0.5/100 patient-years), malignancies (EAIR 1.2/100 patient-years), depression (EAIR 1.8/100 patient-years), or suicide attempts (EAIR 0.1/100 patient-years) did not increase in comparison with the rates found during the 0 to ≤52-week period. No serious opportunistic infections, reactivation of tuberculosis, or clinically meaningful effects on laboratory measurements were reported.
LIMITATIONS: This study had a high dropout rate (21% of patients ongoing >156 weeks); most were unrelated to safety concerns.
CONCLUSIONS: Apremilast demonstrated an acceptable safety profile and was generally well tolerated for ≥156 weeks.

Cao DD, Xu HL, Liu L, et al.
Thalidomide combined with transcatheter artierial chemoembolzation for primary hepatocellular carcinoma: a systematic review and meta-analysis.
Oncotarget. 2017; 8(27):44976-44993 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Transcatheter arterial chemoembolization (TACE) and thalidomide have been used for treating primary hepatocellular carcinoma(HCC). This study aims to evaluate the clinical efficacy and safety of thalidomide and TACE in primary HCC.
METHODS: Randomized controlled trials(RCTs) about efficacy and safety of thalidomide combined with TACE for primary HCC were identified from the Cochrane Library, Pubmed, Embase, CNKI, and Wan Fang until August, 2016. The retrieved trials were reviewed and the data were extracted by two reviewers, independently. Combined analyses of survival rates, overall response rate(ORR), disease control rate(DCR), changes of KPS, parameters of cellular immunity and vascular endothelial growth factor(VEGF), and adverse events were performed using RevMan 5.3 software.
RESULTS: A total of 23 RCTs involving 1836 patients were included. The results showed that thalidomide plus TACE was significantly superior in increasing 6-month survival rate(OR=1.79, 95% CI:1.02-3.15, P=0.04), 1-year survival rate(OR=1.76, 95% CI:1.38-2.24, P<0.0001), 1.5-year survival rate(OR=4.72, 95% CI:2.64-8.43, P<0.001), 2-year survival rate(OR=1.78, 95% CI:1.37-2.30, P<0.001), ORR(OR=1.89, 95% CI:1.48-2.42, P<0.0001), DCR(OR=2.62, 95% CI:1.90-3.63, P<0.001), improvement in cellular immunity(MD=0.63, 95% CI:0.45-0.80, P<0.0001), and reduction of VEGF(MD=-119.71, 95% CI:-135.75-103.68, P<0.0001), when compared with TACE group. The incidences of gastrointestinal reactions, myelosuppression, and liver dysfunction were similar between combination group and TACE group(P>0.05). However, compared to TACE, the combination of thalidomide and TACE had a higher incidence of drug rash(OR=6.35, 95% CI:2.75-14.68, P<0.0001).
CONCLUSION: Our findings suggest that thalidomide combined with TACE shows better clinical efficacy and tolerable adverse events in patients with primary HCC when compared with TACE alone.

Stahl M, Zeidan AM
Lenalidomide use in myelodysplastic syndromes: Insights into the biologic mechanisms and clinical applications.
Cancer. 2017; 123(10):1703-1713 [PubMed] Related Publications
Myelosysplastic syndromes (MDS) include a heterogeneous group of clonal myeloid neoplasms characterized by ineffective hematopoiesis leading to blood cytopenias and a variable risk of progression into acute myeloid leukemia (AML). Although the hypomethylating agent azacitidine prolongs survival among patients with higher risk (HR)-MDS compared with conventional care, no drug has been shown conclusively to prolong survival or delay progression to AML among patients with lower-risk MDS (LR-MDS). Lenalidomide is the drug with the most impressive clinical activity in the subset of anemic LR-MDS patients who harbor a deletion of the long arm of chromosome 5 (5q-), where it leads to high rates of transfusion independence and cytogenetic responses. Furthermore, lenalidomide delays progression to AML and prolongs survival among responders. In this article, we review the recently recognized mechanisms of action of lenalidomide and discuss the most recent clinical data regarding its use in patients with both 5q- MDS as well as non-5q- MDS. Finally, we forecast the future directions to improve the efficacy of lenalidomide in MDS with and without 5q-. Cancer 2017;123:1703-1713. © 2017 American Cancer Society.

Iacopetta D, Carocci A, Sinicropi MS, et al.
Old Drug Scaffold, New Activity: Thalidomide-Correlated Compounds Exert Different Effects on Breast Cancer Cell Growth and Progression.
ChemMedChem. 2017; 12(5):381-389 [PubMed] Related Publications
Thalidomide was first used for relief of morning sickness in pregnant women and then withdrawn from the market because of its dramatic effects on normal fetal development. Over the last decades, it has been used successfully for the treatment of several pathologies, including cancer. Many analogues with improved activity have been synthesized and tested. Herein we report some effects on the growth and progression of MCF-7 and MDA-MB-231 breast cancer cells by a small series of thalidomide-correlated compounds, which are very effective at inducing cancer cell death by triggering TNFα-mediated apoptosis. The most active compounds are able to drastically reduce the migration of breast cancer cells by regulation of the two major proteins involved in epithelial-mesenchymal transition (EMT): vimentin and E-cadherin. Moreover, these compounds diminish the intracellular biosynthesis of vascular endothelial growth factor (VEGF), which is primarily involved in the promotion of angiogenesis, sustaining tumor progression. The multiple features of these compounds that act on various key points of the tumorigenesis process make them good candidates for preclinical studies.

Schmit JM, DeLaune J, Norkin M, Grosbach A
A Case of Plasmablastic Lymphoma Achieving Complete Response and Durable Remission after Lenalidomide-Based Therapy.
Oncol Res Treat. 2017; 40(1-2):46-48 [PubMed] Related Publications
BACKGROUND: Plasmablastic lymphoma (PBL) is an uncommon variant of diffuse large B-cell lymphoma that is characterized by its plasmacytoid features, aggressive tendencies, and frequent association with human immunodeficiency virus (HIV) infection or other immunocompromised states. Multi-agent, intensive chemotherapy regimens are recommended as first-line treatment by the National Comprehensive Cancer Network. However, the toxicity of these regimens is high and prognosis remains poor.
CASE REPORT: We report a patient with HIV-negative PBL who achieved complete response and durable remission using a lenalidomide-based chemotherapy regimen as first-line therapy.
CONCLUSION: Cyclophosphamide, lenalidomide, dexamethasone (CRD) may provide an alternative initial therapeutic option for patients with PBL who cannot tolerate the intensive chemotherapy regimens currently recommended.

Zuo W, Zhu X, Yang J, et al.
Bortezomib combined with lenalidomide as the first-line treatment for the rare synchronous occurrence of multiple myeloma and pulmonary adenocarcinoma: A case report.
Medicine (Baltimore). 2017; 96(1):e5787 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Simultaneous multiple myeloma (MM) and pulmonary adenocarcinoma is a rare occurrence, and thus, treatment is a challenge. This study reports on 1 such case of MM with concurrent lung cancer, where an accurate diagnosis was made and the patient underwent treatment for both cancers.
CASE SUMMARY: A 68-year-old man presented with 2 months of progressive lower back pain. Visualization with magnetic resonance imaging (MRI) revealed multiple collapsed vertebrae from T12 to S3, as well as an altered signal intensity at the T3 vertebra. The patient was diagnosed with MM upon examination. A chest computed tomography (CT) scan revealed a round mass in the left lower lobe of the lungs, and a CT-guided needle biopsy uncovered a moderately differentiated adenocarcinoma. There were no additional notable findings in the left lung using positron emission tomography computed tomography (PET-CT). Therefore, a diagnosis of MM with pulmonary adenocarcinoma was made. Surgery was performed to excise the lung cancer. Bortezomib was used as first-line induction therapy against both tumors and lenalidomide was used for maintenance. The patient went into complete remission. Using this combined chemotherapy, the patient has survived for over 3 years since a diagnosis was made despite relapsing twice after the first year.
CONCLUSION: This report clearly delineates the diagnosis and treatment of a rare case of synchronous MM and pulmonary adenocarcinoma, as well as depicts a potentially positive outcome for the patient. It also overviews some diagnostic and therapeutic implications for clinicians.

Sebastian S, Zhu YX, Braggio E, et al.
Multiple myeloma cells' capacity to decompose H
Blood. 2017; 129(8):991-1007 [PubMed] Free Access to Full Article Related Publications
Lenalidomide is an immunomodulatory drug (IMiDs) with clinical efficacy in multiple myeloma (MM) and other late B-cell neoplasms. Although cereblon (

Han Z, Sun X, Jiang G, Du X
Thalidomide for Control Delayed Vomiting in Cancer Patients Receiving Chemotherapy.
J Coll Physicians Surg Pak. 2016; 26(11):900-903 [PubMed] Related Publications
OBJECTIVE: To explore the efficacy and safety of thalidomide for the treatment of delayed vomiting, induced by chemotherapy in cancer patients.
STUDY DESIGN: Randomized, double-blind controlled study.
PLACE AND DURATION OF STUDY: The Oncology Department of Affiliated Hospital of Xuzhou Medical University, Jiangsu Xuzhou, China, from January 2012 to January 2014.
METHODOLOGY: A total of 78 cancer patients, who had delayed vomiting observed from 24 hours to 1 week after chemotherapy, were included in the study. Patients were divided in a treatment group (40 patients, 51.28%) and a control group (38 patients, 48.71%). The treatment group received thalidomide at an oral dose of 100 mg per night; 50 mg was added daily up to a dose of 200 mg per night, if the curative effect was suboptimal and the medicine was tolerated. Both the treatment and the control groups received a drip of 10 mg azasetron 30 minutes before chemotherapy. The control group only proportions of antiemetic effects and adverse reactions were compared using the c2 test. Antiemetic effects and adverse reactions were assessed from Odds Ratios (OR) with 95% Confidence Intervals(95% CI).
RESULTS: The effective control rate of delayed vomiting in the treatment group was significantly higher than that in the control group (c2=5.174, p=0.023). No significant difference was found between the two groups in other adverse effects of chemotherapy. Karnofsky scores or the overall self-evaluation of the patients (p>0.05).
CONCLUSION: Thalidomide can effectively control the delayed vomiting of cancer patients receiving chemotherapy and the adverse reactions of the agent can be tolerated.

Jones JR, Cairns DA, Gregory WM, et al.
Second malignancies in the context of lenalidomide treatment: an analysis of 2732 myeloma patients enrolled to the Myeloma XI trial.
Blood Cancer J. 2016; 6(12):e506 [PubMed] Free Access to Full Article Related Publications
We have carried out the largest randomised trial to date of newly diagnosed myeloma patients, in which lenalidomide has been used as an induction and maintenance treatment option and here report its impact on second primary malignancy (SPM) incidence and pathology. After review, 104 SPMs were confirmed in 96 of 2732 trial patients. The cumulative incidence of SPM was 0.7% (95% confidence interval (CI) 0.4-1.0%), 2.3% (95% CI 1.6-2.7%) and 3.8% (95% CI 2.9-4.6%) at 1, 2 and 3 years, respectively. Patients receiving maintenance lenalidomide had a significantly higher SPM incidence overall (P=0.011). Age is a risk factor with the highest SPM incidence observed in transplant non-eligible patients aged >74 years receiving lenalidomide maintenance. The 3-year cumulative incidence in this group was 17.3% (95% CI 8.2-26.4%), compared with 6.5% (95% CI 0.2-12.9%) in observation only patients (P=0.049). There was a low overall incidence of haematological SPM (0.5%). The higher SPM incidence in patients receiving lenalidomide maintenance therapy, especially in advanced age, warrants ongoing monitoring although the benefit on survival is likely to outweigh risk.

El-Aarag B, Kasai T, Masuda J, et al.
Anticancer effects of novel thalidomide analogs in A549 cells through inhibition of vascular endothelial growth factor and matrix metalloproteinase-2.
Biomed Pharmacother. 2017; 85:549-555 [PubMed] Related Publications
Lung cancer is one of the major causes of cancer-related mortality worldwide, and non-small-cell lung cancer is the most common form of lung cancer. Several studies had shown that thalidomide has potential for prevention and therapy of cancer. Therefore, the current study aimed to investigate the antitumor effects of two novel thalidomide analogs in human lung cancer A549 cells. The antiproliferative, antimigratory, and apoptotic effects in A549 cells induced by thalidomide analogs were examined. In addition, their effects on the expression of mRNAs encoding vascular endothelial growth factor165 (VEGF165) and matrix metalloproteinase-2 (MMP-2) were evaluated. Their influence on the tumor volume in nude mice was also determined. Results revealed that thalidomide analogs exhibited antiproliferative, antimigratory, and apoptotic activities with more pronounced effect than thalidomide drug. Furthermore, analogs 1 and 2 suppressed the expression levels of VEGF165 by 42% and 53.2% and those of MMP-2 by 45% and 52%, respectively. Thalidomide analogs 1 and 2 also reduced the tumor volume by 30.11% and 53.52%, respectively. Therefore, this study provides evidence that thalidomide analogs may serve as a new therapeutic option for treating lung cancer.

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