toremifene and Fibromatosis--Aggressive

The treatment of desmoid tumours (DTs) is controversial. Anti-oestrogen therapy has frequently been used, but clear information of its efficacy is lacking. In this systematic review we have undertaken a comprehensive analysis to assess the effectiveness of anti-oestrogen therapy in terms of ability to induce partial or complete regression of DTs.. A systematic review of articles published in English between January 1983 and December 2009 was carried out according to the RECIST criteria. A literature search was performed on electronic databases including: United States National Library of Medicine (MEDLINE-PubMed), Excerpta Medica (EMBASE), Cochrane Library and Google search engine. Two-hundred articles dealing with DTs were identified but only fourty-one were were selected as appropriate for the study. The chi-square test was used for statistical analysis.. Data on 168 DTs treated with anti-oestrogen agents, alone or in combination with nonsteroidal anti-inflammatory drugs, were identified with an overall response rate of 51%. There was no difference in response according to the type of DTs or between different anti-oestrogen therapies. Combination with anti-inflammatory drugs did not improve the outcome. Toremifene was sometimes effective in cases resistant to tamoxifen. Response did not seem to be related to oestrogen receptor status.. Despite potential inaccuracies in the methodology, the results of the review indicate that anti-oestrogen therapy produces some effect in about one half of patients with DTs. Its indication compared with other treatments is discussed.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Drug Therapy, Combination; Estrogen Antagonists; Fibromatosis, Aggressive; Humans; Tamoxifen; Toremifene

Topics: Adult; Clinical Trials as Topic; Female; Fibromatosis, Aggressive; Humans; Male; Tamoxifen; Toremifene

Many patients affected by desmoid-type fibromatosis (DF) are treated with a course of hormonal therapy as front line. So far, tamoxifene has been the preferred choice. Toremifene is an anti-oestrogen agent, but possible further mechanisms of action in desmoids are related to its role in regulation of transforming growth factor-beta and β-catenin pathways.. We retrospectively reviewed all patients treated with toremifene between 2005 and 2012 at a reference institution. Indication to toremifene was radiologically progressive disease and/or symptomatic deterioration. Progression-free survival (PFS), clinical benefit (CB) and safety profile were analysed.. Forty-four patients were treated with toremifene 180 mg daily, 20 for radiological progression, 16 for pain and 8 for both. In 28 patients, toremifene was offered as front-line therapy, while in 11 after tamoxifen failure. PFS was 89.6% at 2 years. According to Response Evaluation Criteria in Solid Tumours, partial response, stable disease and disease progression were observed in 25%, 65% and 10% of the patients, respectively. Symptomatic relief was obtained in 75% of patients. Median time to response was 4 months. Overall CB was 86%. Adverse events G≥2 according to National Cancer Institute Common Toxicity Criteria were recorded in ten patients.. Present series provides evidence to make toremifene an option in patients with DF, even after failure on different hormonal agents. A prospective trial is ongoing to confirm these results.

Topics: Adult; Antineoplastic Agents, Hormonal; Disease Progression; Disease-Free Survival; Female; Fibromatosis, Aggressive; Humans; Italy; Kaplan-Meier Estimate; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasms, Hormone-Dependent; Retrospective Studies; Risk Factors; Selective Estrogen Receptor Modulators; Time Factors; Toremifene; Treatment Outcome

Topics: Abdomen; Adenomatous Polyposis Coli Protein; Adult; Colonic Polyps; Estrogen Receptor Modulators; Female; Fibromatosis, Aggressive; Humans; Receptors, Steroid; Tamoxifen; Tomography, X-Ray Computed; Toremifene; Treatment Failure

Tissue infiltration is different in desmoid and fibroma tumours. Both produce high levels of transforming growth factor beta1 (TGFbeta1), which is related to extracellular matrix (ECM) accumulation which in turn regulates cell function and cell migration. Interactions between collagen, proteoglycans and cell surface fibronectin are involved in the assembly and functions of the ECM. As toremifene inhibits collagen and TGFbeta1 synthesis, we tested it in normal, desmoid and fibroma fibroblasts. We will report the changes in glycosaminoglycan (GAG) and collagen synthesis, TGFbeta1 activity, fibronectin mRNA expression and TGFbeta1 receptors after toremifene treatment in normal, fibroma and desmoid fibroblasts. We evaluated GAG and collagen synthesis with 3H-glucosamine and 3H-proline incorporation, TGFbeta1 activity with the ELISA method, TGFbeta1 receptor affinity with 125I-TGFbeta1 binding and total RNA with Northern blot analysis. GAG and collagen synthesis, TGFbeta1 activity and fibronectin levels were higher in fibroma and desmoid than normal fibroblasts. The increase was greater in desmoid than fibroma tumour cells. Toremifene treatment reduced GAG and collagen synthesis, TGFbeta1 activity and fibronectin levels in all cell cultures. The percentage reduction in GAG was similar in all cultures; the reduction in collagen synthesis and TGFbeta1 activity was the highest in desmoid fibroblasts. TGFbeta1 receptors were higher in fibroma and desmoid cells than controls. Toremifene reduced TGFbeta1 receptors only in desmoid fibroblasts, with no effect on the changes in type I, II, and III receptors. Our data show that toremifene modifies the ECM components that regulate cytokine activity and cell migration. The reduction in receptor number only in desmoid cells suggests that toremifene may reduce TGFbeta1's affinity for its receptors. Synthesis of a substance regulating protein kinase activity, which is directly involved in the link between TGFbeta1 and its receptors, cannot be excluded.

Topics: Blotting, Northern; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Collagen; Fibroblasts; Fibroma; Fibromatosis, Aggressive; Fibronectins; Glycosaminoglycans; Humans; Proline; Protein Serine-Threonine Kinases; Proteoglycans; Receptor, Transforming Growth Factor-beta Type I; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; RNA; Selective Estrogen Receptor Modulators; Toremifene; Transforming Growth Factor beta1

Desmoid tumour is a benign, non metastasising neoplasm characterised by an elevated deposition of organic macromolecules in the extracellular matrix (ECM). The matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation of ECM macromolecules. The MMPs and their natural inhibitors (TIMPs) have been implicated in tumour growth, invasion and metastasis. In this study we provide evidence that the in vitro cultured cell line from desmoid tumour accumulates more collagen fibres in the ECM than healthy fibroblasts.. We investigated collagen accumulation by 3H-thymidine incorporation, MMP expression by substrate gel zymography and TIMP expression by Western blot analysis.. Desmoid fibroblasts showed a reduction in MMP activity and an increase of type I and III collagen and TIMPs compared to normal fibroblasts.. The increase in collagen in desmoid fibroblasts was due to inhibited collagen degradation (reduction of MMP activity) rather than to increased collagen synthesis. Adding toremifene, an anti-estrogen triphenylethylene derivate, to desmoid fibroblasts reduced collagen accumulation by decreasing mRNA expression and increasing collagen degradation.

Topics: Antineoplastic Agents, Hormonal; Cell Line, Tumor; Collagen; Collagenases; Fibroblasts; Fibromatosis, Aggressive; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Procollagen; Tissue Inhibitor of Metalloproteinases; Toremifene; Tumor Cells, Cultured; Up-Regulation

To report a case of a pelvic desmoid tumor that was treated with the antiestrogen toremifene after a failed attempt at surgical excision.. Case report.. University reproductive endocrine practice.. A reproductive-aged woman with a recurrent desmoid tumor.. After surgical excision of a desmoid tumor that presented during childbirth, subsequent recurrence resulted in the use of toremifene for tumor stabilization.. Magnetic resonance imaging was used to monitor desmoid tumor size.. One year after postsurgical recurrence of the desmoid tumor, the patient began treatment with the antiestrogen toremifene. Tumor stabilization and regression with symptomatic relief was observed. Nine years of antiestrogen use revealed no progression in tumor size or patient symptoms. After the patient demonstrated perimenopausal symptoms, toremifene administration was discontinued without a return of symptoms or tumor growth after 3 years.. Our case demonstrates that toremifene is a safe and effective therapy that can be used for the stabilization and regression of desmoid tumors. An antiestrogen should be considered as adjuvant therapy after surgery and as a first-line treatment with disease recurrence. Discontinuation of antiestrogen therapy was shown to be done safely after the patient started to show signs of decreased endogenous estrogen production.

Topics: Adult; Estrogen Antagonists; Female; Fibromatosis, Abdominal; Fibromatosis, Aggressive; Humans; Neoplasm Recurrence, Local; Toremifene

Aggressive fibromatosis is a rare, benign tumour with a capacity for infiltration of surrounding structures and a propensity for local recurrence. The cornerstone of therapy is surgery, with various other treatment modalities having ill-defined roles. Assessment of the efficacy of these interventions is difficult. The natural history of the condition is variable and different treatment modalities are often used concurrently. Childhood cases pose particular management problems because of their tendency to occur in the head and neck region and the potential for treatment-related morbidity. Two children presented after surgery with recurrent disease threatening the airway. One remitted spontaneously and remains disease free at 20 years. The other achieved a complete remission with radiotherapy and toremifene. The role of non-surgical treatment, particularly radiotherapy, is reviewed.

Topics: Adolescent; Antineoplastic Agents, Hormonal; Child, Preschool; Fibromatosis, Aggressive; Head and Neck Neoplasms; Humans; Male; Neoplasm Recurrence, Local; Toremifene; Torticollis; Treatment Outcome

The present study provides evidence that the in vitro cultured fibroblast cell line from desmoid tumors differs from normal fibrobasts in its extracellular matrix (ECM) macromolecule composition and is modulated by treatment with toremifene, an antiestrogen that reduces tumor mass by an unknown mechanism. The results showed increased transforming growth factor-beta 1 (TGF-beta1) production, TGF-beta1 mRNA expression, and TGF-beta1 receptor number in desmoid fibroblasts compared with normal cells. As desmoid fibroblasts did not produce tumor necrosis factor-alpha (TNF-alpha) but were sensitive to it, which enhanced glycosaminoglycans (GAG) accumulation, we assessed the TGF-beta1 effects on TNF-alpha production by human monocytes. Our results showed TGF-beta1 significantly increased TNF-alpha secretion by monocytes. Toremifene mediated its effects in desmoid fibroblasts via an estrogen receptor-independent pathway. It inhibited GAG accumulation and the secretion of both latent and active forms of TGF-beta1 and had an inhibitory effect on TNF-alpha production by monocytes. Our results suggest that in reducing TGF-beta1 production by desmoid fibroblasts and TNF-alpha production by monocytes, toremifene may restore the balance between the two growth factors.

Topics: Antineoplastic Agents, Hormonal; Cell Line; Cells, Cultured; Estrogen Antagonists; Fibroblasts; Fibromatosis, Aggressive; Glycosaminoglycans; Humans; Monocytes; Receptors, Transforming Growth Factor beta; RNA, Messenger; RNA, Neoplasm; Toremifene; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Topics: Adolescent; Combined Modality Therapy; Female; Fibromatosis, Aggressive; Humans; Retroperitoneal Neoplasms; Toremifene