fosbretabulin and Thyroid-Carcinoma--Anaplastic

Anaplastic thyroid carcinoma (ATC) is a rare malignancy, accounting for 1-2% of all thyroid cancers. Although rare, ATC accounts for the majority of deaths from thyroid carcinoma. ATC often originates in a pre-existing thyroid cancer lesion, as suggested by the simultaneous presence of areas of differentiated or poorly differentiated thyroid carcinoma. ATC is characterized by the accumulation of several oncogenic alterations, and studies have shown that an increased number of oncogenic alterations equates to an increased level of dedifferentiation and aggressiveness. The clinical management of ATC requires a multidisciplinary approach; according to recent American Thyroid Association guidelines, surgery, radiotherapy and/or chemotherapy should be considered. In addition to conventional therapies, novel molecular targeted therapies are the most promising emerging treatment modalities. These drugs are often multiple receptor tyrosine kinase inhibitors, several of which have been tested in clinical trials with encouraging results so far. Accordingly, clinical trials are ongoing to evaluate the safety, efficacy and effectiveness of these new agents. This Review describes the updated clinical and pathological features of ATC and provides insight into the molecular biology of this disease. The most recent literature regarding conventional, newly available and future therapies for ATC is also discussed.

Topics: Age Factors; Antineoplastic Combined Chemotherapy Protocols; Deglutition Disorders; Dyspnea; GTP Phosphohydrolases; Hoarseness; Humans; Membrane Proteins; Neck Pain; Neoplasm Staging; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Radiation Exposure; Radiotherapy; Respiratory Sounds; Risk Factors; Stilbenes; Telomerase; Thiazolidinediones; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Thyroidectomy

Fosbretabulin tromethamine is a vascular disrupting agent, which is a type of drug that is designed to damage the vasculature (blood vessels) of cancer tumors, causing central necrosis. This drug showed activity against anaplastic thyroid cancer that was demonstrated in orthotopic xenograft models as well as in Phase I/II trials with or without carboplatin and paclitaxel combination therapy. In all of these studies, fosbretabulin was well tolerated.

Topics: Animals; Antineoplastic Agents, Phytogenic; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Evaluation, Preclinical; Humans; Stilbenes; Thyroid Carcinoma, Anaplastic

Anaplastic thyroid cancer (ATC) is a rare and deadly malignancy. There is a need to speed up and support clinical research. This review article focuses on the new molecules that have been developed for the treatment of this aggressive tumor.. Improvement in the knowledge of pathogenesis and genetics of ATC led to the development of a variety of new molecules that may be used to treat this disease. In summary, these molecules are proteasome inhibitors, Aurora kinase inhibitors, vascular targeting agents, and gene therapies. All these molecules demonstrated a potentially therapeutic activity in metastatic ATC. To date, the largest prospective randomized multicenter, open-label, trial was conducted with combretastatin-A4.. More efficient drugs need to be developed through multinational efforts.

Topics: Antineoplastic Agents, Phytogenic; Humans; Neoplasm Metastasis; Randomized Controlled Trials as Topic; Stilbenes; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

Anaplastic thyroid cancer (ATC) is an aggressive neoplasm for which a paucity of data exist about the relative role of operative procedures in disease management.. The FACT trial was a randomized, controlled phase 2/3 trial assessing the safety and efficacy of carboplatin/paclitaxel with CA4P (experimental arm) or without CA4P (control arm) in ATC, 2007-11. Patients were permitted to have had an operation before enrollment, which was stratified on the basis of exposure to operation. A subpopulation of patients who had a cancer-related operation (thyroidectomy) was compared with those who did not, and 1-year and median survival were estimated.. A total of 80 patients were enrolled; 55% had undergone a cancer-related operation, of whom 70% had near-total/total thyroidectomy. Baseline characteristics for operative and nonoperative patients were not substantially different. Median survival for patients who had cancer-related operation was 8.2 months in the CA4P arm versus 4.0 months in the control arm, resulting in a hazard ratio of 0.66 (P = .25) and a suggested associated reduction in risk of death of 35%. 1-year survival was 33.3% in the CA4P arm versus 7.7% in the control arm.. In this largest prospective study ever conducted in ATC, thyroidectomy followed by CA4P combination regimen showed a nonsignificant trend toward improvement in patient survival.

Topics: Aged; Antineoplastic Agents, Phytogenic; Combined Modality Therapy; Female; Humans; Male; Middle Aged; Stilbenes; Survival Rate; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Thyroidectomy

Anaplastic thyroid cancer (ATC), a rare highly vascularized tumor, has a dismal outcome. We conducted an open-label study of doublet carboplatin/paclitaxel chemotherapy with or without fosbretabulin in patients with ATC.. Patients were randomly assigned in a 2:1 ratio to 6 cycles of paclitaxel 200 mg/m(2) followed by carboplatin AUC 6 on day 1 every 3 weeks (CP), or these drugs were given on day 2 after fosbretabulin 60 mg/m(2) (CP/fosbretabulin) on days 1, 8 and 15. After 6 cycles, patients on the fosbretabulin arm without progression could continue to receive fosbretabulin on days 1 and 8 of a 3-week schedule until progression. The primary end point was overall survival (OS).. Eighty patients were assigned (planned, 180) when enrollment was stopped due to rarity of disease and very low accrual. Median OS was 5.2 months [95% confidence interval (CI) 3.1, 9.0] for the CP/fosbretabulin arm (n=55; hazard ratio 0.73 [95% CI 0.44, 1.21]) and 4.0 months [95% CI 2.8, 6.2] for the CP arm (n=25; p=0.22 [log rank test]). One-year survival for CP/fosbretabulin versus CP was 26% versus 9%, respectively. There was no significant difference in progression-free survival between the two arms. Grade 1-2 hypertension and grade 3-4 neutropenia were more common with CP/fosbretabulin. There were no significant adverse cardiovascular side effects.. Although the study did not meet statistical significance in improvement in OS with the addition of fosbretabulin to carboplatin/paclitaxel, it represents the largest prospective randomized trial ever conducted in ATC. The regimen is well tolerated, with AEs and deaths primarily related to ATC and disease progression.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Humans; Male; Middle Aged; Neutropenia; Stilbenes; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Treatment Outcome

Topics: Antineoplastic Agents, Phytogenic; Female; Humans; Male; Stilbenes; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Thyroidectomy