imetelstat and Carcinoma--Papillary

Thyroid cancer incidence has significantly increased in the last three decades and many patients seek medical attention for its treatment every year. Among follicular cell-derived tumors, the majority are differentiated thyroid carcinomas (DTC), whose prognosis is very good with only 15% of the cases presenting disease persistence or recurrence after initial treatment. Medullary thyroid carcinoma has a worse prognosis, especially in patients with diffused cancers at the time of initial surgery. Traditional treatment options for persistent or recurrent disease include additional surgery, radioiodine treatment and TSH-suppression in DTC patients; external beam radiotherapy, and cytotoxic chemotherapy, often have low efficacy and many patients with advanced disease ultimately die. In the last two decades many of the molecular events involved in cancer formation have been uncovered. This knowledge has prompted the development of novel therapeutic strategies mainly based on the inhibition of key molecular mediators of the tumorigenic process. In particular the class of small-molecule tyrosine kinase inhibitors was enriched by many compounds that have reached clinical trials and in some cases have had approval for clinical use in specific cancers. Many of these compounds entered clinical trials also for locally advanced or metastatic thyroid carcinomas showing very promising results.

Topics: Antineoplastic Agents; Axitinib; Benzenesulfonates; Carcinoma, Medullary; Carcinoma, Papillary; Humans; Imidazoles; Indazoles; Indoles; Niacinamide; Oligonucleotides; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Pyridines; Pyrroles; Quinazolines; Sorafenib; Sunitinib; Thyroid Neoplasms

The expression of vascular endothelial growth factor (VEGF) is characteristic of differentiated thyroid cancer and is associated with aggressive tumor behavior and a poor clinical outcome. Motesanib diphosphate (AMG 706) is a novel oral inhibitor of VEGF receptors, platelet-derived growth-factor receptor, and KIT.. In an open-label, single-group, phase 2 study, we treated 93 patients who had progressive, locally advanced or metastatic, radioiodine-resistant differentiated thyroid cancer with 125 mg of motesanib diphosphate, administered orally once daily. The primary end point was an objective response as assessed by an independent radiographic review. Additional end points included the duration of the response, progression-free survival, safety, and changes in serum thyroglobulin concentration.. Of the 93 patients, 57 (61%) had papillary thyroid carcinoma. The objective response rate was 14%. Stable disease was achieved in 67% of the patients, and stable disease was maintained for 24 weeks or longer in 35%; 8% had progressive disease as the best response. The Kaplan-Meier estimate of the median duration of the response was 32 weeks (the lower limit of the 95% confidence interval [CI] was 24; the upper limit could not be estimated because of an insufficient number of events); the estimate of median progression-free survival was 40 weeks (95% CI, 32 to 50). Among the 75 patients in whom thyroglobulin analysis was performed, 81% had decreased serum thyroglobulin concentrations during treatment, as compared with baseline levels. The most common treatment-related adverse events were diarrhea (in 59% of the patients), hypertension (56%), fatigue (46%), and weight loss (40%).. Motesanib diphosphate can induce partial responses in patients with advanced or metastatic differentiated thyroid cancer that is progressive. (ClinicalTrials.gov number, NCT00121628.)

Topics: Adenocarcinoma, Follicular; Adenoma, Oxyphilic; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Papillary; Female; Genotype; Humans; Indoles; Male; Middle Aged; Niacinamide; Oligonucleotides; Proto-Oncogene Proteins c-kit; Receptors, Vascular Endothelial Growth Factor; Survival Analysis; Thyroglobulin; Thyroid Neoplasms