piperidines and Adenocarcinoma--Follicular

Novel targeted agents have been increasingly developed and tested in clinical trials over the past 5-10 years, many with unknown and unanticipated side effects. We describe here a case of a patient with a history of metastatic follicular thyroid carcinoma that we believe developed vandetanib-associated photoallergic dermatitis while enrolled on a phase 1 clinical trial.. A 51-year-old Caucasian female with poorly differentiated, metastatic follicular thyroid carcinoma presented with a cutaneous eruption that developed over 3 to 4 days while treated on phase 1 clinical trial with vandetanib-based therapy. Given the concern for photoallergic dermatitis, vandetanib was discontinued and supportive care provided including topical and oral steroid administration. Her cutaneous eruption improved and she was successfully re-challenged with vandetanib.. Tyrosine kinase inhibitors, such as typo-vandetinib, with various therapeutic targets have come to the forefront of oncologic therapy in recent years. It is important to have a better understanding of the side effect profile and management in order to anticipate adverse events and maintain patient safety in future clinical trials.

Topics: Adenocarcinoma, Follicular; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Dermatitis, Photoallergic; Everolimus; Female; Humans; Middle Aged; Piperidines; Protein-Tyrosine Kinases; Quinazolines; Thyroid Neoplasms

No effective standard treatment exists for patients with radioiodine-refractory, advanced differentiated thyroid carcinoma. We aimed to assess efficacy and safety of vandetanib, a tyrosine kinase inhibitor of RET, VEGFR and EGFR signalling, in this setting.. In this randomised, double-blind, phase 2 trial, we enrolled adults (aged ≥18 years) with locally advanced or metastatic differentiated thyroid carcinoma (papillary, follicular, or poorly differentiated) at 16 European medical centres. Eligible patients were sequentially randomised in a 1:1 ratio with a standard computerised scheme to receive either vandetanib 300 mg per day (vandetanib group) or matched placebo (placebo group), balanced by centre. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population based on investigator assessment. This study is registered with ClinicalTrials.gov, number NCT00537095.. Between Sept 28, 2007, and Oct 16, 2008, we randomly allocated 72 patients to the vandetanib group and 73 patients to the placebo group. By data cutoff (Dec 2, 2009), 113 (78%) patients had progressed (52 [72%] patients in the vandetanib group and 61 [84%] in the placebo group) and 40 (28%) had died (19 [26%] patients in the vandetanib group and 21 [29%] in the placebo group). Patients who received vandetanib had longer PFS than did those who received placebo (hazard ratio [HR] 0·63, 60% CI 0·54-0·74; one-sided p=0·008): median PFS was 11·1 months (95% CI 7·7-14·0) for patients in the vandetanib group and 5·9 months (4·0-8·9) for patients in the placebo group. The most common grade 3 or worse adverse events were QTc prolongation (ten [14%] of 73 patients in the vandetanib group vs none in the placebo group), diarrhoea (seven [10%] vs none), asthenia (five [7%] vs three [4%]), and fatigue (four [5%] vs none). Two patients in the vandetanib group and one in the placebo group died from treatment-related serious adverse events (haemorrhage from skin metastases and pneumonia in the vandetanib group and pneumonia in the placebo group).. Vandetanib is the first targeted drug to show evidence of efficacy in a randomised phase 2 trial in patients with locally advanced or metastatic differentiated thyroid carcinoma. Further investigation of tyrosine-kinase inhibitors in this setting is warranted.. AstraZeneca.

Topics: Adenocarcinoma, Follicular; Adolescent; Adult; Aged; Antineoplastic Agents; Bone Neoplasms; Carcinoma; Carcinoma, Papillary; Diarrhea; Disease-Free Survival; Double-Blind Method; Electrocardiography; ErbB Receptors; Female; Heart Conduction System; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Piperidines; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Skin Neoplasms; Survival Analysis; Thyroid Cancer, Papillary; Thyroid Neoplasms; Young Adult

The purpose of the study was to assess the endocrine effects of vandetanib, a multikinase inhibitor targeting RET, vascular endothelial growth factor receptor, and epidermal growth factor receptor, in 39 patients with progressive thyroid cancer included in two randomized placebo-controlled trials using vandetanib 300 mg/d.. Endocrine samplings were performed at baseline and then every 6 months. We compared differences in endocrine parameters between baseline and on vandetanib therapy or placebo.. During vandetanib treatment, several changes were observed. 1) Calcium (P = 0.0004) and vitamin D (P = 0.001) mean replacement doses were increased; calcium level remained unchanged, but serum 25(OH) vitamin D level decreased (P = 0.001); and serum PTH (P = 0.01) and 1,25(OH)(2) vitamin D (P = 0.01) levels increased, suggesting a decreased intestinal absorption of vitamin D or lack of sun exposure as a result of photosensitization. 2) l-T(4) doses were increased (P < 0.0001) to maintain serum TSH within the normal range. 3) In male patients, total testosterone (P = 0.048), bioavailable testosterone (P = 0.03), and SHBG (P = 0.02) levels increased. Serum inhibin B decreased (P = 0.02) and stimulated FSH increased (P = 0.006), suggesting a Sertoli cells insufficiency. 4) Cortisol level increased (P = 0.007) as well as ACTH level (P = 0.03) and cortisol-binding globulin (P = 0.02), but free urinary cortisol levels remained in the normal range. None of these changes were observed in patients randomized to the placebo arm.. In patients with locally advanced or metastatic thyroid cancer, the tyrosine kinase inhibitor vandetanib has several endocrine effects. Thyroid hormone, calcium, and vitamin D analog requirements increased, but consequences of the biological alterations on phosphocalcic metabolism and gonadotrope and adrenal functions are unknown.

Topics: Adenocarcinoma, Follicular; Adenocarcinoma, Papillary; Adult; Aged; Aged, 80 and over; Blood Glucose; Calcium; Cross-Over Studies; Enzyme Inhibitors; ErbB Receptors; Female; Humans; Male; Middle Aged; Parathyroid Hormone; Piperidines; Proto-Oncogene Proteins c-ret; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Testosterone; Thyroid Neoplasms; Treatment Outcome; Vitamin D

Tyrosine kinase inhibitors (TKIs) are used to treat patients with advanced thyroid cancers. We retrospectively investigated the efficacy of TKIs administered outside of clinical trials in metastatic sites or locally advanced thyroid cancer patients from five French oncology centers.. THERE WERE 62 PATIENTS (37 MEN, MEAN AGE: 61 years) treated with sorafenib (62%), sunitinib (22%), and vandetanib (16%) outside of clinical trials; 22 had papillary, five had follicular, five had Hürthle cell, 13 had poorly differentiated, and 17 had medullary thyroid carcinoma (MTC). Thirty-three, 25, and four patients were treated with one, two, and three lines of TKIs respectively. Primary endpoints were objective tumor response rate and progression-free survival (PFS). Sequential treatments and tumor response according to metastatic sites were secondary endpoints.. Among the 39 sorafenib and 12 sunitinib treatments in differentiated thyroid carcinoma (DTC) patients, partial response (PR) rate was 15 and 8% respectively. In the 11 MTC patients treated with vandetanib, 36% had PR. Median PFS was similar in second-line compared with first-line sorafenib or sunitinib therapy (6.7 vs 7.0 months) in DTC patients, but there was no PR with second- and third-line treatments. Bone and pleural lesions were the most refractory sites to treatment.. This is the largest retrospective study evaluating TKI therapies outside of clinical trials. DTC patients treated with second-line therapy had stable disease as best response, but had a similar median PFS compared with the first-line treatment.

Topics: Adenocarcinoma; Adenocarcinoma, Follicular; Adenoma, Oxyphilic; Adult; Aged; Antineoplastic Agents; Bone Neoplasms; Carcinoma; Carcinoma, Neuroendocrine; Carcinoma, Papillary; Disease-Free Survival; Female; Humans; Indoles; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Piperidines; Pleural Neoplasms; Protein-Tyrosine Kinases; Pyrroles; Quinazolines; Retrospective Studies; Sorafenib; Sunitinib; Thyroid Cancer, Papillary; Thyroid Neoplasms; Treatment Outcome

Topics: Adenocarcinoma, Follicular; Antineoplastic Agents; Carcinoma; Carcinoma, Papillary; Female; Humans; Male; Piperidines; Quinazolines; Thyroid Cancer, Papillary; Thyroid Neoplasms

Topics: Adenocarcinoma, Follicular; Antineoplastic Agents; Carcinoma; Carcinoma, Papillary; Female; Humans; Male; Piperidines; Quinazolines; Thyroid Cancer, Papillary; Thyroid Neoplasms