Vandetanib for the Treatment of Metastatic Medullary Thyroid Cancer

Medullary thyroid cancer (MTC) represents an aggressive form of thyroid malignancy. Some may occur spontaneously or can be associated with Multiple Endocrine Neoplasia syndromes, or Familial Medullary Thyroid Cancer syndrome. In these patients, the protooncogene RET (rearranged during transfection) is mutated. In patients who have unresectable or metastatic disease, the long term prognosis is poor. New treatments for this disease have focused on the use of targeted agents that inhibit the receptor tyrosine kinase of RET. One of these treatments, Vandetanib (Caprelsa, Astra Zeneca), recently has received approval from the Food and Drug Administration for the treatment of patients with progressive locally advanced and/or metastatic disease. This review highlights the studies that led to the drug’s approval, and discusses on the potential financial costs of treatment and side effects of this therapy. The main clinical studies evaluating Vandetanib for the treatment of other solid tumors will also be reviewed

Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up F. Pacini, M. G. Castagna, L. Brilli & G. Pentheroudakis On behalf of the ESMO Guidelines Working Group* Section of Endocrinology and Metabolism, Department of Internal Medicine, Endocrinology and Metabolism and Biochemistry, Section of Endocrinology and Metabolism, University of Siena, Siena, Italy; Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greec

Time Until Partial Response in Metastatic Adrenocortical Carcinoma Long-Term Survivors

A partial response (PR) has been proposed as a surrogate for overall survival in advanced adrenocortical carcinoma (ACC). The primary endpoint of the study was to characterize the time until a PR in patients with metastatic ACC treated with a standard therapy is achieved. Long-term survivors were selected to allow evaluation of delayed tumor response to mitotane. Records from patients with metastatic ACC that survived for > 24 months were retrieved. Tumor response was analyzed according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Time until a tumor response, after treatment initiation or therapeutic plasma mitotane level, was analyzed. Sixty-eight patients were analyzed. The first-line systemic therapy was mitotane as a monotherapy (M) (n = 57) or cytotoxic polychemotherapy plus/minus mitotane (PC ± M) (n = 11). The second-line therapy was M (n = 2) or PC ± M (n = 41). Thirty-two PRs occurred in 30/68 patients (44.1%): this was obtained for 13 (40.6%) during M and during PC ± M for 19/32 responders (59.4%). PRs were observed within 6 months of starting M or PC ± M in 76.9 and 94.7% of responses, respectively, within 6 months of therapeutic plasma mitotane being first observed in 88.9% of responses with M and in 53.3% of responses with PC ± M. All PRs (but one) occurred within 1 year after initiating treatment. To conclude, Most patients with metastatic ACC and long survival times had PRs within the first 6 months of standard systemic therapy, and almost all within the first year. The absence of response after that period could be considered as a treatment failure. Maintenance of mitotane therapy in non-responders after 1 year should be questioned in future randomized trials

FAK acts as a suppressor of RTK-MAP kinase signalling in Drosophila melanogaster epithelia and human cancer cells

Receptor Tyrosine Kinases (RTKs) and Focal Adhesion Kinase (FAK) regulate multiple signalling pathways, including mitogen-activated protein (MAP) kinase pathway. FAK interacts with several RTKs but little is known about how FAK regulates their downstream signalling. Here we investigated how FAK regulates signalling resulting from the overexpression of the RTKs RET and EGFR. FAK suppressed RTKs signalling in Drosophila melanogaster epithelia by impairing MAPK pathway. This regulation was also observed in MDA-MB-231 human breast cancer cells, suggesting it is a conserved phenomenon in humans. Mechanistically, FAK reduced receptor recycling into the plasma membrane, which resulted in lower MAPK activation. Conversely, increasing the membrane pool of the receptor increased MAPK pathway signalling. FAK is widely considered as a therapeutic target in cancer biology; however, it also has tumour suppressor properties in some contexts. Therefore, the FAK-mediated negative regulation of RTK/MAPK signalling described here may have potential implications in the designing of therapy strategies for RTK-driven tumours

Prognostic factors in stage III-IV adrenocortical carcinomas (ACC): an European Network for the Study of Adrenal Tumor (ENSAT) study.

BACKGROUND: The clinical course of advanced adrenocortical carcinoma (ACC) is heterogeneous. Our study aimed primarily to refine and make headway in the prognostic stratification of advanced ACC. PATIENTS AND METHODS: Patients with advanced ENSAT ACC (stage III or stage IV) at diagnosis registered between 2000 and 2009 in the ENSAT database were enrolled. The primary end point was overall survival (OS). Parameters of potential prognostic relevance were selected. Univariate and multivariate analyses were carried out: model 1 'before surgery'; model 2 'post-surgery'. RESULTS: Four hundred and forty-four patients with advanced ENSAT ACC (stage III: 210; stage IV: 234) were analyzed. After a median follow-up of 55.2 months, the median OS was 24 months. A modified ENSAT (mENSAT) classification was validated: stage III (invasion of surrounding tissues/organs or the vena renalis/cava) and stage IVa, IVb, IVc (2, 3 or >3 metastatic organs, including N, respectively). Two- or 5-year OS was 73%, 46%, 26% and 15% or 50%, 15%, 14% and 2% for stages III, IVa, IVb and IVc, respectively. In the multivariate analysis, mENSAT stages (stages IVa, IVb, or IVc, respectively) were significantly correlated with OS (P 6 and/or Ki67 ≥20%, P = 0.06) in model 2. CONCLUSION: The mENSAT classification and GRAS parameters (Grade, R status, Age and Symptoms) were found to best stratify the prognosis of patients with advanced ACC

Vandetanib for the Treatment of Advanced Medullary Thyroid Cancer Outside a Clinical Trial: Results from a French Cohort

BACKGROUND: A randomized phase III trial demonstrated that vandetanib treatment is effective in patients with metastatic medullary thyroid cancer (MTC), leading to regulatory approval, but its use may be associated with toxicities that require specific monitoring and management. The objective of the present study performed in France was to describe the toxicity profile and efficacy of vandetanib treatment when given outside any trial. METHODS: Sixty-eight patients were treated with vandetanib in the frame of a temporary use authorization (ATU) in France from August 2010 to February 2012, when the drug was available on request for patients with locally advanced or metastatic MTC. Patients were registered by the French health authorities, and characteristics, treatment parameters, toxicity profile, and efficacy were retrospectively reviewed. Eight patients were excluded from the analysis because vandetanib treatment was not administered (n=3), had been given in a trial before ATU (n=3), or was given for a non-MTC cancer (n=2). RESULTS: Data from the 60 MTC patients were analyzed. Mean age was 58 years (range 11-83 years), 39 patients were male, and six had hereditary MTC. Fifty-six (93%) had metastatic disease in the mediastinum (82%), bones (65%), liver (53%), or lung (53%), and four had only locally advanced disease. At the time of study evaluation, with a median follow-up of 20 months and a median duration of treatment of 9.7 months (range 0.3-36 months), 15 patients were continuing vandetanib treatment (range 18-36 months). Median progression-free survival was 16.1 months. Twenty-five patients discontinued treatment for disease progression (range 0.3-29 months). Best tumor response was a complete response in one patient, a partial response in 12 (20%), stable disease in 33 (55%), and progression in seven patients (12%). All patients had at least one adverse event (AE) during treatment. The main AEs were skin toxicity, diarrhea, and asthenia. Sixteen patients (27%) discontinued treatment for toxicity, and one patient died from vandetanib-induced cardiac toxicity. CONCLUSIONS: Vandetanib is an effective option for patients with advanced MTC. AEs should be monitored carefully and should be minimized by educating both patients and care providers and by applying symptomatic treatment and dose reduction