This phase II study investigated the efficacy and safety of everolimus, an inhibitor of mammalian target of rapamycin (mTOR), in locally advanced or metastatic thyroid cancer. Patients with thyroid cancer of any histology that was resistant or not appropriate for 131I received everolimus 10 mg daily orally until unacceptable toxicity or disease progression. The primary end point was disease control rate [partial response (PR) + stable response ≥12 weeks]. Secondary end points included response rates, clinical benefit (PD + durable stable disease (SD)], progression-free survival (PFS), overall survival, duration of response, and safety. Thirty-eight of 40 enrolled patients were evaluable for efficacy. The disease control rate was 81% and two (5%) patients achieved objective response; their duration of response was 21+ and 24+ weeks. Stable disease (SD) and progressive disease was reported in 76% and 17% of patients, respectively. Seventeen (45%) patients showed durable SD (≥24 weeks) and clinical benefit was reported in 19 (50%) patients. Median PFS was 47 weeks [95% confidence interval (CI) 14.9–78.5]. Calcitonin, CEA, and thyroglobulin concentrations were ≥50% lower than baseline in three (30%) and four (44%) patients with medullary thyroid cancer and five (33%) patients with PTC, respectively. The most common treatment-related adverse events were mucositis (84%), anorexia (44%), and aspartate transaminase/alanine transaminase elevation (26%). Everolimus had a limited activity with low response rate in locally advanced or metastatic thyroid cancer. Reasonable clinical benefit rate and safety profile may warrant further investigation. NCT01164176.
Gastric cancer is the fourth most common cancer, and the second-highest cause of cancer-related deaths worldwide. Despite extensive research to identify novel diagnostic and therapeutic agents, patients with advanced gastric cancer suffer from a poor quality of life and poor prognosis, and treatment is dependent mainly on conventional cytotoxic chemotherapy. To improve the quality of life and survival of gastric cancer patients, a better understanding of the underlying molecular pathologies, and their application towards the development of novel targeted therapies, is urgently needed. Chemokines are a group of small proteins associated with cytoskeletal rearrangements, the directional migration of several cell types during development and physiology, and the host immune response via interactions with G-protein coupled receptors. There is also growing evidence to suggest that chemokines not only play a role in the immune system, but are also involved in the development and progression of tumors. In gastric cancer, CXC chemokines and chemokine receptors regulate the trafficking of cells in and out of the tumor microenvironment. CXC chemokines and their receptors can also directly influence tumorigenesis by modulating tumor transformation, survival, growth, invasion and metastasis, as well as indirectly by regulating angiogenesis, and tumor-leukocyte interactions. In this review, we will focus on the roles of CXC chemokines and their receptors in the development, progression, and metastasis of gastric tumors, and discuss their therapeutic potential for gastric cancer.