The findings of several recently published phase II trials suggest that personalized treatment might soon become a reality for patients with advanced thyroid cancers.

Few options are currently available to treat advanced thyroid cancers, which tend to respond poorly to conventional chemotherapy. As a consequence, novel therapeutic strategies that exploit biological pathways involved in thyroid cancer are now being explored.

Formation of a de novo blood supply is required to sustain tumor growth. The process of angiogenesis occurs via activation of receptor tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR), proteins that are constitutively active in some thyroid tumors. Blocking the activity of these kinases with multitarget drugs, such as sorafenib, has already shown some promise in the treatment of patients with advanced thyroid cancers.

Keith Bible and colleagues investigated the efficacy of pazopanib (an inhibitor of VEGFR, PDGFR and KIT) in 37 patients with progressive, metastatic thyroid cancers that were refractory to treatment with radioactive iodine. Participants received 800 mg pazopanib daily, administered continuously in 4-week cycles, until drug intolerance and/or disease progression occurred. The primary end point was the tumor response rate.

The study group included patients with follicular, Hürthle cell and papillary thyroid cancers. Treatment was discontinued in 22 patients owing to disease progression; 16 patients required dose reductions and two patients withdrew from the study as the result of adverse events. No patients had a complete response to pazopanib; however, 18 patients experienced a partial effect (48% response rate). The probability of this response lasting for more than 1 year was 66%. A strong correlation was observed between individual response and the plasma concentration of pazopanib during the first treatment cycle.

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In a second trial, Huan Ha et al. enrolled 11 patients with PDGFR-positive, advanced anaplastic thyroid cancer. The investigators aimed to evaluate the response of these tumors to imatinib, an inhibitor of PDGFR, KIT and BCR–ABL. Participants received 400 mg imatinib twice daily; the dosage was lowered to 300 mg if adverse events occurred. Tumor responses were assessed every 8 weeks.

Response rate was evaluable in eight patients: two achieved a partial response and four exhibited stable disease. No patients achieved a complete response to imatinib. The 6-month, progression-free survival rate was 27%, with an overall survival rate of 46%. Three of the participants required dose reductions after experiencing adverse events.

The studies of Bible et al. and Ha et al. provide proof of principle that targeting angiogenesis could be beneficial for patients with advanced thyroid cancers. However, in order to truly tailor therapy, clinicians need to know who is most likely to respond to these novel drugs. This issue was addressed by Michael Bass and colleagues. These researchers had previously shown that the concentration of placenta growth factor (PlGF; a member of the VEGF family) is elevated after administration of motesanib—an inhibitor of VEGFR, PDGFR and KIT—in a dose-dependent fashion. Furthermore, the increase in PlGF correlated with a reduction in tumor size. The team, therefore, decided to evaluate PlGF as a potential biomarker of response to motesanib therapy.

Bass et al. measured circulating levels of PlGF in 184 patients who received 125 mg motesanib daily to treat advanced differentiated or medullary thyroid cancers. Mean serum PlGF levels increased significantly from baseline after 1 week of treatment and correlated with tumor response. A marked separation of patients who achieved a partial response versus those who did not was observed at a 4.7-fold increase in PlGF concentration. A serum PlGF level above this cut-off value was associated with a 30% response rate, compared with just a 3% response rate below this level.

The next step will be to evaluate the efficacy of these angiogenesis inhibitors in phase III clinical trials. The costs and risks involved must also be assessed. However, as Bass points out, “the ability to quickly identify responders would allow exclusion of nonresponders, thereby sparing them from potential side effects and allowing them to more quickly explore alternative therapies.”