New Directions in the Systemic Treatment of Metastatic Thyroid Cancer
By Michaela J. Higgins, MRCPI, Arlene Forastiere, MD, Shanthi Marur, MD |
August 14, 2009
1Fellow in Medical Oncology, The Johns Hopkins School of Medicine, Sidney Kimmel Comprehensive Cancer Center
2Professor in Oncology, Upper Aerodigestive Cancer Program, The Johns Hopkins University School of Medicine, The Sidney Kimmel Comprehensive Cancer Center
3Faculty in Oncology, Upper Aerodigestive Cancer Program, The Johns Hopkins University School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
Many of the key oncogenic events in thyroid cancer are activating mutations of signaling pathways involving tyrosine kinases, making kinase inhibitors a rational choice of anti–thyroid cancer therapy. One such multitargeted kinase inhibitor with known activity against VEGF receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), RET, and BRAF is sorafenib(Drug information on sorafenib) (Nexavar), which is currently approved by the US Food and Drug Administration (FDA) for the treatment of renal cell carcinoma and hepatocellular carcinoma.
Summary of Trial Results of Sorafenib and Sunitinib in Thyroid Cancer
In a recent phase II study of 30 patients with differentiated or medullary thyroid cancer who took sorafenib at a dose of 400 mg twice a day orally, an overall clinical response (defined as either a partial response or stable disease) was seen in 77%, and the median progression-free survival was 79 weeks (Table 2). Approximately 23% experienced a partial response by Response Evaluation Criteria in Solid Tumors (RECIST). The most common treatment-related adverse events included fatigue, rash, diarrhea, palmar-plantar erythema, musculoskeletal pain, and weight loss. One patient with medullary thyroid cancer experienced grade 4 liver toxicity, which may have been treatment-related, and died.
Similar results and side effects were recorded in a further small study, which suggested that sorafenib has significant antitumor activity in patients with advanced thyroid cancer and warrants further study in this group.
Much enthusiasm has been generated following recent studies using sunitinib (Sutent), an oral agent with inhibitory activity against RET, VEGFR, and PDGFR, and thus the potential to be active in both differentiated and medullary thyroid cancers.[49-51] Sunitinib is FDA approved for renal cell cancer and imatinib(Drug information on imatinib) (Gleevec)-refractory gastrointestinal stromal tumors.
In the largest study of sunitinib in thyroid cancer to date, 43 patients with radioactive iodine(Drug information on iodine)–resistant disease were treated with sunitinib, 50 mg daily, on a 4-week-on/2-week-off schedule. Among patients with differentiated carcinomas, 13% achieved a partial response and 68% had stable disease. In contrast, 83% of patients with medullary thyroid carcinomas had stable disease (Table 2). This was a heavily pretreated group of patients, and reported adverse effects were similar to those seen with sorafenib but also included neutropenia in 49% and thrombocytopenia in 16%.
Motesanib diphosphate (AMG 706) is a potent, oral multikinase inhibitor that targets VEGF, PDGFR, KIT, and RET receptors and has both antiangiogenic and antitumor activity. In a small subgroup analysis of a phase I trial, three thyroid cancer patients treated with motesanib had a partial response and three experienced disease stabilization. This prompted a large open-label, phase II study in which 93 patients with progressive, locally advanced or metastatic, radioiodine-resistant differentiated thyroid cancer were treated with 125 mg of motesanib administered once daily. Stable disease was achieved in 67% of the patients and was maintained for 24 weeks or longer in 35%. The most common treatment-related adverse events were diarrhea (59% incidence), hypertension (56%), fatigue (46%), and weight loss (40%).
Axitinib is a potent, selective, orally administered inhibitor of VEGF receptors 1, 2, and 3. It is more than 10-fold less potent for inhibiting PDGFR and cKIT in cell-based assays, and this relative selectivity, in combination with the recognized importance of angiogenesis in thyroid cancer, made it an excellent choice for further study in this disease.
A recent, multi-institutional study assessed its safety and activity in 60 patients with thyroid cancer of any histology that was resistant to iodine-131. The drug was given at a dose of 5 mg twice daily. Partial responses were observed in 30% of patients, and stable disease lasting at least 16 weeks was reported in another 38%. Median progression-free survival was over 18 months. These results are more impressive when we consider that the majority of patients were male and had metastatic disease, which are risk factors for poor prognosis. Common treatment-related adverse events were fatigue, diarrhea, nausea, anorexia, hypertension, stomatitis, weight decrease, and headache, but very few high-grade events were recorded.
Vandetanib (ZD6474, Zactima) is another novel tyrosine kinase inhibitor that acts as a potent and reversible inhibitor of ATP binding to VEGF and EGF receptors. The drug has also demonstrated selective inhibition of RET-dependent thyroid tumor cell growth in vitro. This provided the rationale for studying the activity of vandetanib in hereditary medullary thyroid cancer, which is associated with findings in family members of point mutations in the RET proto-oncogene. The most recent phase II study of this drug in patients with locally advanced or metastatic hereditary medullary thyroid cancer enrolled 19 patients. Preliminary results showed a partial response in two patients, and stable disease for at least 24 weeks in six patients (ie, a disease control rate of 42.1%). A randomized, placebo-controlled, international phase III study of vandetanib in medullary thyroid cancer is currently accruing.
The studies discussed above show a renewed interest in refractory thyroid cancer management and suggest that small-molecule inhibitors offer promising prospects for the treatment of these patients. Several other multitargeted tyrosine kinase inhibitors are in development. We would propose treatment of refractory thyroid cancer patients in a clinical trial wherever possible, and where studies are unavailable, off-label use of the currently available oral multikinase inhibitors such as sorafenib and sunitinib. A summary of drugs in development that may target pathways involved in thyroid cancer is shown in Table 1.
Gefinitib (Iressa) is a tyrosine kinase inhibitor of the epidermal growth factor receptor, approved in the United States for locally advanced or metastatic non–small-cell lung cancer after failure of first-line chemotherapies. Preclinical data support a role for EGFR inhibition in thyroid carcinomas, and in particular, anaplastic thyroid cancer. The most recent study of the drug in radioactive iodine–refractory thyroid cancers of all histologic subtypes failed to show any objective responses among 25 patients. Approximately 32% of patients experienced a reduction in tumor volume that did not meet criteria for a partial response, but some had prolonged periods of stable disease, suggesting biologic activity.
Another logical therapeutic intervention is the monoclonal antibody to EGFR, cetuximab(Drug information on cetuximab) (Erbitux). This agent has previously shown synergism with chemotherapy such as irinotecan(Drug information on irinotecan) in the treatment of patients with colorectal cancer. This same combination has demonstrated synergistic inhibition of the growth of orthotopic anaplastic thyroid carcinoma xenografts in nude mice but has yet to be studied in humans.
Combretastatin A4 phosphate is a novel drug whose precise mechanism of action is unknown. It is structurally similar to colchicine(Drug information on colchicine) and causes antitumor effects by binding tubulin and disrupting vascular supply within tumors. In combination with paclitaxel(Drug information on paclitaxel), combretastatin A4 phosphate demonstrated excellent antineoplastic activity against anaplastic thyroid cancer in a nude mouse xenograft model. When given to patients with advanced cancer in a phase I trial, a single patient with anaplastic thyroid cancer had a complete response that lasted more than 30 months after treatment. No traditional “cytotoxic” side effects such as myelotoxicity, stomatitis, or alopecia were noted. However, tumor pain occurred in 10% of treatment cycles.
It is possible that combretastatin, in addition to disrupting tumor vasculature, may cause transient changes in other vascular beds—two episodes of acute coronary syndrome were noted among 25 patients treated on this trial. Preliminary data from a subsequent phase II study failed to obtain any objective responses, but a number of patients achieved disease stabilization. A phase III trial of this agent in combination with carboplatin(Drug information on carboplatin) and paclitaxel chemotherapy is currently accruing.
Traditional cytotoxic chemotherapies have been studied with variable and usually poor responses in 131I-resistant thyroid cancers. Single-agent doxorubicin(Drug information on doxorubicin) (the most studied chemotherapy drug) provides partial response rates in the 10%-37% range.[65,66] Trials of other drugs such as cisplatin(Drug information on cisplatin) and paclitaxel have not yielded improved response rates, and combination regimens have merely increased toxicity.[66,67] Because of the minimal efficacy associated with cytotoxic treatment, the National Comprehensive Cancer Network guidelines, among others, recommend enrollment in clinical trials for such patients.
Attempts have also been made to enhance or prolong the beneficial effects of 131I using all-trans retinoic acid (ATRA) to “redifferentiate” metastatic thyroid cancer. Chinese investigators treated 11 patients with dedifferentiated thyroid cancer using 1 mg/kg/d of ATRA followed by radioactive iodine. They obtained mixed responses. A British study has failed to demonstrate clinically significant 131I uptake after administration of the retinoid.[69,70]
An area of growing interest involves the use of the antiangiogenic drugs thalidomide(Drug information on thalidomide) (Thalomid) and lenalidomide (Revlimid) to target hypervascular thyroid carcinomas. Of 28 evaluable patients with refractory, differentiated thyroid cancer who received thalidomide in a phase II trial, 18% obtained a partial response and 32% experienced stable disease. Early results of a phase II study of lenalidomide in the same population also showed this agent to be well tolerated, with 22% of 21 patients achieving a partial response and 44% experiencing disease stabilization.
Enhanced knowledge of the epigenetic pathways involved in carcinogenesis has led to discovery of the importance of acetylation of histone tails and hypermethylation of DNA in regulator regions. Dysregulated histone deacetylase (HDAC) activity has been found in a number of cancers, and HDAC inhibitors have demonstrated anticancer effects.[73,74] HDAC inhibitors have depressed the growth of thyroid cancer cell lines in vitro, providing a rationale for the potential use of these drugs in the clinic.
Preliminary studies suggest a role for DNA methylation in the loss of human sodium iodide symporter expression in thyroid carcinomas, as well as a potential application for chemical demethylation therapy in restoring responsiveness to therapeutic radioiodide.
The prognosis for patients with metastatic radioactive iodine–resistant thyroid cancer remains poor. Recent progress in understanding the molecular pathways involved, however, has rekindled an interest in targeted treatment of this challenging disease. Many of the new studies discussed here are still in early phases, and further large, randomized trials are required. It is evident that the landscape of treatment for this group is evolving rapidly, and there is an ever-increasing role for the medical oncologist. In the absence of strong phase III data, we strongly propose that patients be enrolled in clinical trials wherever possible. Moreover, the currently available oral multikinase inhibitors such as sorafenib and sunitinib should be the off-study treatment of choice for patients with metastatic radioiodine-insensitive thyroid cancers.
Financial Disclosure: Drs. Higgins and Marur have no conflicts of interest or relevant financial relationships to disclose. Dr. Forastiere has received research funding from Amgen and Pfizer, and is on an advisory board for Merck-Serono.
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