Community Translations Commentary Promising data, but challenges remain in selecting appropriate TKIs

Hamid Mirshahidi, MD
Loma Linda University School of Medicine, Loma Linda, CA

Medullary thyroid cancer (MTC) is a rare but aggressive disease. Unfortunately, there is not an effective conventional chemotherapy regimen for the disease. New strategies to treat metastatic MTC, including radioimmunotherapy and vaccine-based therapies, have been tested, with no major achievement. 1 Therefore, targeted therapy may offer a novel therapeutic approach for advanced MTC based on the role of mutations in the RET proto- oncogene and vascular endothelial growth factor receptor (VEGFR) activity in the pathogenesis of hereditary and sporadic MTC.2 VEGFR and RET may be common targets among multitargeted tyrosine kinase inhibitors (TKIs), such as sunitinib (Sutent), sorafenib (Nexavar), cabozantinib, motesanib, and vandetanib (Caprelsa).

Early responses with multitargeted TKIs
Sunitinib targets VEGFR 1-2, platelet-derived growth factor receptor (PDGFR), c-KIT, FLT3, and RET. It was tested in 7 patients with metastatic MTC and 28 patients with radioiodine-refractory well-differentiated thyroid carcinoma in a phase II study. Of the 33 evaluable patients, 1 patient with MTC (3%) achieved a complete response, 10 patients (28%) achieved a partial response, and 16 patients (46%) had stable disease, suggesting sunitinib may have activity in MTC.3

Sunitinib was also studied in 25 patients with rapidly progressing MTC in another phase II trial. Partial response was achieved in 8 of 24 patients (33%), with a median duration of response of 37 weeks, and 54 % of patients had SD, with a median duration of 32 weeks. As of May 2010, progression-free survival (PFS) was 49 weeks. Interestingly, patients with and without RET mutations showed a clinical benefit. Patients with the M918T RET mutation have a worse prognosis, and it may be associated with a durable response.4

Sorafenib showed clinical activity in patients with metastatic and radioiodine nonresponsive papillary thyroid carcinomas.5 Sorafenib inhibits the RAF, VEGFR 2-3, PDGFRβ, FLT3, c-KIT, and RET kinases. It also inhibits the growth of RET mutation-positive and wild-type MTC in vitro and in vivo. Therefore, sorafenib was evaluated in a phase II clinical trial to investigate its activity in patients with advanced MTC. Although only one partial response was observed in patients with sporadic MTC, 50% of patients showed stable disease of ≥ 15 months, with tumor shrinkage ranging from 8%–27%. Sorafenib was reasonably well tolerated in this study. The median duration of treatment and PFS were 15 and 17.9 months, respectively. The median overall survival was not reached at the time of data analysis.6

Motesanib is a novel inhibitor of VEGFR 1-2-3, PDGFR, and c-KIT. It has activity in wild-type but not mutant RET. Motesanib was studied in 91 patients with locally advanced or metastatic MTC in a phase II trial. Only two patients (2%) had an objective response, 81% of patients achieved or maintained stable disease, and 76% experienced a decrease from baseline in tumor measurement. In patients who had tumor marker analysis, 83% and 75% had a decrease in circulating concentrations of calcitonin and carcinoembryonic antigen (CEA), respectively. PFS was also 48 weeks. These data were encouraging and suggested the role of VEGF/RET-targeted therapies for MTC, as suggested in other studies.7

Cabozantinib (XL184) is an oral inhibitor of MET, VEGFR2, and RET. It was studied in a phase I trial in patients with different malignancies (37 had MTC). A partial response was observed in 10 patients (29%), and 25 patients (68%) had either a partial response or prolonged stable disease ≥ 6 months. Responses have been observed in patients with MTC with and without RET mutations. This study showed promising results to conduct an ongoing randomized phase III study of cabozantinib in MTC.8

Clinical trials of vandetanib
Wells et al presented the results of a double-blind randomized phase III trial of vandetanib in locally advanced or metastatic MTC (the ZETA trial). Vandetanib targets the RET, VEGFR, and epidermal growth factor re ceptor signaling pathways. The researchers randomized 331 patients with 90% sporadic MTC 2:1 to receive vandetanib or placebo. Patients in the placebo arm crossed over after disease progression and also received vandetanib.

Statistically significant prolongation of PFS (the primary objective) was observed for vandetanib compared with placebo (hazard ratio, 0.45; P < 0.0001), as well as improvement in objective response rate, disease control rate, time to worsening of pain, and biochemical response.9 This study was the first phase III trial that showed efficacy of a new multitargeted TKI with extension of PFS and improved quality of life in MTC. Subsequent data showed a median PFS of 16.4 months in the placebo arm and at least 22.6 months in the vandetanib arm; however, there was no significant improvement in overall survival. Based on this new information, the US Food and Drug Administration approved vandetanib as a new treatment for MTC in April 2011

Conclusion
These are promising data suggesting efficacy of vandetanib, motesanib, cabozantinib, sorafenib, and sunitinib in the treatment of MTC. The RET-inhibitory effect of these multitargeted agents in RET mutation-driven MTC and their antiangiogenic effect in wild-type RET cases could explain the effectiveness of these agents in these patients. A comparable low partial response rate, but a high rate of stable disease, was observed in all of these phase II studies. However, the same results may not be replicable in phase III studies, as MTC is a clinically heterogeneous disorder. Many challenges remain in selecting appropriate TKIs for MTC.

Correlative studies are required to identify RET genotypes and markers in MTC that could predict the patterns of response or resistance to these TKIs. It would be more challenging to identify these markers and regulatory signaling pathways in wild-type RET MTC. The observation made by the authors that patients without identifiable RET mutations had responses raises the question of whether VEGFR2 inhibition contributes to the treatment effect. We should also be cautious about selecting targeted agents and stepping forward from a phase I study to a randomized phase III trial without having sufficient knowledge of the biology that directs the disease phenotype.

Disclosures
Dr. Mirshahidi is on the speakers’ bureau of Genentech and on the advisory boards of Celgene and Genentech.

References
1. Kraeber-Bodéré F, Goldenberg DM, Chatal JF, Barbet J. Pretargeted radioimmunotherapy in the treatment of metastatic medullary thyroid cancer. Curr Oncol 2009;16:3–8.

2. Eng C, Clayton D, Schuffenecker I, et al. The relationship between specific RET protooncogene mutations and disease phenotype in multiple endocrine neoplasia type 2: international RET mutation consortium analysis. JAMA 1996;276:1575–1579.

3. Carr LL, Mankoff DA, Goulart BH, et al. Phase II study of daily sunitinib in FDG-PETpositive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin Cancer Res 2010;16:5260–5268.

4. De Souza JA, Busaidy N, Zimrin A, et al. Phase II trial of sunitinib in medullary thyroid cancer (MTC). J Clin Oncol 2010;28(15S):5504.

5. Kloos RT, Ringel MD, Knopp MV, et al. Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol 2009;27:1675–1684.

6. Lam ET, Ringel MD, Kloos RT, et al. Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. J Clin Oncol 2010;28:2323–2330.

7. Schlumberger MJ, Elisei R, Bastholt L, et al. Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer. J Clin Oncol 2009;27:3794–3801.

8. Kurzrock R, Cohen EE, Sherman SI, et al. Long-term results in a cohort of medullary thyroid cancer (MTC) patients (pts) in a phase I study of XL184 (BMS 907351), an oral inhibitor of MET, VEGFR2, and RET. J Clin Oncol 2010;28(15S):5502.

9. Wells SA, Robinson BG, Gagel RF, et al. Vandetanib (VAN) in locally advanced or metastatic medullary thyroid cancer (MTC): a randomized, double-blind phase III trial (ZETA). J Clin Oncol 2010;28(15S):5503.

How I treat medullary thyroid cancer
Hamid Mirshahidi, MD

Medullary thyroid carcinoma (MTC) develops from the neuroendocrine parafollicular C cells of the thyroid. These cells secrete neuroendocrine peptides, including calcitonin and carcinoembryonic antigen (CEA). The hereditary form presents as inherited tumor syndromes; they include multiple endocrine neoplasia type 2A (MEN 2A), which is the most common type; MEN 2B; and familial MTC. Typically, patients develop sporadic disease in their 50s or 60s, and those with familial forms of the disease tend to be younger.

Total thyroidectomy with or without central neck dissection is the primary treatment of locoregional disease. Ipsilateral or bilateral modified neck dissection is recommended if ipsilateral or contralateral cervical lymph nodes are clinically or radiologically evident. Adjuvant external-beam radiotherapy (EBRT) may be considered in selected cases, such as for patients with extrathyroidal disease or extensive nodal metastases. Postoperative surveillance of patients with MTC consists of measurement of calcitonin levels, which should be checked preoperatively as a baseline as well. Following thyroidectomy, the calcitonin level reaches a new steady state in about 72 hours. In patients with undetectable calcitonin levels and a normalized CEA level, annual measurement of both markers should still be checked and annual cervical ultrasonography should be considered.

MTC most commonly metastasizes to the liver, bones, and lungs. Palliative resection, EBRT, radiofrequency ablation, or chemoembolization should be considered for patients with locoregional symptoms and distant metastasis to maintain locoregional disease control. Radioiodine treatment and conventional cytotoxic chemotherapy, such as doxorubicin- and dacarbazine-based chemotherapies, are not effective in these patients. Clinical trial enrollment and novel small molecule tyrosine kinase inhibitors targeting the RET and vascular endothelial growth factor receptor should be considered as alternative therapies.

Hamid Mirshahidi, MD
Loma Linda University School of Medicine, Loma Linda, CA

Medullary thyroid cancer (MTC) is a rare but aggressive disease. Unfortunately, there is not an effective conventional chemotherapy regimen for the disease. New strategies to treat metastatic MTC, including radioimmunotherapy and vaccine-based therapies, have been tested, with no major achievement. 1 Therefore, targeted therapy may offer a novel therapeutic approach for advanced MTC based on the role of mutations in the RET proto- oncogene and vascular endothelial growth factor receptor (VEGFR) activity in the pathogenesis of hereditary and sporadic MTC.2 VEGFR and RET may be common targets among multitargeted tyrosine kinase inhibitors (TKIs), such as sunitinib (Sutent), sorafenib (Nexavar), cabozantinib, motesanib, and vandetanib (Caprelsa).

Early responses with multitargeted TKIs
Sunitinib targets VEGFR 1-2, platelet-derived growth factor receptor (PDGFR), c-KIT, FLT3, and RET. It was tested in 7 patients with metastatic MTC and 28 patients with radioiodine-refractory well-differentiated thyroid carcinoma in a phase II study. Of the 33 evaluable patients, 1 patient with MTC (3%) achieved a complete response, 10 patients (28%) achieved a partial response, and 16 patients (46%) had stable disease, suggesting sunitinib may have activity in MTC.3

Sunitinib was also studied in 25 patients with rapidly progressing MTC in another phase II trial. Partial response was achieved in 8 of 24 patients (33%), with a median duration of response of 37 weeks, and 54 % of patients had SD, with a median duration of 32 weeks. As of May 2010, progression-free survival (PFS) was 49 weeks. Interestingly, patients with and without RET mutations showed a clinical benefit. Patients with the M918T RET mutation have a worse prognosis, and it may be associated with a durable response.4

Sorafenib showed clinical activity in patients with metastatic and radioiodine nonresponsive papillary thyroid carcinomas.5 Sorafenib inhibits the RAF, VEGFR 2-3, PDGFRβ, FLT3, c-KIT, and RET kinases. It also inhibits the growth of RET mutation-positive and wild-type MTC in vitro and in vivo. Therefore, sorafenib was evaluated in a phase II clinical trial to investigate its activity in patients with advanced MTC. Although only one partial response was observed in patients with sporadic MTC, 50% of patients showed stable disease of ≥ 15 months, with tumor shrinkage ranging from 8%–27%. Sorafenib was reasonably well tolerated in this study. The median duration of treatment and PFS were 15 and 17.9 months, respectively. The median overall survival was not reached at the time of data analysis.6

Motesanib is a novel inhibitor of VEGFR 1-2-3, PDGFR, and c-KIT. It has activity in wild-type but not mutant RET. Motesanib was studied in 91 patients with locally advanced or metastatic MTC in a phase II trial. Only two patients (2%) had an objective response, 81% of patients achieved or maintained stable disease, and 76% experienced a decrease from baseline in tumor measurement. In patients who had tumor marker analysis, 83% and 75% had a decrease in circulating concentrations of calcitonin and carcinoembryonic antigen (CEA), respectively. PFS was also 48 weeks. These data were encouraging and suggested the role of VEGF/RET-targeted therapies for MTC, as suggested in other studies.7

Cabozantinib (XL184) is an oral inhibitor of MET, VEGFR2, and RET. It was studied in a phase I trial in patients with different malignancies (37 had MTC). A partial response was observed in 10 patients (29%), and 25 patients (68%) had either a partial response or prolonged stable disease ≥ 6 months. Responses have been observed in patients with MTC with and without RET mutations. This study showed promising results to conduct an ongoing randomized phase III study of cabozantinib in MTC.8

Clinical trials of vandetanib
Wells et al presented the results of a double-blind randomized phase III trial of vandetanib in locally advanced or metastatic MTC (the ZETA trial). Vandetanib targets the RET, VEGFR, and epidermal growth factor re ceptor signaling pathways. The researchers randomized 331 patients with 90% sporadic MTC 2:1 to receive vandetanib or placebo. Patients in the placebo arm crossed over after disease progression and also received vandetanib.

Statistically significant prolongation of PFS (the primary objective) was observed for vandetanib compared with placebo (hazard ratio, 0.45; P < 0.0001), as well as improvement in objective response rate, disease control rate, time to worsening of pain, and biochemical response.9 This study was the first phase III trial that showed efficacy of a new multitargeted TKI with extension of PFS and improved quality of life in MTC. Subsequent data showed a median PFS of 16.4 months in the placebo arm and at least 22.6 months in the vandetanib arm; however, there was no significant improvement in overall survival. Based on this new information, the US Food and Drug Administration approved vandetanib as a new treatment for MTC in April 2011

Conclusion
These are promising data suggesting efficacy of vandetanib, motesanib, cabozantinib, sorafenib, and sunitinib in the treatment of MTC. The RET-inhibitory effect of these multitargeted agents in RET mutation-driven MTC and their antiangiogenic effect in wild-type RET cases could explain the effectiveness of these agents in these patients. A comparable low partial response rate, but a high rate of stable disease, was observed in all of these phase II studies. However, the same results may not be replicable in phase III studies, as MTC is a clinically heterogeneous disorder. Many challenges remain in selecting appropriate TKIs for MTC.

Correlative studies are required to identify RET genotypes and markers in MTC that could predict the patterns of response or resistance to these TKIs. It would be more challenging to identify these markers and regulatory signaling pathways in wild-type RET MTC. The observation made by the authors that patients without identifiable RET mutations had responses raises the question of whether VEGFR2 inhibition contributes to the treatment effect. We should also be cautious about selecting targeted agents and stepping forward from a phase I study to a randomized phase III trial without having sufficient knowledge of the biology that directs the disease phenotype.

Disclosures
Dr. Mirshahidi is on the speakers’ bureau of Genentech and on the advisory boards of Celgene and Genentech.

References
1. Kraeber-Bodéré F, Goldenberg DM, Chatal JF, Barbet J. Pretargeted radioimmunotherapy in the treatment of metastatic medullary thyroid cancer. Curr Oncol 2009;16:3–8.

2. Eng C, Clayton D, Schuffenecker I, et al. The relationship between specific RET protooncogene mutations and disease phenotype in multiple endocrine neoplasia type 2: international RET mutation consortium analysis. JAMA 1996;276:1575–1579.

3. Carr LL, Mankoff DA, Goulart BH, et al. Phase II study of daily sunitinib in FDG-PETpositive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin Cancer Res 2010;16:5260–5268.

4. De Souza JA, Busaidy N, Zimrin A, et al. Phase II trial of sunitinib in medullary thyroid cancer (MTC). J Clin Oncol 2010;28(15S):5504.

5. Kloos RT, Ringel MD, Knopp MV, et al. Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol 2009;27:1675–1684.

6. Lam ET, Ringel MD, Kloos RT, et al. Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. J Clin Oncol 2010;28:2323–2330.

7. Schlumberger MJ, Elisei R, Bastholt L, et al. Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer. J Clin Oncol 2009;27:3794–3801.

8. Kurzrock R, Cohen EE, Sherman SI, et al. Long-term results in a cohort of medullary thyroid cancer (MTC) patients (pts) in a phase I study of XL184 (BMS 907351), an oral inhibitor of MET, VEGFR2, and RET. J Clin Oncol 2010;28(15S):5502.

9. Wells SA, Robinson BG, Gagel RF, et al. Vandetanib (VAN) in locally advanced or metastatic medullary thyroid cancer (MTC): a randomized, double-blind phase III trial (ZETA). J Clin Oncol 2010;28(15S):5503.

How I treat medullary thyroid cancer
Hamid Mirshahidi, MD

Medullary thyroid carcinoma (MTC) develops from the neuroendocrine parafollicular C cells of the thyroid. These cells secrete neuroendocrine peptides, including calcitonin and carcinoembryonic antigen (CEA). The hereditary form presents as inherited tumor syndromes; they include multiple endocrine neoplasia type 2A (MEN 2A), which is the most common type; MEN 2B; and familial MTC. Typically, patients develop sporadic disease in their 50s or 60s, and those with familial forms of the disease tend to be younger.

Total thyroidectomy with or without central neck dissection is the primary treatment of locoregional disease. Ipsilateral or bilateral modified neck dissection is recommended if ipsilateral or contralateral cervical lymph nodes are clinically or radiologically evident. Adjuvant external-beam radiotherapy (EBRT) may be considered in selected cases, such as for patients with extrathyroidal disease or extensive nodal metastases. Postoperative surveillance of patients with MTC consists of measurement of calcitonin levels, which should be checked preoperatively as a baseline as well. Following thyroidectomy, the calcitonin level reaches a new steady state in about 72 hours. In patients with undetectable calcitonin levels and a normalized CEA level, annual measurement of both markers should still be checked and annual cervical ultrasonography should be considered.

MTC most commonly metastasizes to the liver, bones, and lungs. Palliative resection, EBRT, radiofrequency ablation, or chemoembolization should be considered for patients with locoregional symptoms and distant metastasis to maintain locoregional disease control. Radioiodine treatment and conventional cytotoxic chemotherapy, such as doxorubicin- and dacarbazine-based chemotherapies, are not effective in these patients. Clinical trial enrollment and novel small molecule tyrosine kinase inhibitors targeting the RET and vascular endothelial growth factor receptor should be considered as alternative therapies.

Hamid Mirshahidi, MD
Loma Linda University School of Medicine, Loma Linda, CA

Medullary thyroid cancer (MTC) is a rare but aggressive disease. Unfortunately, there is not an effective conventional chemotherapy regimen for the disease. New strategies to treat metastatic MTC, including radioimmunotherapy and vaccine-based therapies, have been tested, with no major achievement. 1 Therefore, targeted therapy may offer a novel therapeutic approach for advanced MTC based on the role of mutations in the RET proto- oncogene and vascular endothelial growth factor receptor (VEGFR) activity in the pathogenesis of hereditary and sporadic MTC.2 VEGFR and RET may be common targets among multitargeted tyrosine kinase inhibitors (TKIs), such as sunitinib (Sutent), sorafenib (Nexavar), cabozantinib, motesanib, and vandetanib (Caprelsa).

Early responses with multitargeted TKIs
Sunitinib targets VEGFR 1-2, platelet-derived growth factor receptor (PDGFR), c-KIT, FLT3, and RET. It was tested in 7 patients with metastatic MTC and 28 patients with radioiodine-refractory well-differentiated thyroid carcinoma in a phase II study. Of the 33 evaluable patients, 1 patient with MTC (3%) achieved a complete response, 10 patients (28%) achieved a partial response, and 16 patients (46%) had stable disease, suggesting sunitinib may have activity in MTC.3

Sunitinib was also studied in 25 patients with rapidly progressing MTC in another phase II trial. Partial response was achieved in 8 of 24 patients (33%), with a median duration of response of 37 weeks, and 54 % of patients had SD, with a median duration of 32 weeks. As of May 2010, progression-free survival (PFS) was 49 weeks. Interestingly, patients with and without RET mutations showed a clinical benefit. Patients with the M918T RET mutation have a worse prognosis, and it may be associated with a durable response.4

Sorafenib showed clinical activity in patients with metastatic and radioiodine nonresponsive papillary thyroid carcinomas.5 Sorafenib inhibits the RAF, VEGFR 2-3, PDGFRβ, FLT3, c-KIT, and RET kinases. It also inhibits the growth of RET mutation-positive and wild-type MTC in vitro and in vivo. Therefore, sorafenib was evaluated in a phase II clinical trial to investigate its activity in patients with advanced MTC. Although only one partial response was observed in patients with sporadic MTC, 50% of patients showed stable disease of ≥ 15 months, with tumor shrinkage ranging from 8%–27%. Sorafenib was reasonably well tolerated in this study. The median duration of treatment and PFS were 15 and 17.9 months, respectively. The median overall survival was not reached at the time of data analysis.6

Motesanib is a novel inhibitor of VEGFR 1-2-3, PDGFR, and c-KIT. It has activity in wild-type but not mutant RET. Motesanib was studied in 91 patients with locally advanced or metastatic MTC in a phase II trial. Only two patients (2%) had an objective response, 81% of patients achieved or maintained stable disease, and 76% experienced a decrease from baseline in tumor measurement. In patients who had tumor marker analysis, 83% and 75% had a decrease in circulating concentrations of calcitonin and carcinoembryonic antigen (CEA), respectively. PFS was also 48 weeks. These data were encouraging and suggested the role of VEGF/RET-targeted therapies for MTC, as suggested in other studies.7

Cabozantinib (XL184) is an oral inhibitor of MET, VEGFR2, and RET. It was studied in a phase I trial in patients with different malignancies (37 had MTC). A partial response was observed in 10 patients (29%), and 25 patients (68%) had either a partial response or prolonged stable disease ≥ 6 months. Responses have been observed in patients with MTC with and without RET mutations. This study showed promising results to conduct an ongoing randomized phase III study of cabozantinib in MTC.8

Clinical trials of vandetanib
Wells et al presented the results of a double-blind randomized phase III trial of vandetanib in locally advanced or metastatic MTC (the ZETA trial). Vandetanib targets the RET, VEGFR, and epidermal growth factor re ceptor signaling pathways. The researchers randomized 331 patients with 90% sporadic MTC 2:1 to receive vandetanib or placebo. Patients in the placebo arm crossed over after disease progression and also received vandetanib.

Statistically significant prolongation of PFS (the primary objective) was observed for vandetanib compared with placebo (hazard ratio, 0.45; P < 0.0001), as well as improvement in objective response rate, disease control rate, time to worsening of pain, and biochemical response.9 This study was the first phase III trial that showed efficacy of a new multitargeted TKI with extension of PFS and improved quality of life in MTC. Subsequent data showed a median PFS of 16.4 months in the placebo arm and at least 22.6 months in the vandetanib arm; however, there was no significant improvement in overall survival. Based on this new information, the US Food and Drug Administration approved vandetanib as a new treatment for MTC in April 2011

Conclusion
These are promising data suggesting efficacy of vandetanib, motesanib, cabozantinib, sorafenib, and sunitinib in the treatment of MTC. The RET-inhibitory effect of these multitargeted agents in RET mutation-driven MTC and their antiangiogenic effect in wild-type RET cases could explain the effectiveness of these agents in these patients. A comparable low partial response rate, but a high rate of stable disease, was observed in all of these phase II studies. However, the same results may not be replicable in phase III studies, as MTC is a clinically heterogeneous disorder. Many challenges remain in selecting appropriate TKIs for MTC.

Correlative studies are required to identify RET genotypes and markers in MTC that could predict the patterns of response or resistance to these TKIs. It would be more challenging to identify these markers and regulatory signaling pathways in wild-type RET MTC. The observation made by the authors that patients without identifiable RET mutations had responses raises the question of whether VEGFR2 inhibition contributes to the treatment effect. We should also be cautious about selecting targeted agents and stepping forward from a phase I study to a randomized phase III trial without having sufficient knowledge of the biology that directs the disease phenotype.

Disclosures
Dr. Mirshahidi is on the speakers’ bureau of Genentech and on the advisory boards of Celgene and Genentech.

References
1. Kraeber-Bodéré F, Goldenberg DM, Chatal JF, Barbet J. Pretargeted radioimmunotherapy in the treatment of metastatic medullary thyroid cancer. Curr Oncol 2009;16:3–8.

2. Eng C, Clayton D, Schuffenecker I, et al. The relationship between specific RET protooncogene mutations and disease phenotype in multiple endocrine neoplasia type 2: international RET mutation consortium analysis. JAMA 1996;276:1575–1579.

3. Carr LL, Mankoff DA, Goulart BH, et al. Phase II study of daily sunitinib in FDG-PETpositive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin Cancer Res 2010;16:5260–5268.

4. De Souza JA, Busaidy N, Zimrin A, et al. Phase II trial of sunitinib in medullary thyroid cancer (MTC). J Clin Oncol 2010;28(15S):5504.

5. Kloos RT, Ringel MD, Knopp MV, et al. Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol 2009;27:1675–1684.

6. Lam ET, Ringel MD, Kloos RT, et al. Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. J Clin Oncol 2010;28:2323–2330.

7. Schlumberger MJ, Elisei R, Bastholt L, et al. Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer. J Clin Oncol 2009;27:3794–3801.

8. Kurzrock R, Cohen EE, Sherman SI, et al. Long-term results in a cohort of medullary thyroid cancer (MTC) patients (pts) in a phase I study of XL184 (BMS 907351), an oral inhibitor of MET, VEGFR2, and RET. J Clin Oncol 2010;28(15S):5502.

9. Wells SA, Robinson BG, Gagel RF, et al. Vandetanib (VAN) in locally advanced or metastatic medullary thyroid cancer (MTC): a randomized, double-blind phase III trial (ZETA). J Clin Oncol 2010;28(15S):5503.

How I treat medullary thyroid cancer
Hamid Mirshahidi, MD

Medullary thyroid carcinoma (MTC) develops from the neuroendocrine parafollicular C cells of the thyroid. These cells secrete neuroendocrine peptides, including calcitonin and carcinoembryonic antigen (CEA). The hereditary form presents as inherited tumor syndromes; they include multiple endocrine neoplasia type 2A (MEN 2A), which is the most common type; MEN 2B; and familial MTC. Typically, patients develop sporadic disease in their 50s or 60s, and those with familial forms of the disease tend to be younger.

Total thyroidectomy with or without central neck dissection is the primary treatment of locoregional disease. Ipsilateral or bilateral modified neck dissection is recommended if ipsilateral or contralateral cervical lymph nodes are clinically or radiologically evident. Adjuvant external-beam radiotherapy (EBRT) may be considered in selected cases, such as for patients with extrathyroidal disease or extensive nodal metastases. Postoperative surveillance of patients with MTC consists of measurement of calcitonin levels, which should be checked preoperatively as a baseline as well. Following thyroidectomy, the calcitonin level reaches a new steady state in about 72 hours. In patients with undetectable calcitonin levels and a normalized CEA level, annual measurement of both markers should still be checked and annual cervical ultrasonography should be considered.

MTC most commonly metastasizes to the liver, bones, and lungs. Palliative resection, EBRT, radiofrequency ablation, or chemoembolization should be considered for patients with locoregional symptoms and distant metastasis to maintain locoregional disease control. Radioiodine treatment and conventional cytotoxic chemotherapy, such as doxorubicin- and dacarbazine-based chemotherapies, are not effective in these patients. Clinical trial enrollment and novel small molecule tyrosine kinase inhibitors targeting the RET and vascular endothelial growth factor receptor should be considered as alternative therapies.