The Journal of Community and Supportive Oncology

The roles of the estrogen receptor signaling pathway in endocrine agents for breast cancer in postmenopausal women and of vandetanib in treating patients with advanced hereditary medullary thyroid cancer are among the topics from the August issue of Community Oncology that are discussed by Dr. David H. Henry.

The roles of the estrogen receptor signaling pathway in endocrine agents for breast cancer in postmenopausal women and of vandetanib in treating patients with advanced hereditary medullary thyroid cancer are among the topics from the August issue of Community Oncology that are discussed by Dr. David H. Henry.

The roles of the estrogen receptor signaling pathway in endocrine agents for breast cancer in postmenopausal women and of vandetanib in treating patients with advanced hereditary medullary thyroid cancer are among the topics from the August issue of Community Oncology that are discussed by Dr. David H. Henry.

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.

By John J. Fried

Almost as soon as the iPhone—and then its imitators—colonized belts, bags, and lab coat pockets, the effort to stay abreast of the latest developments in oncology took on a new dimension. Medical book publishers, medical organizations, and journals flooded iTunes, Android Market, and other Web sites with oncology-related apps for the devices.

Thus, in the smartphone era, while standing by a patient’s bedside, you could tap the eOpioid icon, stab at the screen a couple of times, and obtain the guidance you need to convert her to a different painkiller. In an examining room, you could turn to Blausen Cancer Atlas to help you explain the disease to a prostate cancer patient. Upon learning that a patient had started taking vitamins while receiving chemotherapy, you might consult Epocrates to help your patient avoid harmful interactions.

Somewhere along the line, however, it may have become apparent that there could be drawbacks to using those smartphone apps. The device’s small screen forces you to resort to a lot of finger flicking to move through articles and other printed materials, and it can be difficult to discern important details in graphics. Also, if you are, ahem, of a certain age, the small font size can prove a challenge.

When the iPad—and its imitators— came along, there was reason to hope that there would also be apps designed to take advantage of the larger screens. The endless scrolling and the squinting would be things of the past. Well, in many cases, it has not worked out that way.

Some publishers have gone the extra mile, adapting their medical apps to the much more generous screen size of tablets. Others, however, have taken the easy way out, doing no more than making their existing smartphone apps sort of compatible with tablets. Download many an app to your tablet and you’ll find that the app only fills in a 4-inch area within the tablet’s large screen.

Here, then, is a look at the way some important and popular apps are likely to function on your tablet. Note: All apps were reviewed on an iPad only. Some apps, as noted, are also available for some other devices.

NCCN Guidelines
www.nccn.org/mobile/default.asp
As of July 2011, the National Comprehensive Cancer Network (NCCN) was still trying to decide whether it should develop a full-sized tablet app, according to an e-mail I received from the network’s tech support. While it agonizes over that issue, you will only be able to use the smartphone version of the NCCN Guidelines app on your tablet.

Look on the bright side: If you are already familiar with the smartphone app, you are not likely to find many (if any) surprises when you load it onto your tablet. You will find any guideline of importance to you by selecting it from an alphabetical list or by entering appropriate key words in a search box. You can save the guidelines to your tablet, in case you have to consult them off line. Need help? Click the Settings icon, and then click on Help. You’ll find an e-mail link to use for obtaining support.

You can use the 2× magnifier icon in the lower right-hand corner of the tablet to fill the screen. However, you may find the resolution of the text a little fuzzy and probably not of much help. An app also is available for Android mobile devices.

Epocrates
www.epocrates.com/products
In case you have not run across Epocrates or have not paid attention to it in a while, its products include more than half a dozen digital references and medical tools. Some are free, including a guide to drugs (with a drug interaction checker) as well as an app with more than 100 CMErelated activities. Others carry subscription fees. For $99 a year, for example, you get access to Epocrates Rx Pro, which includes an infectious disease treatment guide and a guide to more than 600 herbal medicines. For $159 a year, you get what is included in Epocrates Rx Pro plus hundreds of disease monographs, high-resolution disease images, and lots of diagnostic and laboratory tests. If you have $199 a year to spare, you can buy Epocrates Essentials Deluxe, which also brings you ICD-9 and CPT codes in addition to the tools included in the other Epocrates works.

The bad news? The apps are smartphone size. As with the NCCN Guidelines app, you can use 2× resolution to fill the tablet screen. But look out for the fuzzy type.

The Epocrates Web site says that as of July 2011, Epocrates “supports Android tablets with OS version 2.2 only. Android tablets with OS 2.3 or higher are not yet officially supported....” That “officially” might be code for “download and see what happens.” Moreover, the website adds, “although it remains possible to install Epocrates to Android tablets with OS 2.3 or higher, the assistance that could be offered in the event of difficulties may be limited.” Support for BlackBerry, the publishers say, is still under consideration.

Medscape
www.medscape.com
Strictly speaking, Medscape is not an oncology reference work. However, with its tools for researching drugs and drug interactions; obtaining upto- date information on 4,000 diseases; reading medical news articles; enrolling in CME courses; and viewing images, videos, and tables, it can come in handy in almost any clinical setting.

To view its 2,500-plus images, watch its 150 videos, obtain the latest medical news, or take a CME course, you’ll need to keep your tablet connected to the Internet. To save battery life, however, you can download much of Medscape’s text-based information to the tablet and read it offline. And, yes, it takes full advantage of every millimeter of your tablet’s screen. There is a Medscape for Android devices running OS 2.1, according to a Medscape representative.

TNM 7.0
www.cancerstaging.org/staging
The TNM 7.0 app may be simplicity at its best. You need only tell it the size of your patient’s primary tumor, whether there are cells in nearby lymph nodes, and whether there are metastases elsewhere in the body. In a split second, you have your answer. TNM 7.0, which will cost you $14.99, is strictly small screen. How- Technology ever, given its uncomplicated interface, its inability to use a tablet’s full real estate is not a disadvantage.

Care360
www.questdiagnostics.com/hcp/connect/physician.html
If you want to see what a first rate tablet app should look like and you refer your patients to Quest Diagnostics for lab work, check out Quest’s Care360 app. It’s full sized, colorful, well organized, and easy to navigate. Care360’s main mission is to give you fast digital access to lab tests you ordered for your patients. You can use the app to order tests and then review the results. The basic Care360 is free. However, for $23 a month per prescribing physician, your practice can also use Care360 to manage prescriptions.  

By John J. Fried

Almost as soon as the iPhone—and then its imitators—colonized belts, bags, and lab coat pockets, the effort to stay abreast of the latest developments in oncology took on a new dimension. Medical book publishers, medical organizations, and journals flooded iTunes, Android Market, and other Web sites with oncology-related apps for the devices.

Thus, in the smartphone era, while standing by a patient’s bedside, you could tap the eOpioid icon, stab at the screen a couple of times, and obtain the guidance you need to convert her to a different painkiller. In an examining room, you could turn to Blausen Cancer Atlas to help you explain the disease to a prostate cancer patient. Upon learning that a patient had started taking vitamins while receiving chemotherapy, you might consult Epocrates to help your patient avoid harmful interactions.

Somewhere along the line, however, it may have become apparent that there could be drawbacks to using those smartphone apps. The device’s small screen forces you to resort to a lot of finger flicking to move through articles and other printed materials, and it can be difficult to discern important details in graphics. Also, if you are, ahem, of a certain age, the small font size can prove a challenge.

When the iPad—and its imitators— came along, there was reason to hope that there would also be apps designed to take advantage of the larger screens. The endless scrolling and the squinting would be things of the past. Well, in many cases, it has not worked out that way.

Some publishers have gone the extra mile, adapting their medical apps to the much more generous screen size of tablets. Others, however, have taken the easy way out, doing no more than making their existing smartphone apps sort of compatible with tablets. Download many an app to your tablet and you’ll find that the app only fills in a 4-inch area within the tablet’s large screen.

Here, then, is a look at the way some important and popular apps are likely to function on your tablet. Note: All apps were reviewed on an iPad only. Some apps, as noted, are also available for some other devices.

NCCN Guidelines
www.nccn.org/mobile/default.asp
As of July 2011, the National Comprehensive Cancer Network (NCCN) was still trying to decide whether it should develop a full-sized tablet app, according to an e-mail I received from the network’s tech support. While it agonizes over that issue, you will only be able to use the smartphone version of the NCCN Guidelines app on your tablet.

Look on the bright side: If you are already familiar with the smartphone app, you are not likely to find many (if any) surprises when you load it onto your tablet. You will find any guideline of importance to you by selecting it from an alphabetical list or by entering appropriate key words in a search box. You can save the guidelines to your tablet, in case you have to consult them off line. Need help? Click the Settings icon, and then click on Help. You’ll find an e-mail link to use for obtaining support.

You can use the 2× magnifier icon in the lower right-hand corner of the tablet to fill the screen. However, you may find the resolution of the text a little fuzzy and probably not of much help. An app also is available for Android mobile devices.

Epocrates
www.epocrates.com/products
In case you have not run across Epocrates or have not paid attention to it in a while, its products include more than half a dozen digital references and medical tools. Some are free, including a guide to drugs (with a drug interaction checker) as well as an app with more than 100 CMErelated activities. Others carry subscription fees. For $99 a year, for example, you get access to Epocrates Rx Pro, which includes an infectious disease treatment guide and a guide to more than 600 herbal medicines. For $159 a year, you get what is included in Epocrates Rx Pro plus hundreds of disease monographs, high-resolution disease images, and lots of diagnostic and laboratory tests. If you have $199 a year to spare, you can buy Epocrates Essentials Deluxe, which also brings you ICD-9 and CPT codes in addition to the tools included in the other Epocrates works.

The bad news? The apps are smartphone size. As with the NCCN Guidelines app, you can use 2× resolution to fill the tablet screen. But look out for the fuzzy type.

The Epocrates Web site says that as of July 2011, Epocrates “supports Android tablets with OS version 2.2 only. Android tablets with OS 2.3 or higher are not yet officially supported....” That “officially” might be code for “download and see what happens.” Moreover, the website adds, “although it remains possible to install Epocrates to Android tablets with OS 2.3 or higher, the assistance that could be offered in the event of difficulties may be limited.” Support for BlackBerry, the publishers say, is still under consideration.

Medscape
www.medscape.com
Strictly speaking, Medscape is not an oncology reference work. However, with its tools for researching drugs and drug interactions; obtaining upto- date information on 4,000 diseases; reading medical news articles; enrolling in CME courses; and viewing images, videos, and tables, it can come in handy in almost any clinical setting.

To view its 2,500-plus images, watch its 150 videos, obtain the latest medical news, or take a CME course, you’ll need to keep your tablet connected to the Internet. To save battery life, however, you can download much of Medscape’s text-based information to the tablet and read it offline. And, yes, it takes full advantage of every millimeter of your tablet’s screen. There is a Medscape for Android devices running OS 2.1, according to a Medscape representative.

TNM 7.0
www.cancerstaging.org/staging
The TNM 7.0 app may be simplicity at its best. You need only tell it the size of your patient’s primary tumor, whether there are cells in nearby lymph nodes, and whether there are metastases elsewhere in the body. In a split second, you have your answer. TNM 7.0, which will cost you $14.99, is strictly small screen. How- Technology ever, given its uncomplicated interface, its inability to use a tablet’s full real estate is not a disadvantage.

Care360
www.questdiagnostics.com/hcp/connect/physician.html
If you want to see what a first rate tablet app should look like and you refer your patients to Quest Diagnostics for lab work, check out Quest’s Care360 app. It’s full sized, colorful, well organized, and easy to navigate. Care360’s main mission is to give you fast digital access to lab tests you ordered for your patients. You can use the app to order tests and then review the results. The basic Care360 is free. However, for $23 a month per prescribing physician, your practice can also use Care360 to manage prescriptions.  

By John J. Fried

Almost as soon as the iPhone—and then its imitators—colonized belts, bags, and lab coat pockets, the effort to stay abreast of the latest developments in oncology took on a new dimension. Medical book publishers, medical organizations, and journals flooded iTunes, Android Market, and other Web sites with oncology-related apps for the devices.

Thus, in the smartphone era, while standing by a patient’s bedside, you could tap the eOpioid icon, stab at the screen a couple of times, and obtain the guidance you need to convert her to a different painkiller. In an examining room, you could turn to Blausen Cancer Atlas to help you explain the disease to a prostate cancer patient. Upon learning that a patient had started taking vitamins while receiving chemotherapy, you might consult Epocrates to help your patient avoid harmful interactions.

Somewhere along the line, however, it may have become apparent that there could be drawbacks to using those smartphone apps. The device’s small screen forces you to resort to a lot of finger flicking to move through articles and other printed materials, and it can be difficult to discern important details in graphics. Also, if you are, ahem, of a certain age, the small font size can prove a challenge.

When the iPad—and its imitators— came along, there was reason to hope that there would also be apps designed to take advantage of the larger screens. The endless scrolling and the squinting would be things of the past. Well, in many cases, it has not worked out that way.

Some publishers have gone the extra mile, adapting their medical apps to the much more generous screen size of tablets. Others, however, have taken the easy way out, doing no more than making their existing smartphone apps sort of compatible with tablets. Download many an app to your tablet and you’ll find that the app only fills in a 4-inch area within the tablet’s large screen.

Here, then, is a look at the way some important and popular apps are likely to function on your tablet. Note: All apps were reviewed on an iPad only. Some apps, as noted, are also available for some other devices.

NCCN Guidelines
www.nccn.org/mobile/default.asp
As of July 2011, the National Comprehensive Cancer Network (NCCN) was still trying to decide whether it should develop a full-sized tablet app, according to an e-mail I received from the network’s tech support. While it agonizes over that issue, you will only be able to use the smartphone version of the NCCN Guidelines app on your tablet.

Look on the bright side: If you are already familiar with the smartphone app, you are not likely to find many (if any) surprises when you load it onto your tablet. You will find any guideline of importance to you by selecting it from an alphabetical list or by entering appropriate key words in a search box. You can save the guidelines to your tablet, in case you have to consult them off line. Need help? Click the Settings icon, and then click on Help. You’ll find an e-mail link to use for obtaining support.

You can use the 2× magnifier icon in the lower right-hand corner of the tablet to fill the screen. However, you may find the resolution of the text a little fuzzy and probably not of much help. An app also is available for Android mobile devices.

Epocrates
www.epocrates.com/products
In case you have not run across Epocrates or have not paid attention to it in a while, its products include more than half a dozen digital references and medical tools. Some are free, including a guide to drugs (with a drug interaction checker) as well as an app with more than 100 CMErelated activities. Others carry subscription fees. For $99 a year, for example, you get access to Epocrates Rx Pro, which includes an infectious disease treatment guide and a guide to more than 600 herbal medicines. For $159 a year, you get what is included in Epocrates Rx Pro plus hundreds of disease monographs, high-resolution disease images, and lots of diagnostic and laboratory tests. If you have $199 a year to spare, you can buy Epocrates Essentials Deluxe, which also brings you ICD-9 and CPT codes in addition to the tools included in the other Epocrates works.

The bad news? The apps are smartphone size. As with the NCCN Guidelines app, you can use 2× resolution to fill the tablet screen. But look out for the fuzzy type.

The Epocrates Web site says that as of July 2011, Epocrates “supports Android tablets with OS version 2.2 only. Android tablets with OS 2.3 or higher are not yet officially supported....” That “officially” might be code for “download and see what happens.” Moreover, the website adds, “although it remains possible to install Epocrates to Android tablets with OS 2.3 or higher, the assistance that could be offered in the event of difficulties may be limited.” Support for BlackBerry, the publishers say, is still under consideration.

Medscape
www.medscape.com
Strictly speaking, Medscape is not an oncology reference work. However, with its tools for researching drugs and drug interactions; obtaining upto- date information on 4,000 diseases; reading medical news articles; enrolling in CME courses; and viewing images, videos, and tables, it can come in handy in almost any clinical setting.

To view its 2,500-plus images, watch its 150 videos, obtain the latest medical news, or take a CME course, you’ll need to keep your tablet connected to the Internet. To save battery life, however, you can download much of Medscape’s text-based information to the tablet and read it offline. And, yes, it takes full advantage of every millimeter of your tablet’s screen. There is a Medscape for Android devices running OS 2.1, according to a Medscape representative.

TNM 7.0
www.cancerstaging.org/staging
The TNM 7.0 app may be simplicity at its best. You need only tell it the size of your patient’s primary tumor, whether there are cells in nearby lymph nodes, and whether there are metastases elsewhere in the body. In a split second, you have your answer. TNM 7.0, which will cost you $14.99, is strictly small screen. How- Technology ever, given its uncomplicated interface, its inability to use a tablet’s full real estate is not a disadvantage.

Care360
www.questdiagnostics.com/hcp/connect/physician.html
If you want to see what a first rate tablet app should look like and you refer your patients to Quest Diagnostics for lab work, check out Quest’s Care360 app. It’s full sized, colorful, well organized, and easy to navigate. Care360’s main mission is to give you fast digital access to lab tests you ordered for your patients. You can use the app to order tests and then review the results. The basic Care360 is free. However, for $23 a month per prescribing physician, your practice can also use Care360 to manage prescriptions.  

Alyssa Trenery,1 Zaina P. Qureshi, PhD, MPH,2,3 Randall Rowen, PharmD,2 Terry Day, MD,4,5 LeAnn Norris, PharmD,2 and Charles L. Bennett, MD, PhD, MPP2,3,4
1 College of Arts and Sciences, University of South Carolina, Columbia, SC; 2 The South Carolina Center of Economic Excellence for Medication Safety, South Carolina College of Pharmacy, Columbia, SC; 3 Health Services, Policy and Management, Arnold School of Public Health, University of South Carolina, Columbia, SC; 4 Hollings Cancer Center of the Medical University of South Carolina, Charleston, SC; and 5 Head and Neck Tumor Center, Medical University of South Carolina, Charleston, SC

First-bite syndrome is a relatively uncommon and recently identified problem associated with surgery involving the parotid gland, neck tumors, parapharyngeal- space masses, and paragangliomas. Treatments for first-bite syndrome offer variable results, with botulinum toxin being perhaps the most promising option.

Case presentation
A 55-year-old man was referred for excision of an asymptomatic left parapharyngeal mass thought to be a carotid body paraganglioma. The patient had been treated previously with antibiotics for a possible sinus infection, without resolution. He underwent CT and angiographic embolization of the tumor prior to excision of the mass. Pretreatment imaging was consistent with a carotid body tumor. The patient was presented with treatment options, including surgical resection.

Preoperatively, the surgeon informed the patient of the potential for neurologic and cranial nerverelated complications and other perioperative risks. Surgery was performed via a transcervical incision. Through careful subadventitial dissection, the tumor was separated from the carotid artery and the carotid artery bifurcation. Excision of the tumor involved separation from and/or mobilization of the marginal mandibular branch of the facial nerve, hypoglossal nerve, spinal accessory nerve, glossopharyngeal nerve, and vagus nerve but was free of the sympathetic trunk and ganglion. However, the tumor was attached to and required ligation of the external carotid artery.

A few days after surgery, the patient experienced pain in his left jaw and ear immediately upon ingesting the first bite of solid food. The sensation was described as a “strong electrical jolt” with severe cramping, which was initially painful but then slowly dissipated after 5–15 minutes. In addition, the patient reported that the pain returned a few minutes after eating and persisted for up to 15 minutes.

About 2 weeks after surgery, the postprandial pain began to diminish in intensity, with complete resolution about 3 weeks thereafter. The first-bite syndrome pain, however, continued with similar intensity and duration 3.5 months post surgery. Selftreatment with acetaminophen and ibuprofen did not eliminate the pain.

Background discussion
First-bite syndrome is a relatively uncommon and recently identified problem associated with surgeries involving the parotid gland and/or the parapharyngeal space.1 The current description of the syndrome was initially reported in 1998 by Netterville,2 and the term “first-bite” syndrome was thought to be an appropriate name for the findings. In 1986, a gastrointestinal surgeon, Haubrich, had associated “first-bite syndrome” with a different clinical syndrome: esophageal dysfunction in patients who complained of an inability to swallow the first few bites of a meal ac companied by retrosternal pain. These individuals’ symptoms were relieved by regurgitation. 3

The true incidence of “first-bite syndrome” as characterized by Netterville is unknown, but cases have been reported after surgery of the parotid gland, neck tumors, parapharyngeal-space masses, and paragangliomas (Table 1).4–7 Those with the syndrome typically develop an intense, sharp, and sometimes cramping pain in the ipsilateral parotid region after the first bite of each meal.3 The severe pain lessens with each subsequent bite of the meal only to return at the first bite of the next meal.2

Netterville et al2 proposed that firstbite syndrome is due to the loss of sympathetic innervation to the parotid gland, resulting in the denervation and supersensitivity of the sympathetic receptors that control the myoepithelial cells. The pain comes from a supramaximal response of the myoepithelial cells stimulated by parasympathetic neurotransmitters, causing a spasm with the initial intake of food after a period of salivary rest (Figure 1). This etiology holds true in the majority of cases, although not all. A common feature for those afflicted with first-bite syndrome is residual parotid gland tissue. In some cases, even the thought of eating may cause a reaction by the salivary glands.

Tumors of the parapharyngeal space are rare; they typically evade diagnosis until found incidentally on imaging for another reason or grow to a size that becomes symptomatic or deforming. Imaging should be performed to evaluate the extent of the mass in the parapharyngeal area and the surrounding vascular structures preoperatively and to assure appropriate surgical planning and patient advisement.1 Biopsy is not recommended for carotid body tumors due to the risk of vascular injury, bleeding, and more severe complications.

Common surgical procedures that a b can result in first-bite syndrome include parotidectomy, neck dissection, transcervical excision of a sympathetic chain schwannoma, paraganglioma excision, and excision of a deep lobe parotid pleomorphic adenoma.8 In a retrospective study by Kawashima et al,4 9 of 22 patients who underwent surgery to remove a tumor in the parapharyngeal space postoperatively developed first-bite syndrome. All five patients who had external carotid artery ligation and resection of the deep lobe in the parotid gland during surgery developed first-bite syndrome. One patient underwent ligation of the external carotid artery from the sympathetic pathway and ligation of the auriculotemporal nerve from the parasympathetic pathway (Figure 1) and did not develop first-bite syndrome.

Therapy options
Treatments for first-bite syndrome offer variable results. Treatment outcomes experienced by patients in the various studies focusing on first-bite and Horner’s syndromes are summarized in Table 2, with only a few therapies having reported positive effects. Concomitant amitriptyline (25 mg at bedtime) reduced the intensity as well as the duration of pain, as reported by Phillips and Farquhar-Smith.9 In the cases from Chiu et al,8 two of three patients with first-bite syndrome found slight pain relief following tympanic neurectomy. Another patient found that amitriptyline and carbamazepine reduced the pain to only the first few bites.9 Casserly et al1 reported on a patient with Horner’s syndrome and first-bite syndrome whose pain improved with pregabalin (Lyrica).

Perhaps the most promising treatment is botulinum toxin. In a study by Ali et al,5 a woman who received no benefit from multiple narcotics and surgeries received an injection of botulinum toxin into the side of the parotid gland, where the pain was most intense. Four months after undergoing tympanic neurectomy (to relieve the symptoms of four surgical resections including mandibular osteotomies and parapharyngeal-space dissection), the patient received an injection of 75 units of botulinum toxin diluted in 2 mL of saline solution into the right parotid gland. Less than 48 hours later, the patient reported that the pain was markedly improved.5 If untreated, the pain associated with first-bite syndrome goes; it has been reported to resolve gradually, up to 21 months following its original onset.

Conclusion
The potential for first-bite syndrome should be included in the preoperative discussion for those undergoing surgery of the parotid gland, neck, and/or parapharyngeal space. Patients who undergo external carotid artery ligation as part of these surgeries or who develop Horner’s syndrome postoperatively appear to be at highest risk for development of firstbite syndrome. Additional reports on the efficacy of botulinum toxin in alleviating the pain associated with firstbite syndrome are eagerly awaited.

Disclosures
The authors have no conflicts of interest to disclose. Funding was provided by the University of South Carolina and the South Carolina Center of Economic Excellence Center for Medication Safety initiative (C.L.B.).

References
1. Casserly P, Kiely P, Fenton JE. Cervical sympathetic chain schwannoma masquerading as a carotid body tumour with a postoperative complication of first-bite syndrome. Eur Arch Otorhinolaryngol 2009;266:1659–1662.

 2. Netterville JL, Jackson CG, Miller FR, Wanamaker JR, Glasscock ME. Vagal paraganglioma: a review of 46 patients treated during a 20-year period. Arch Otolaryngol Head Neck Surg 1998;124:1133–1140.

 3. Haubrich WS. The first-bite syndrome. Henry Ford Hosp Med J 1986;34:275–278.

 4. Kawashima Y, Sumi T, Sugimoto T, Kishimoto S. First-bite syndrome: a review of 29 patients with parapharyngeal space tumor. Auris Nasus Larynx 2008;35:109–113.

 5. Ali MJ, Orloff LA, Lustig LR, Eisele DW. Botulinum toxin in the treatment of first bite syndrome. Otolaryngol Head Neck Surg 2008;139:742–743.

 6. Mandel L, Syrop SB. First-bite syndrome after parapharyngeal surgery for cervical schwannoma. J Am Dent Assoc 2008;139:1480– 1483.

 7. Albasri H, Eley KA, Saeed NR. Chronic pain related to first bite syndrome: report of two cases. Br J Oral Maxillofac Surg 2011;49:154–156.

 8. Chiu AG, Cohen JI, Burningham AR, Andersen PE, Davidson BJ. First bite syndrome: a complication of surgery involving the parapharyngeal space. Head Neck 2002;24:996–999.

 9. Phillips TJ, Farquhar-Smith WP. Pharmacological treatment of a patient with firstbite syndrome. Anaesthesia 2009;64:97–98.

Alyssa Trenery,1 Zaina P. Qureshi, PhD, MPH,2,3 Randall Rowen, PharmD,2 Terry Day, MD,4,5 LeAnn Norris, PharmD,2 and Charles L. Bennett, MD, PhD, MPP2,3,4
1 College of Arts and Sciences, University of South Carolina, Columbia, SC; 2 The South Carolina Center of Economic Excellence for Medication Safety, South Carolina College of Pharmacy, Columbia, SC; 3 Health Services, Policy and Management, Arnold School of Public Health, University of South Carolina, Columbia, SC; 4 Hollings Cancer Center of the Medical University of South Carolina, Charleston, SC; and 5 Head and Neck Tumor Center, Medical University of South Carolina, Charleston, SC

First-bite syndrome is a relatively uncommon and recently identified problem associated with surgery involving the parotid gland, neck tumors, parapharyngeal- space masses, and paragangliomas. Treatments for first-bite syndrome offer variable results, with botulinum toxin being perhaps the most promising option.

Case presentation
A 55-year-old man was referred for excision of an asymptomatic left parapharyngeal mass thought to be a carotid body paraganglioma. The patient had been treated previously with antibiotics for a possible sinus infection, without resolution. He underwent CT and angiographic embolization of the tumor prior to excision of the mass. Pretreatment imaging was consistent with a carotid body tumor. The patient was presented with treatment options, including surgical resection.

Preoperatively, the surgeon informed the patient of the potential for neurologic and cranial nerverelated complications and other perioperative risks. Surgery was performed via a transcervical incision. Through careful subadventitial dissection, the tumor was separated from the carotid artery and the carotid artery bifurcation. Excision of the tumor involved separation from and/or mobilization of the marginal mandibular branch of the facial nerve, hypoglossal nerve, spinal accessory nerve, glossopharyngeal nerve, and vagus nerve but was free of the sympathetic trunk and ganglion. However, the tumor was attached to and required ligation of the external carotid artery.

A few days after surgery, the patient experienced pain in his left jaw and ear immediately upon ingesting the first bite of solid food. The sensation was described as a “strong electrical jolt” with severe cramping, which was initially painful but then slowly dissipated after 5–15 minutes. In addition, the patient reported that the pain returned a few minutes after eating and persisted for up to 15 minutes.

About 2 weeks after surgery, the postprandial pain began to diminish in intensity, with complete resolution about 3 weeks thereafter. The first-bite syndrome pain, however, continued with similar intensity and duration 3.5 months post surgery. Selftreatment with acetaminophen and ibuprofen did not eliminate the pain.

Background discussion
First-bite syndrome is a relatively uncommon and recently identified problem associated with surgeries involving the parotid gland and/or the parapharyngeal space.1 The current description of the syndrome was initially reported in 1998 by Netterville,2 and the term “first-bite” syndrome was thought to be an appropriate name for the findings. In 1986, a gastrointestinal surgeon, Haubrich, had associated “first-bite syndrome” with a different clinical syndrome: esophageal dysfunction in patients who complained of an inability to swallow the first few bites of a meal ac companied by retrosternal pain. These individuals’ symptoms were relieved by regurgitation. 3

The true incidence of “first-bite syndrome” as characterized by Netterville is unknown, but cases have been reported after surgery of the parotid gland, neck tumors, parapharyngeal-space masses, and paragangliomas (Table 1).4–7 Those with the syndrome typically develop an intense, sharp, and sometimes cramping pain in the ipsilateral parotid region after the first bite of each meal.3 The severe pain lessens with each subsequent bite of the meal only to return at the first bite of the next meal.2

Netterville et al2 proposed that firstbite syndrome is due to the loss of sympathetic innervation to the parotid gland, resulting in the denervation and supersensitivity of the sympathetic receptors that control the myoepithelial cells. The pain comes from a supramaximal response of the myoepithelial cells stimulated by parasympathetic neurotransmitters, causing a spasm with the initial intake of food after a period of salivary rest (Figure 1). This etiology holds true in the majority of cases, although not all. A common feature for those afflicted with first-bite syndrome is residual parotid gland tissue. In some cases, even the thought of eating may cause a reaction by the salivary glands.

Tumors of the parapharyngeal space are rare; they typically evade diagnosis until found incidentally on imaging for another reason or grow to a size that becomes symptomatic or deforming. Imaging should be performed to evaluate the extent of the mass in the parapharyngeal area and the surrounding vascular structures preoperatively and to assure appropriate surgical planning and patient advisement.1 Biopsy is not recommended for carotid body tumors due to the risk of vascular injury, bleeding, and more severe complications.

Common surgical procedures that a b can result in first-bite syndrome include parotidectomy, neck dissection, transcervical excision of a sympathetic chain schwannoma, paraganglioma excision, and excision of a deep lobe parotid pleomorphic adenoma.8 In a retrospective study by Kawashima et al,4 9 of 22 patients who underwent surgery to remove a tumor in the parapharyngeal space postoperatively developed first-bite syndrome. All five patients who had external carotid artery ligation and resection of the deep lobe in the parotid gland during surgery developed first-bite syndrome. One patient underwent ligation of the external carotid artery from the sympathetic pathway and ligation of the auriculotemporal nerve from the parasympathetic pathway (Figure 1) and did not develop first-bite syndrome.

Therapy options
Treatments for first-bite syndrome offer variable results. Treatment outcomes experienced by patients in the various studies focusing on first-bite and Horner’s syndromes are summarized in Table 2, with only a few therapies having reported positive effects. Concomitant amitriptyline (25 mg at bedtime) reduced the intensity as well as the duration of pain, as reported by Phillips and Farquhar-Smith.9 In the cases from Chiu et al,8 two of three patients with first-bite syndrome found slight pain relief following tympanic neurectomy. Another patient found that amitriptyline and carbamazepine reduced the pain to only the first few bites.9 Casserly et al1 reported on a patient with Horner’s syndrome and first-bite syndrome whose pain improved with pregabalin (Lyrica).

Perhaps the most promising treatment is botulinum toxin. In a study by Ali et al,5 a woman who received no benefit from multiple narcotics and surgeries received an injection of botulinum toxin into the side of the parotid gland, where the pain was most intense. Four months after undergoing tympanic neurectomy (to relieve the symptoms of four surgical resections including mandibular osteotomies and parapharyngeal-space dissection), the patient received an injection of 75 units of botulinum toxin diluted in 2 mL of saline solution into the right parotid gland. Less than 48 hours later, the patient reported that the pain was markedly improved.5 If untreated, the pain associated with first-bite syndrome goes; it has been reported to resolve gradually, up to 21 months following its original onset.

Conclusion
The potential for first-bite syndrome should be included in the preoperative discussion for those undergoing surgery of the parotid gland, neck, and/or parapharyngeal space. Patients who undergo external carotid artery ligation as part of these surgeries or who develop Horner’s syndrome postoperatively appear to be at highest risk for development of firstbite syndrome. Additional reports on the efficacy of botulinum toxin in alleviating the pain associated with firstbite syndrome are eagerly awaited.

Disclosures
The authors have no conflicts of interest to disclose. Funding was provided by the University of South Carolina and the South Carolina Center of Economic Excellence Center for Medication Safety initiative (C.L.B.).

References
1. Casserly P, Kiely P, Fenton JE. Cervical sympathetic chain schwannoma masquerading as a carotid body tumour with a postoperative complication of first-bite syndrome. Eur Arch Otorhinolaryngol 2009;266:1659–1662.

 2. Netterville JL, Jackson CG, Miller FR, Wanamaker JR, Glasscock ME. Vagal paraganglioma: a review of 46 patients treated during a 20-year period. Arch Otolaryngol Head Neck Surg 1998;124:1133–1140.

 3. Haubrich WS. The first-bite syndrome. Henry Ford Hosp Med J 1986;34:275–278.

 4. Kawashima Y, Sumi T, Sugimoto T, Kishimoto S. First-bite syndrome: a review of 29 patients with parapharyngeal space tumor. Auris Nasus Larynx 2008;35:109–113.

 5. Ali MJ, Orloff LA, Lustig LR, Eisele DW. Botulinum toxin in the treatment of first bite syndrome. Otolaryngol Head Neck Surg 2008;139:742–743.

 6. Mandel L, Syrop SB. First-bite syndrome after parapharyngeal surgery for cervical schwannoma. J Am Dent Assoc 2008;139:1480– 1483.

 7. Albasri H, Eley KA, Saeed NR. Chronic pain related to first bite syndrome: report of two cases. Br J Oral Maxillofac Surg 2011;49:154–156.

 8. Chiu AG, Cohen JI, Burningham AR, Andersen PE, Davidson BJ. First bite syndrome: a complication of surgery involving the parapharyngeal space. Head Neck 2002;24:996–999.

 9. Phillips TJ, Farquhar-Smith WP. Pharmacological treatment of a patient with firstbite syndrome. Anaesthesia 2009;64:97–98.

Alyssa Trenery,1 Zaina P. Qureshi, PhD, MPH,2,3 Randall Rowen, PharmD,2 Terry Day, MD,4,5 LeAnn Norris, PharmD,2 and Charles L. Bennett, MD, PhD, MPP2,3,4
1 College of Arts and Sciences, University of South Carolina, Columbia, SC; 2 The South Carolina Center of Economic Excellence for Medication Safety, South Carolina College of Pharmacy, Columbia, SC; 3 Health Services, Policy and Management, Arnold School of Public Health, University of South Carolina, Columbia, SC; 4 Hollings Cancer Center of the Medical University of South Carolina, Charleston, SC; and 5 Head and Neck Tumor Center, Medical University of South Carolina, Charleston, SC

First-bite syndrome is a relatively uncommon and recently identified problem associated with surgery involving the parotid gland, neck tumors, parapharyngeal- space masses, and paragangliomas. Treatments for first-bite syndrome offer variable results, with botulinum toxin being perhaps the most promising option.

Case presentation
A 55-year-old man was referred for excision of an asymptomatic left parapharyngeal mass thought to be a carotid body paraganglioma. The patient had been treated previously with antibiotics for a possible sinus infection, without resolution. He underwent CT and angiographic embolization of the tumor prior to excision of the mass. Pretreatment imaging was consistent with a carotid body tumor. The patient was presented with treatment options, including surgical resection.

Preoperatively, the surgeon informed the patient of the potential for neurologic and cranial nerverelated complications and other perioperative risks. Surgery was performed via a transcervical incision. Through careful subadventitial dissection, the tumor was separated from the carotid artery and the carotid artery bifurcation. Excision of the tumor involved separation from and/or mobilization of the marginal mandibular branch of the facial nerve, hypoglossal nerve, spinal accessory nerve, glossopharyngeal nerve, and vagus nerve but was free of the sympathetic trunk and ganglion. However, the tumor was attached to and required ligation of the external carotid artery.

A few days after surgery, the patient experienced pain in his left jaw and ear immediately upon ingesting the first bite of solid food. The sensation was described as a “strong electrical jolt” with severe cramping, which was initially painful but then slowly dissipated after 5–15 minutes. In addition, the patient reported that the pain returned a few minutes after eating and persisted for up to 15 minutes.

About 2 weeks after surgery, the postprandial pain began to diminish in intensity, with complete resolution about 3 weeks thereafter. The first-bite syndrome pain, however, continued with similar intensity and duration 3.5 months post surgery. Selftreatment with acetaminophen and ibuprofen did not eliminate the pain.

Background discussion
First-bite syndrome is a relatively uncommon and recently identified problem associated with surgeries involving the parotid gland and/or the parapharyngeal space.1 The current description of the syndrome was initially reported in 1998 by Netterville,2 and the term “first-bite” syndrome was thought to be an appropriate name for the findings. In 1986, a gastrointestinal surgeon, Haubrich, had associated “first-bite syndrome” with a different clinical syndrome: esophageal dysfunction in patients who complained of an inability to swallow the first few bites of a meal ac companied by retrosternal pain. These individuals’ symptoms were relieved by regurgitation. 3

The true incidence of “first-bite syndrome” as characterized by Netterville is unknown, but cases have been reported after surgery of the parotid gland, neck tumors, parapharyngeal-space masses, and paragangliomas (Table 1).4–7 Those with the syndrome typically develop an intense, sharp, and sometimes cramping pain in the ipsilateral parotid region after the first bite of each meal.3 The severe pain lessens with each subsequent bite of the meal only to return at the first bite of the next meal.2

Netterville et al2 proposed that firstbite syndrome is due to the loss of sympathetic innervation to the parotid gland, resulting in the denervation and supersensitivity of the sympathetic receptors that control the myoepithelial cells. The pain comes from a supramaximal response of the myoepithelial cells stimulated by parasympathetic neurotransmitters, causing a spasm with the initial intake of food after a period of salivary rest (Figure 1). This etiology holds true in the majority of cases, although not all. A common feature for those afflicted with first-bite syndrome is residual parotid gland tissue. In some cases, even the thought of eating may cause a reaction by the salivary glands.

Tumors of the parapharyngeal space are rare; they typically evade diagnosis until found incidentally on imaging for another reason or grow to a size that becomes symptomatic or deforming. Imaging should be performed to evaluate the extent of the mass in the parapharyngeal area and the surrounding vascular structures preoperatively and to assure appropriate surgical planning and patient advisement.1 Biopsy is not recommended for carotid body tumors due to the risk of vascular injury, bleeding, and more severe complications.

Common surgical procedures that a b can result in first-bite syndrome include parotidectomy, neck dissection, transcervical excision of a sympathetic chain schwannoma, paraganglioma excision, and excision of a deep lobe parotid pleomorphic adenoma.8 In a retrospective study by Kawashima et al,4 9 of 22 patients who underwent surgery to remove a tumor in the parapharyngeal space postoperatively developed first-bite syndrome. All five patients who had external carotid artery ligation and resection of the deep lobe in the parotid gland during surgery developed first-bite syndrome. One patient underwent ligation of the external carotid artery from the sympathetic pathway and ligation of the auriculotemporal nerve from the parasympathetic pathway (Figure 1) and did not develop first-bite syndrome.

Therapy options
Treatments for first-bite syndrome offer variable results. Treatment outcomes experienced by patients in the various studies focusing on first-bite and Horner’s syndromes are summarized in Table 2, with only a few therapies having reported positive effects. Concomitant amitriptyline (25 mg at bedtime) reduced the intensity as well as the duration of pain, as reported by Phillips and Farquhar-Smith.9 In the cases from Chiu et al,8 two of three patients with first-bite syndrome found slight pain relief following tympanic neurectomy. Another patient found that amitriptyline and carbamazepine reduced the pain to only the first few bites.9 Casserly et al1 reported on a patient with Horner’s syndrome and first-bite syndrome whose pain improved with pregabalin (Lyrica).

Perhaps the most promising treatment is botulinum toxin. In a study by Ali et al,5 a woman who received no benefit from multiple narcotics and surgeries received an injection of botulinum toxin into the side of the parotid gland, where the pain was most intense. Four months after undergoing tympanic neurectomy (to relieve the symptoms of four surgical resections including mandibular osteotomies and parapharyngeal-space dissection), the patient received an injection of 75 units of botulinum toxin diluted in 2 mL of saline solution into the right parotid gland. Less than 48 hours later, the patient reported that the pain was markedly improved.5 If untreated, the pain associated with first-bite syndrome goes; it has been reported to resolve gradually, up to 21 months following its original onset.

Conclusion
The potential for first-bite syndrome should be included in the preoperative discussion for those undergoing surgery of the parotid gland, neck, and/or parapharyngeal space. Patients who undergo external carotid artery ligation as part of these surgeries or who develop Horner’s syndrome postoperatively appear to be at highest risk for development of firstbite syndrome. Additional reports on the efficacy of botulinum toxin in alleviating the pain associated with firstbite syndrome are eagerly awaited.

Disclosures
The authors have no conflicts of interest to disclose. Funding was provided by the University of South Carolina and the South Carolina Center of Economic Excellence Center for Medication Safety initiative (C.L.B.).

References
1. Casserly P, Kiely P, Fenton JE. Cervical sympathetic chain schwannoma masquerading as a carotid body tumour with a postoperative complication of first-bite syndrome. Eur Arch Otorhinolaryngol 2009;266:1659–1662.

 2. Netterville JL, Jackson CG, Miller FR, Wanamaker JR, Glasscock ME. Vagal paraganglioma: a review of 46 patients treated during a 20-year period. Arch Otolaryngol Head Neck Surg 1998;124:1133–1140.

 3. Haubrich WS. The first-bite syndrome. Henry Ford Hosp Med J 1986;34:275–278.

 4. Kawashima Y, Sumi T, Sugimoto T, Kishimoto S. First-bite syndrome: a review of 29 patients with parapharyngeal space tumor. Auris Nasus Larynx 2008;35:109–113.

 5. Ali MJ, Orloff LA, Lustig LR, Eisele DW. Botulinum toxin in the treatment of first bite syndrome. Otolaryngol Head Neck Surg 2008;139:742–743.

 6. Mandel L, Syrop SB. First-bite syndrome after parapharyngeal surgery for cervical schwannoma. J Am Dent Assoc 2008;139:1480– 1483.

 7. Albasri H, Eley KA, Saeed NR. Chronic pain related to first bite syndrome: report of two cases. Br J Oral Maxillofac Surg 2011;49:154–156.

 8. Chiu AG, Cohen JI, Burningham AR, Andersen PE, Davidson BJ. First bite syndrome: a complication of surgery involving the parapharyngeal space. Head Neck 2002;24:996–999.

 9. Phillips TJ, Farquhar-Smith WP. Pharmacological treatment of a patient with firstbite syndrome. Anaesthesia 2009;64:97–98.

Report prepared by Matt Stenger, MS

Medullary thyroid cancer (MTC), the third most common type of thyroid cancer, presents in a sporadic form in about 75% of cases and in a hereditary form in about 25%. Ten-year survival in MTC that has been treated early is between 70% and 80% but is less than 50% in patients with distant metastatic disease. Currently, there is no effective therapy for patients with distant metastases of MTC.

Germline mutations in the RET proto-oncogene cause hereditary MTC, and somatic RET mutations are present in up to 50% of sporadic MTC cases. Thyroid tumors are vascular, and increased expression of vascular endothelial growth factor (VEGF) is associated with increased tumor growth and invasiveness.

Vandetanib (Caprelsa) is a oncedaily oral agent that targets RETdependent, VEGF receptor-dependent, and epidermal growth factor receptor-dependent signaling. In a recent open-label, single-arm, phase II study, vandetanib produced durable objective responses and disease control in patients with unresectable locally advanced or metastatic hereditary MTC.1

Objective responses and disease control
This study consisted of 30 patients (21 women), with a median age of 49 years and a mean time since MTC diagnosis of 16 years. They received vandetanib (300 mg/day) until disease progression, unacceptable toxicity, or withdrawal of consent. Twenty-nine patients had distant metastases, including metastasis to the liver (80%), lymph nodes (70%), and lungs (63%). Patients had a mean of 3.6 disease sites. All of the patients had undergone previous surgery, 37% had received radiation therapy, 20% had had chemotherapy, and 10% had received biologic therapy.

A total of 29 patients were assessable for investigator-judged response, with all 30 being included in the intent-to-treat analysis of efficacy and the safety analysis. At the time of data cutoff, after a median duration of vandetanib treatment of 18.8 months, 17 patients were still receiving vandetanib therapy, including 4 patients who had progressive disease by Response Evaluation Criteria in Solid Tumors (RECIST) but who were judged by their physician to be receiving clinical benefit from treatment. Among the remaining patients, seven discontinued treatment because of adverse events, four discontinued treatment because of disease progression, and two withdrew consent

On investigator assessment, a confirmed partial response (PR) was achieved in six patients (30%), with a median duration of response at data cutoff of 10.2 months (range, 1.9– 16.9 months); three patients subsequently developed progressive disease, at 10.6, 27.3, and 27.9 months. Stable disease for ≥ 24 weeks was observed in 16 patients (53%), yielding a disease  control (objective response plus stable disease) rate of 73%. Six patients had stable disease for ≥ 8 weeks but < 24 weeks, and one patient had progressive disease as best response. Overall, 25 patients (83%) had some reduction in tumor size during vandetanib treatment. In addition to the six patients with a confirmed PR, five had an unconfirmed PR; one had a single RECIST assessment indicating a PR but was found to have progressive disease at next assessment, and the PRs in the other four patients occurred at the final assessment before data cutoff. There was no apparent relationship between specific germline RET mutations and response to vandetanib treatment.

At the time of data cutoff, estimated median progression-free survival (PFS) was 27.9 months; 8 patients (27%) had disease progression, 20 patients (67%) had stable disease and were alive at the time of analysis, and 2 patients had died at > 3 months after the final RECIST assessment (one of cardiac failure and one of colon cancer). On independent central review, 5 patients had a confirmed PR, 22 had stable disease, 1 patient had progressive disease, and 2 patients were not evaluable; the estimated median PFS was 34.7 months.

Primarily low-grade adverse events
Toxicity of vandetanib treatment was manageable in this phase II study. Adverse events were mostly grade 1 or 2, with the most frequent being diarrhea, rash, fatigue, and nausea (Table 1). The most common grade 3 adverse event was QTc prolongation (seven patients); next were diarrhea, nausea, and hypertension (three patients each). Two grade 4 adverse events were reported, consisting of azotemia and muscle weakness; neither one was considered to be related to vandetanib. Other notable adverse events included mild visual disturbances (grade 1) in 3 patients owing to vandetanib-related corneal changes, which were managed with a dose adjustment in vandetanib; hypophosphatemia in 3 patients (grade 2 in 2, grade 1 in 1); and increases in blood pressure > 30 mm Hg systolic in 23 patients, which did not lead to permanent discontinuation of treatment in any of the patients. Of the seven patients (23%) discontinuing vandetanib treatment because of adverse events, five patients had adverse events considered possibly related to vandetanib treatment, including hemorrhagic diarrhea, nausea, increased blood creatinine and blood urea nitrogen levels, acne, and asymptomatic QTc prolongation. Vandetanib dosing was reduced or interrupted in 24 patients (both in 21), with diarrhea being the most common reason (7 patients).

Reference
1. Wells SA Jr, Gosnell JE, Gagel RF, et al. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol 2010;28:767–772.

What’s new, what’s important

Jame Abraham, MD, Editor

Vandetanib (Caprelsa), an oral kinase inhibitor, was approved in April 2011 by the US Food and Drug Administration for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease.

The recommended dose of vandetanib is 300 mg/day PO; in patients with renal impairment, it should be reduced to 200 mg/day. Treatment should be continued until disease progression or intolerable side effects occur.

Vandetanib can prolong the QT interval, and cases of torsades de pointes and sudden death were reported in clinical trials. Because of this risk, vandetanib is only available through a Risk Evaluation and Mitigation Strategy (REMS) program.

Because of the risk of QT prolongation, electrocardiograms and serum levels of potassium, calcium, magnesium, and thyroid stimulating hormone should be monitored at baseline, 2–4 weeks, and 8–12 weeks after starting treatment and every 3 months thereafter or following dose adjustments. The most common (> 20%) adverse drug reactions observed with vandetanib are diarrhea (57%), rash (53%), acne (35%), nausea (33%), hypertension (33%), headache (26%), fatigue (24%), decreased appetite (21%), and abdominal pain (21%). The most common (> 20%) laboratory abnormalities are decreases in serum calcium (57%) and glucose (24%) levels and increases in alanine aminotransferase levels (51%).

Vandetanib is a promising drug for patients with inoperable advanced or metastatic medullary thyroid cancer.

Report prepared by Matt Stenger, MS

Medullary thyroid cancer (MTC), the third most common type of thyroid cancer, presents in a sporadic form in about 75% of cases and in a hereditary form in about 25%. Ten-year survival in MTC that has been treated early is between 70% and 80% but is less than 50% in patients with distant metastatic disease. Currently, there is no effective therapy for patients with distant metastases of MTC.

Germline mutations in the RET proto-oncogene cause hereditary MTC, and somatic RET mutations are present in up to 50% of sporadic MTC cases. Thyroid tumors are vascular, and increased expression of vascular endothelial growth factor (VEGF) is associated with increased tumor growth and invasiveness.

Vandetanib (Caprelsa) is a oncedaily oral agent that targets RETdependent, VEGF receptor-dependent, and epidermal growth factor receptor-dependent signaling. In a recent open-label, single-arm, phase II study, vandetanib produced durable objective responses and disease control in patients with unresectable locally advanced or metastatic hereditary MTC.1

Objective responses and disease control
This study consisted of 30 patients (21 women), with a median age of 49 years and a mean time since MTC diagnosis of 16 years. They received vandetanib (300 mg/day) until disease progression, unacceptable toxicity, or withdrawal of consent. Twenty-nine patients had distant metastases, including metastasis to the liver (80%), lymph nodes (70%), and lungs (63%). Patients had a mean of 3.6 disease sites. All of the patients had undergone previous surgery, 37% had received radiation therapy, 20% had had chemotherapy, and 10% had received biologic therapy.

A total of 29 patients were assessable for investigator-judged response, with all 30 being included in the intent-to-treat analysis of efficacy and the safety analysis. At the time of data cutoff, after a median duration of vandetanib treatment of 18.8 months, 17 patients were still receiving vandetanib therapy, including 4 patients who had progressive disease by Response Evaluation Criteria in Solid Tumors (RECIST) but who were judged by their physician to be receiving clinical benefit from treatment. Among the remaining patients, seven discontinued treatment because of adverse events, four discontinued treatment because of disease progression, and two withdrew consent

On investigator assessment, a confirmed partial response (PR) was achieved in six patients (30%), with a median duration of response at data cutoff of 10.2 months (range, 1.9– 16.9 months); three patients subsequently developed progressive disease, at 10.6, 27.3, and 27.9 months. Stable disease for ≥ 24 weeks was observed in 16 patients (53%), yielding a disease  control (objective response plus stable disease) rate of 73%. Six patients had stable disease for ≥ 8 weeks but < 24 weeks, and one patient had progressive disease as best response. Overall, 25 patients (83%) had some reduction in tumor size during vandetanib treatment. In addition to the six patients with a confirmed PR, five had an unconfirmed PR; one had a single RECIST assessment indicating a PR but was found to have progressive disease at next assessment, and the PRs in the other four patients occurred at the final assessment before data cutoff. There was no apparent relationship between specific germline RET mutations and response to vandetanib treatment.

At the time of data cutoff, estimated median progression-free survival (PFS) was 27.9 months; 8 patients (27%) had disease progression, 20 patients (67%) had stable disease and were alive at the time of analysis, and 2 patients had died at > 3 months after the final RECIST assessment (one of cardiac failure and one of colon cancer). On independent central review, 5 patients had a confirmed PR, 22 had stable disease, 1 patient had progressive disease, and 2 patients were not evaluable; the estimated median PFS was 34.7 months.

Primarily low-grade adverse events
Toxicity of vandetanib treatment was manageable in this phase II study. Adverse events were mostly grade 1 or 2, with the most frequent being diarrhea, rash, fatigue, and nausea (Table 1). The most common grade 3 adverse event was QTc prolongation (seven patients); next were diarrhea, nausea, and hypertension (three patients each). Two grade 4 adverse events were reported, consisting of azotemia and muscle weakness; neither one was considered to be related to vandetanib. Other notable adverse events included mild visual disturbances (grade 1) in 3 patients owing to vandetanib-related corneal changes, which were managed with a dose adjustment in vandetanib; hypophosphatemia in 3 patients (grade 2 in 2, grade 1 in 1); and increases in blood pressure > 30 mm Hg systolic in 23 patients, which did not lead to permanent discontinuation of treatment in any of the patients. Of the seven patients (23%) discontinuing vandetanib treatment because of adverse events, five patients had adverse events considered possibly related to vandetanib treatment, including hemorrhagic diarrhea, nausea, increased blood creatinine and blood urea nitrogen levels, acne, and asymptomatic QTc prolongation. Vandetanib dosing was reduced or interrupted in 24 patients (both in 21), with diarrhea being the most common reason (7 patients).

Reference
1. Wells SA Jr, Gosnell JE, Gagel RF, et al. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol 2010;28:767–772.

What’s new, what’s important

Jame Abraham, MD, Editor

Vandetanib (Caprelsa), an oral kinase inhibitor, was approved in April 2011 by the US Food and Drug Administration for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease.

The recommended dose of vandetanib is 300 mg/day PO; in patients with renal impairment, it should be reduced to 200 mg/day. Treatment should be continued until disease progression or intolerable side effects occur.

Vandetanib can prolong the QT interval, and cases of torsades de pointes and sudden death were reported in clinical trials. Because of this risk, vandetanib is only available through a Risk Evaluation and Mitigation Strategy (REMS) program.

Because of the risk of QT prolongation, electrocardiograms and serum levels of potassium, calcium, magnesium, and thyroid stimulating hormone should be monitored at baseline, 2–4 weeks, and 8–12 weeks after starting treatment and every 3 months thereafter or following dose adjustments. The most common (> 20%) adverse drug reactions observed with vandetanib are diarrhea (57%), rash (53%), acne (35%), nausea (33%), hypertension (33%), headache (26%), fatigue (24%), decreased appetite (21%), and abdominal pain (21%). The most common (> 20%) laboratory abnormalities are decreases in serum calcium (57%) and glucose (24%) levels and increases in alanine aminotransferase levels (51%).

Vandetanib is a promising drug for patients with inoperable advanced or metastatic medullary thyroid cancer.

Report prepared by Matt Stenger, MS

Medullary thyroid cancer (MTC), the third most common type of thyroid cancer, presents in a sporadic form in about 75% of cases and in a hereditary form in about 25%. Ten-year survival in MTC that has been treated early is between 70% and 80% but is less than 50% in patients with distant metastatic disease. Currently, there is no effective therapy for patients with distant metastases of MTC.

Germline mutations in the RET proto-oncogene cause hereditary MTC, and somatic RET mutations are present in up to 50% of sporadic MTC cases. Thyroid tumors are vascular, and increased expression of vascular endothelial growth factor (VEGF) is associated with increased tumor growth and invasiveness.

Vandetanib (Caprelsa) is a oncedaily oral agent that targets RETdependent, VEGF receptor-dependent, and epidermal growth factor receptor-dependent signaling. In a recent open-label, single-arm, phase II study, vandetanib produced durable objective responses and disease control in patients with unresectable locally advanced or metastatic hereditary MTC.1

Objective responses and disease control
This study consisted of 30 patients (21 women), with a median age of 49 years and a mean time since MTC diagnosis of 16 years. They received vandetanib (300 mg/day) until disease progression, unacceptable toxicity, or withdrawal of consent. Twenty-nine patients had distant metastases, including metastasis to the liver (80%), lymph nodes (70%), and lungs (63%). Patients had a mean of 3.6 disease sites. All of the patients had undergone previous surgery, 37% had received radiation therapy, 20% had had chemotherapy, and 10% had received biologic therapy.

A total of 29 patients were assessable for investigator-judged response, with all 30 being included in the intent-to-treat analysis of efficacy and the safety analysis. At the time of data cutoff, after a median duration of vandetanib treatment of 18.8 months, 17 patients were still receiving vandetanib therapy, including 4 patients who had progressive disease by Response Evaluation Criteria in Solid Tumors (RECIST) but who were judged by their physician to be receiving clinical benefit from treatment. Among the remaining patients, seven discontinued treatment because of adverse events, four discontinued treatment because of disease progression, and two withdrew consent

On investigator assessment, a confirmed partial response (PR) was achieved in six patients (30%), with a median duration of response at data cutoff of 10.2 months (range, 1.9– 16.9 months); three patients subsequently developed progressive disease, at 10.6, 27.3, and 27.9 months. Stable disease for ≥ 24 weeks was observed in 16 patients (53%), yielding a disease  control (objective response plus stable disease) rate of 73%. Six patients had stable disease for ≥ 8 weeks but < 24 weeks, and one patient had progressive disease as best response. Overall, 25 patients (83%) had some reduction in tumor size during vandetanib treatment. In addition to the six patients with a confirmed PR, five had an unconfirmed PR; one had a single RECIST assessment indicating a PR but was found to have progressive disease at next assessment, and the PRs in the other four patients occurred at the final assessment before data cutoff. There was no apparent relationship between specific germline RET mutations and response to vandetanib treatment.

At the time of data cutoff, estimated median progression-free survival (PFS) was 27.9 months; 8 patients (27%) had disease progression, 20 patients (67%) had stable disease and were alive at the time of analysis, and 2 patients had died at > 3 months after the final RECIST assessment (one of cardiac failure and one of colon cancer). On independent central review, 5 patients had a confirmed PR, 22 had stable disease, 1 patient had progressive disease, and 2 patients were not evaluable; the estimated median PFS was 34.7 months.

Primarily low-grade adverse events
Toxicity of vandetanib treatment was manageable in this phase II study. Adverse events were mostly grade 1 or 2, with the most frequent being diarrhea, rash, fatigue, and nausea (Table 1). The most common grade 3 adverse event was QTc prolongation (seven patients); next were diarrhea, nausea, and hypertension (three patients each). Two grade 4 adverse events were reported, consisting of azotemia and muscle weakness; neither one was considered to be related to vandetanib. Other notable adverse events included mild visual disturbances (grade 1) in 3 patients owing to vandetanib-related corneal changes, which were managed with a dose adjustment in vandetanib; hypophosphatemia in 3 patients (grade 2 in 2, grade 1 in 1); and increases in blood pressure > 30 mm Hg systolic in 23 patients, which did not lead to permanent discontinuation of treatment in any of the patients. Of the seven patients (23%) discontinuing vandetanib treatment because of adverse events, five patients had adverse events considered possibly related to vandetanib treatment, including hemorrhagic diarrhea, nausea, increased blood creatinine and blood urea nitrogen levels, acne, and asymptomatic QTc prolongation. Vandetanib dosing was reduced or interrupted in 24 patients (both in 21), with diarrhea being the most common reason (7 patients).

Reference
1. Wells SA Jr, Gosnell JE, Gagel RF, et al. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol 2010;28:767–772.

What’s new, what’s important

Jame Abraham, MD, Editor

Vandetanib (Caprelsa), an oral kinase inhibitor, was approved in April 2011 by the US Food and Drug Administration for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease.

The recommended dose of vandetanib is 300 mg/day PO; in patients with renal impairment, it should be reduced to 200 mg/day. Treatment should be continued until disease progression or intolerable side effects occur.

Vandetanib can prolong the QT interval, and cases of torsades de pointes and sudden death were reported in clinical trials. Because of this risk, vandetanib is only available through a Risk Evaluation and Mitigation Strategy (REMS) program.

Because of the risk of QT prolongation, electrocardiograms and serum levels of potassium, calcium, magnesium, and thyroid stimulating hormone should be monitored at baseline, 2–4 weeks, and 8–12 weeks after starting treatment and every 3 months thereafter or following dose adjustments. The most common (> 20%) adverse drug reactions observed with vandetanib are diarrhea (57%), rash (53%), acne (35%), nausea (33%), hypertension (33%), headache (26%), fatigue (24%), decreased appetite (21%), and abdominal pain (21%). The most common (> 20%) laboratory abnormalities are decreases in serum calcium (57%) and glucose (24%) levels and increases in alanine aminotransferase levels (51%).

Vandetanib is a promising drug for patients with inoperable advanced or metastatic medullary thyroid cancer.

Adam M. Brufsky, MD, PhD
University of Pittsburgh School of Medicine, Pittsburgh, PA

Estrogen receptor (ER) signaling plays a critical role in many breast cancers. As a result, endocrine therapy is a mainstay in the treatment plan for patients with hormone receptor-positive breast cancer. Although patients with metastatic breast cancer (MBC) are often given several lines of endocrine therapy throughout the course of their disease, the optimal sequence of and exact mechanisms of resistance to endocrine therapy remain unclear. Endocrine therapies include aromatase inhibitors, selective ER modulators, and selective ER downregulators. These agents interfere with ER signaling and inhibit breast cancer growth, but their mechanisms of action (MOAs) are distinct and potential mechanisms of resistance vary. Patient-specific factors (eg, tumor characteristics, burden of disease, patient preferences, and treatment history) and the MOAs of the available agents are important considerations. This review discusses the latest understanding of ER biology, the mechanistic differences between endocrine therapies, and future directions in endocrine therapy for MBC.

Although many different agents have been used in the clinic to treat these patients, aromatase inhibitors (AIs) and antiestrogens form the two major categories of endocrine therapy in current use. These two types of agents have distinct mechanisms of action (MOAs).1 AIs reduce circulating estrogen levels by preventing the conversion of androstenedione into estrogen in peripheral tissues. 1 Antiestrogens, also referred to as ER antagonists, can be further classified into two subgroups based on their MOA: the selective ER modulators (SERMs), typified by tamoxifen, and the selective ER downregulators (SERDs), exemplified by fulvestrant (Faslodex).1

A number of randomized clinical studies have demonstrated the efficacy of tamoxifen and the AIs (anastrozole, letrozole, and exemestane) in the adjuvant2–5 and metastatic6–8 settings. Fulvestrant has demonstrated effectiveness in the metastatic setting.9–13

For a PDF of the complete article, click on the link to the left of this article.

Adam M. Brufsky, MD, PhD
University of Pittsburgh School of Medicine, Pittsburgh, PA

Estrogen receptor (ER) signaling plays a critical role in many breast cancers. As a result, endocrine therapy is a mainstay in the treatment plan for patients with hormone receptor-positive breast cancer. Although patients with metastatic breast cancer (MBC) are often given several lines of endocrine therapy throughout the course of their disease, the optimal sequence of and exact mechanisms of resistance to endocrine therapy remain unclear. Endocrine therapies include aromatase inhibitors, selective ER modulators, and selective ER downregulators. These agents interfere with ER signaling and inhibit breast cancer growth, but their mechanisms of action (MOAs) are distinct and potential mechanisms of resistance vary. Patient-specific factors (eg, tumor characteristics, burden of disease, patient preferences, and treatment history) and the MOAs of the available agents are important considerations. This review discusses the latest understanding of ER biology, the mechanistic differences between endocrine therapies, and future directions in endocrine therapy for MBC.

Although many different agents have been used in the clinic to treat these patients, aromatase inhibitors (AIs) and antiestrogens form the two major categories of endocrine therapy in current use. These two types of agents have distinct mechanisms of action (MOAs).1 AIs reduce circulating estrogen levels by preventing the conversion of androstenedione into estrogen in peripheral tissues. 1 Antiestrogens, also referred to as ER antagonists, can be further classified into two subgroups based on their MOA: the selective ER modulators (SERMs), typified by tamoxifen, and the selective ER downregulators (SERDs), exemplified by fulvestrant (Faslodex).1

A number of randomized clinical studies have demonstrated the efficacy of tamoxifen and the AIs (anastrozole, letrozole, and exemestane) in the adjuvant2–5 and metastatic6–8 settings. Fulvestrant has demonstrated effectiveness in the metastatic setting.9–13

For a PDF of the complete article, click on the link to the left of this article.

Adam M. Brufsky, MD, PhD
University of Pittsburgh School of Medicine, Pittsburgh, PA

Estrogen receptor (ER) signaling plays a critical role in many breast cancers. As a result, endocrine therapy is a mainstay in the treatment plan for patients with hormone receptor-positive breast cancer. Although patients with metastatic breast cancer (MBC) are often given several lines of endocrine therapy throughout the course of their disease, the optimal sequence of and exact mechanisms of resistance to endocrine therapy remain unclear. Endocrine therapies include aromatase inhibitors, selective ER modulators, and selective ER downregulators. These agents interfere with ER signaling and inhibit breast cancer growth, but their mechanisms of action (MOAs) are distinct and potential mechanisms of resistance vary. Patient-specific factors (eg, tumor characteristics, burden of disease, patient preferences, and treatment history) and the MOAs of the available agents are important considerations. This review discusses the latest understanding of ER biology, the mechanistic differences between endocrine therapies, and future directions in endocrine therapy for MBC.

Although many different agents have been used in the clinic to treat these patients, aromatase inhibitors (AIs) and antiestrogens form the two major categories of endocrine therapy in current use. These two types of agents have distinct mechanisms of action (MOAs).1 AIs reduce circulating estrogen levels by preventing the conversion of androstenedione into estrogen in peripheral tissues. 1 Antiestrogens, also referred to as ER antagonists, can be further classified into two subgroups based on their MOA: the selective ER modulators (SERMs), typified by tamoxifen, and the selective ER downregulators (SERDs), exemplified by fulvestrant (Faslodex).1

A number of randomized clinical studies have demonstrated the efficacy of tamoxifen and the AIs (anastrozole, letrozole, and exemestane) in the adjuvant2–5 and metastatic6–8 settings. Fulvestrant has demonstrated effectiveness in the metastatic setting.9–13

For a PDF of the complete article, click on the link to the left of this article.

Dr. David H Henry summarizes key articles in the July issue of the journal Community Oncology. Topics include Exemestane for postmenopausal women at increased risk of breast cancer and a summary of key research from the 2011 ASCO meeting, including crizotinib for ALK+ non-small cell lung cancer and vemurafenib and ipilimumab for metastatic melanoma.

Dr. David H Henry summarizes key articles in the July issue of the journal Community Oncology. Topics include Exemestane for postmenopausal women at increased risk of breast cancer and a summary of key research from the 2011 ASCO meeting, including crizotinib for ALK+ non-small cell lung cancer and vemurafenib and ipilimumab for metastatic melanoma.

Dr. David H Henry summarizes key articles in the July issue of the journal Community Oncology. Topics include Exemestane for postmenopausal women at increased risk of breast cancer and a summary of key research from the 2011 ASCO meeting, including crizotinib for ALK+ non-small cell lung cancer and vemurafenib and ipilimumab for metastatic melanoma.