Head & Neck/Thyroid Cancers

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.

Despite an overall increase in the use of radioactive iodine following total thyroidectomy for primary thyroid cancer, there are still significant variations in use among institutions and across demographically different populations.

That variation, however, doesn’t appear to have had much of an impact on disease severity, according to a study published online Aug. 16 in JAMA.

"The recent increase in the incidence of small, low-risk thyroid cancer mandates an understanding of patterns of care in thyroid cancer," wrote lead author Dr. Megan R. Haymart and her colleagues (JAMA 2011;306:721-8).

Moreover, "the significant between-hospital variation in radioactive iodine use suggests clinical uncertainty about the role of radioactive iodine in thyroid cancer management."

Dr. Haymart, of the University of Michigan, Ann Arbor, and her coauthors analyzed the cases of 189,219 patients with primary thyroid cancer who underwent total thyroidectomy between 1990 and 2008. Data were culled from the National Cancer Database, which captures close to 85% of all thyroid cancers in the United States, according to the investigators.

They found that in 1990, 1,373 of 3,397 patients with the diagnosis received radioactive iodine (40%).

By 2008, that number had jumped to 11,539 of 20,620 cases (56%) – a significant increase (P less than .001).

The authors then conducted a subgroup analysis involving 85,948 patients diagnosed between 2004 and 2008, in order to "define the most contemporary practice patterns." They found that "younger age and absence of comorbidity were associated with a small but significantly greater likelihood of receiving radioactive iodine after total thyroidectomy."

Younger patients (aged 44 years and less) had an odds ratio of 2.15 for receiving the treatment compared with patients aged 60 years and older (95% confidence interval, 2.04-2.26).

Similarly, patients with a Charlson-Deyo comorbidity index score of 0 registered an OR of 1.19 for receiving radioactive iodine following thyroidectomy, compared to patients with scores of 2 or greater (95% CI, 1.07-1.35).

Factors significantly associated with a lower rate of radioactive iodine use were female sex (OR, 0.87; 95% CI, 0.84-0.91), African American race (OR, 0.83; 95% CI, 0.77-0.89), and the absence of private/government insurance (OR, 0.84; 95% CI, 0.81-0.88).

By comparison, disease severity appeared to play less of a role in treatment patterns. There was a significant difference between radioactive iodine use between American Joint Committee on Cancer designation stage I and stage IV (OR for stage I vs. stage IV, 0.34; 95% CI, 0.31-0.37). However, no difference in use existed between stage II and stage IV (OR for stage II vs. stage IV, 0.97; 95% CI, 0.88-1.07). Nor was there a significant difference in use between stage III and stage IV (OR, 1.06; 95% CI, 0.95-1.17).

The number of cases of post-thyroidectomy thyroid cancers seen at a particular institution per year also affected the use of radioactive treatment. Compared with high-volume institutions, defined as treating 35 or more cases per year, there was significantly less use of radioactive iodine at low-volume centers, treating 6 or fewer cases per year (OR, 0.44; 95% CI, 0.33-0.58) and medium-volume centers, treating 7-11 cases per year (OR, 0.62; 95% CI, 0.48-0.80).

According to Dr. Haymart and her colleagues, the conflicting use patterns are not easily explained, although some uncertainty may be due to a lack of clinical trials, as well as previous conflicting, single-institution studies. "Because of limited clinical evidence, clinical guidelines have left radioactive iodine use to physician discretion in many cases," they wrote.

"In the interest of curbing the increasing health care costs and preventing both overtreatment and undertreatment of disease, indications for radioactive iodine should be clearly defined and disease severity should become the primary driver of radioactive iodine use," they said.

The authors reported no potential conflicts of interest. The study was funded by a grant to Dr. Haymart from the National Institutes of Health.

Despite an overall increase in the use of radioactive iodine following total thyroidectomy for primary thyroid cancer, there are still significant variations in use among institutions and across demographically different populations.

That variation, however, doesn’t appear to have had much of an impact on disease severity, according to a study published online Aug. 16 in JAMA.

"The recent increase in the incidence of small, low-risk thyroid cancer mandates an understanding of patterns of care in thyroid cancer," wrote lead author Dr. Megan R. Haymart and her colleagues (JAMA 2011;306:721-8).

Moreover, "the significant between-hospital variation in radioactive iodine use suggests clinical uncertainty about the role of radioactive iodine in thyroid cancer management."

Dr. Haymart, of the University of Michigan, Ann Arbor, and her coauthors analyzed the cases of 189,219 patients with primary thyroid cancer who underwent total thyroidectomy between 1990 and 2008. Data were culled from the National Cancer Database, which captures close to 85% of all thyroid cancers in the United States, according to the investigators.

They found that in 1990, 1,373 of 3,397 patients with the diagnosis received radioactive iodine (40%).

By 2008, that number had jumped to 11,539 of 20,620 cases (56%) – a significant increase (P less than .001).

The authors then conducted a subgroup analysis involving 85,948 patients diagnosed between 2004 and 2008, in order to "define the most contemporary practice patterns." They found that "younger age and absence of comorbidity were associated with a small but significantly greater likelihood of receiving radioactive iodine after total thyroidectomy."

Younger patients (aged 44 years and less) had an odds ratio of 2.15 for receiving the treatment compared with patients aged 60 years and older (95% confidence interval, 2.04-2.26).

Similarly, patients with a Charlson-Deyo comorbidity index score of 0 registered an OR of 1.19 for receiving radioactive iodine following thyroidectomy, compared to patients with scores of 2 or greater (95% CI, 1.07-1.35).

Factors significantly associated with a lower rate of radioactive iodine use were female sex (OR, 0.87; 95% CI, 0.84-0.91), African American race (OR, 0.83; 95% CI, 0.77-0.89), and the absence of private/government insurance (OR, 0.84; 95% CI, 0.81-0.88).

By comparison, disease severity appeared to play less of a role in treatment patterns. There was a significant difference between radioactive iodine use between American Joint Committee on Cancer designation stage I and stage IV (OR for stage I vs. stage IV, 0.34; 95% CI, 0.31-0.37). However, no difference in use existed between stage II and stage IV (OR for stage II vs. stage IV, 0.97; 95% CI, 0.88-1.07). Nor was there a significant difference in use between stage III and stage IV (OR, 1.06; 95% CI, 0.95-1.17).

The number of cases of post-thyroidectomy thyroid cancers seen at a particular institution per year also affected the use of radioactive treatment. Compared with high-volume institutions, defined as treating 35 or more cases per year, there was significantly less use of radioactive iodine at low-volume centers, treating 6 or fewer cases per year (OR, 0.44; 95% CI, 0.33-0.58) and medium-volume centers, treating 7-11 cases per year (OR, 0.62; 95% CI, 0.48-0.80).

According to Dr. Haymart and her colleagues, the conflicting use patterns are not easily explained, although some uncertainty may be due to a lack of clinical trials, as well as previous conflicting, single-institution studies. "Because of limited clinical evidence, clinical guidelines have left radioactive iodine use to physician discretion in many cases," they wrote.

"In the interest of curbing the increasing health care costs and preventing both overtreatment and undertreatment of disease, indications for radioactive iodine should be clearly defined and disease severity should become the primary driver of radioactive iodine use," they said.

The authors reported no potential conflicts of interest. The study was funded by a grant to Dr. Haymart from the National Institutes of Health.

Despite an overall increase in the use of radioactive iodine following total thyroidectomy for primary thyroid cancer, there are still significant variations in use among institutions and across demographically different populations.

That variation, however, doesn’t appear to have had much of an impact on disease severity, according to a study published online Aug. 16 in JAMA.

"The recent increase in the incidence of small, low-risk thyroid cancer mandates an understanding of patterns of care in thyroid cancer," wrote lead author Dr. Megan R. Haymart and her colleagues (JAMA 2011;306:721-8).

Moreover, "the significant between-hospital variation in radioactive iodine use suggests clinical uncertainty about the role of radioactive iodine in thyroid cancer management."

Dr. Haymart, of the University of Michigan, Ann Arbor, and her coauthors analyzed the cases of 189,219 patients with primary thyroid cancer who underwent total thyroidectomy between 1990 and 2008. Data were culled from the National Cancer Database, which captures close to 85% of all thyroid cancers in the United States, according to the investigators.

They found that in 1990, 1,373 of 3,397 patients with the diagnosis received radioactive iodine (40%).

By 2008, that number had jumped to 11,539 of 20,620 cases (56%) – a significant increase (P less than .001).

The authors then conducted a subgroup analysis involving 85,948 patients diagnosed between 2004 and 2008, in order to "define the most contemporary practice patterns." They found that "younger age and absence of comorbidity were associated with a small but significantly greater likelihood of receiving radioactive iodine after total thyroidectomy."

Younger patients (aged 44 years and less) had an odds ratio of 2.15 for receiving the treatment compared with patients aged 60 years and older (95% confidence interval, 2.04-2.26).

Similarly, patients with a Charlson-Deyo comorbidity index score of 0 registered an OR of 1.19 for receiving radioactive iodine following thyroidectomy, compared to patients with scores of 2 or greater (95% CI, 1.07-1.35).

Factors significantly associated with a lower rate of radioactive iodine use were female sex (OR, 0.87; 95% CI, 0.84-0.91), African American race (OR, 0.83; 95% CI, 0.77-0.89), and the absence of private/government insurance (OR, 0.84; 95% CI, 0.81-0.88).

By comparison, disease severity appeared to play less of a role in treatment patterns. There was a significant difference between radioactive iodine use between American Joint Committee on Cancer designation stage I and stage IV (OR for stage I vs. stage IV, 0.34; 95% CI, 0.31-0.37). However, no difference in use existed between stage II and stage IV (OR for stage II vs. stage IV, 0.97; 95% CI, 0.88-1.07). Nor was there a significant difference in use between stage III and stage IV (OR, 1.06; 95% CI, 0.95-1.17).

The number of cases of post-thyroidectomy thyroid cancers seen at a particular institution per year also affected the use of radioactive treatment. Compared with high-volume institutions, defined as treating 35 or more cases per year, there was significantly less use of radioactive iodine at low-volume centers, treating 6 or fewer cases per year (OR, 0.44; 95% CI, 0.33-0.58) and medium-volume centers, treating 7-11 cases per year (OR, 0.62; 95% CI, 0.48-0.80).

According to Dr. Haymart and her colleagues, the conflicting use patterns are not easily explained, although some uncertainty may be due to a lack of clinical trials, as well as previous conflicting, single-institution studies. "Because of limited clinical evidence, clinical guidelines have left radioactive iodine use to physician discretion in many cases," they wrote.

"In the interest of curbing the increasing health care costs and preventing both overtreatment and undertreatment of disease, indications for radioactive iodine should be clearly defined and disease severity should become the primary driver of radioactive iodine use," they said.

The authors reported no potential conflicts of interest. The study was funded by a grant to Dr. Haymart from the National Institutes of Health.

Meet the Health Buddy, a telehealth technology intervention that significantly improved the symptoms and quality of life for head and neck cancer patients in a randomized trial by delivering symptom management in the comfort of the patient’s home, computer not required.

Cynthia Ellis Keeney, RN, MSN, couldn’t contain her excitement as she presented her group’s study findings in a poster session at a palliative care summit in Bethesda, Md. The meeting was sponsored by the National Institute of Nursing Research and partner organizations.

Photo credit: Courtesy of Wikimedia Commons user Arglos, collected via GNU Free Documentation License

Head and neck cancer patients suffer terribly from a range of symptoms, and they often find it difficult to talk and uncomfortable to leave the house, said Ms. Keeney.

She and her colleagues randomized 80 newly diagnosed head and neck cancer patients to an intervention with a telehealth device or usual care. The telehealth device was connected to a landline phone and featured a small screen with large buttons.

The device allowed patients with limited computer savvy and no internet access to benefit from the convenience of the telehealth intervention, Ms. Keeney emphasized.

Each day, a green light on the Health Buddy would blink, prompting patients to respond to questions about how they were feeling that day. Based on their answers, the system would recommend an intervention, such as asking the doctor for a drug to treat a particular symptom (for example, constipation). Symptom control algorithms had been used to generate questions based on symptoms that are most likely to occur during the active phase of cancer treatment. The phone number of the patient’s doctor had been programmed into the system for immediate access.

After the active phase of their cancer treatments, patients in the Health Buddy group reported significantly higher physical well being than did controls.

Although the doctors and patients weren’t connected visually in real time, the patients felt that being able to define their symptoms through the Health Buddy and receive suggestions for symptom management allowed them to have better conversations with their doctors, Ms. Keeney said. As a result, “the patients in the intervention group thought they got better care,” than if they had not used the Health Buddy, she added.

–Heidi Splete (on Twitter @hsplete)

Meet the Health Buddy, a telehealth technology intervention that significantly improved the symptoms and quality of life for head and neck cancer patients in a randomized trial by delivering symptom management in the comfort of the patient’s home, computer not required.

Cynthia Ellis Keeney, RN, MSN, couldn’t contain her excitement as she presented her group’s study findings in a poster session at a palliative care summit in Bethesda, Md. The meeting was sponsored by the National Institute of Nursing Research and partner organizations.

Photo credit: Courtesy of Wikimedia Commons user Arglos, collected via GNU Free Documentation License

Head and neck cancer patients suffer terribly from a range of symptoms, and they often find it difficult to talk and uncomfortable to leave the house, said Ms. Keeney.

She and her colleagues randomized 80 newly diagnosed head and neck cancer patients to an intervention with a telehealth device or usual care. The telehealth device was connected to a landline phone and featured a small screen with large buttons.

The device allowed patients with limited computer savvy and no internet access to benefit from the convenience of the telehealth intervention, Ms. Keeney emphasized.

Each day, a green light on the Health Buddy would blink, prompting patients to respond to questions about how they were feeling that day. Based on their answers, the system would recommend an intervention, such as asking the doctor for a drug to treat a particular symptom (for example, constipation). Symptom control algorithms had been used to generate questions based on symptoms that are most likely to occur during the active phase of cancer treatment. The phone number of the patient’s doctor had been programmed into the system for immediate access.

After the active phase of their cancer treatments, patients in the Health Buddy group reported significantly higher physical well being than did controls.

Although the doctors and patients weren’t connected visually in real time, the patients felt that being able to define their symptoms through the Health Buddy and receive suggestions for symptom management allowed them to have better conversations with their doctors, Ms. Keeney said. As a result, “the patients in the intervention group thought they got better care,” than if they had not used the Health Buddy, she added.

–Heidi Splete (on Twitter @hsplete)

Meet the Health Buddy, a telehealth technology intervention that significantly improved the symptoms and quality of life for head and neck cancer patients in a randomized trial by delivering symptom management in the comfort of the patient’s home, computer not required.

Cynthia Ellis Keeney, RN, MSN, couldn’t contain her excitement as she presented her group’s study findings in a poster session at a palliative care summit in Bethesda, Md. The meeting was sponsored by the National Institute of Nursing Research and partner organizations.

Photo credit: Courtesy of Wikimedia Commons user Arglos, collected via GNU Free Documentation License

Head and neck cancer patients suffer terribly from a range of symptoms, and they often find it difficult to talk and uncomfortable to leave the house, said Ms. Keeney.

She and her colleagues randomized 80 newly diagnosed head and neck cancer patients to an intervention with a telehealth device or usual care. The telehealth device was connected to a landline phone and featured a small screen with large buttons.

The device allowed patients with limited computer savvy and no internet access to benefit from the convenience of the telehealth intervention, Ms. Keeney emphasized.

Each day, a green light on the Health Buddy would blink, prompting patients to respond to questions about how they were feeling that day. Based on their answers, the system would recommend an intervention, such as asking the doctor for a drug to treat a particular symptom (for example, constipation). Symptom control algorithms had been used to generate questions based on symptoms that are most likely to occur during the active phase of cancer treatment. The phone number of the patient’s doctor had been programmed into the system for immediate access.

After the active phase of their cancer treatments, patients in the Health Buddy group reported significantly higher physical well being than did controls.

Although the doctors and patients weren’t connected visually in real time, the patients felt that being able to define their symptoms through the Health Buddy and receive suggestions for symptom management allowed them to have better conversations with their doctors, Ms. Keeney said. As a result, “the patients in the intervention group thought they got better care,” than if they had not used the Health Buddy, she added.

–Heidi Splete (on Twitter @hsplete)

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.

CHICAGO – Human papillomavirus infection was firmly linked to the recent rise in oropharyngeal cancers in the United States, based on data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results program.

If current trends continue, the incidence of HPV-related oral cancers will soon surpass that of cervical cancers, senior author Dr. Maura Gillison reported at the annual meeting of the American Society of Clinical Oncology.

The incidence of HPV-positive oropharyngeal cancers increased 225% – from 0.8 per 100,000 to 2.8 per 100,000 – between 1988 and 2004, the researchers found. At the same time, the incidence rate for HPV-negative oropharyngeal cancers, which are strongly related to tobacco and alcohol use, declined by 50% – from 2.0 per 100,000 to 1.0 per 100,000.

Consequently, the overall incidence of oropharyngeal cancers increased 28%.

Even by the conservative estimate that 70% of oropharyngeal cancers in 2020 will be HPV positive, the annual number of HPV-positive oral squamous cell carcinomas (8,653 cases) is expected to surpass cervical cancers (7,726 cases). Further, the majority will occur among men (7,426 cases), said Dr. Gillison, a medical oncologist and the Jeg Coughlin Chair in Cancer Research at Ohio State University Comprehensive Cancer Center in Columbus.

Changes in sexual behavior among recent birth cohorts and increased oral HPV exposure probably influenced the increases in incidence and prevalence, Dr. Gillison speculated. Having a high lifetime number of sexual partners is a known risk factor for HPV infection.

Although the rise in oral cancers in the United States has been attributed to HPV infection, the empirical evidence to back the contention was uncovered prior to the SEER study. A previous study by Dr. Gillison and her colleagues helped to establish that HPV infection causes an epidemiologically and clinically different form of oral cancer. Their findings documented a major increase in the incidence of HPV-related oral cancers in the United States, particularly among young, white men, and that survival rates are significantly higher in patients with HPV-related oral cancers than in those with HPV-negative cancers (J. Clin. Oncol. 2008;26:612-9).

The evidence surrounding HPV-related oral cancers has been mounting, "but I don’t think there is a lot of awareness in the general medical community," Dr. Gillison said in an interview. Most of her head-and-neck cancer patients who are nonsmokers were referred to her after undergoing months of antibiotic therapy for presumed tonsillitis.

Screening the sexual partners of oropharyngeal cancer patients has been discussed, but there is no evidence to support the practice. The risk for oral cancer is fourfold higher in HPV-positive patients’ partners, but the absolute risk is low, Dr. Gillison said. Alternatively, there are now three or four case reports of husband-wife couples with HPV16-positive tonsillar cancer.

"Probably 80% of people have HPV exposures in their life and 99.1% clear the infections without consequence," she said. "So, whatever [stable sexual partners] have swapped in terms of infection, they’ve already swapped. Just because they suddenly found that one of them got cancer from it doesn’t mean the other one will."

The researchers called for more studies to evaluate the efficacy of HPV vaccines in preventing oral HPV infections.

Dr. Gillison worked for 3 years with Merck & Co., the maker of the HPV vaccine Gardasil, and commented that Merck will not likely pursue this indication. Merck was interested in studying the vaccine in prevention of oral cancers but saw the endeavor as too much of an uphill battle in part because oral cancers are not readily accessible visibly or through biopsy. Merck instead successfully opted to seek approval for the prevention of anal cancers, an indication that was approved in December 2010 for male and females 9-26 years old.

It was already approved in the same age groups for the prevention of cervical, vulvar, and vaginal cancer and of genital warts caused by HPV types 6, 11, 16, and 18 in females and for the prevention of genital warts caused by HPV types 6 and 11 in males.

Invited discussant Dr. Lisa Licitra of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, said that oral cancers are on the rise in Europe in both men and women and that a vaccine should be pursued. Data on oropharyngeal cancer from her institute did not find a greater contribution from men.

"A preventive vaccine is worth considering," she said. "In particular, when we consider the European data, I think that in this direction, action should be taken."

In their study, Dr. Gillison and her colleagues used four different assays to determine the HPV status for 271 oropharyngeal cancer cases collected from 1984 to 2004 by three population-based cancer registries of the National Cancer Institute’s Surveillance, Epidemiology, and End Results program in Hawaii, Iowa, and Los Angeles. Trends in HPV prevalence across four calendar periods were estimated using logistic regression.

The HPV prevalence in oropharyngeal cancer significantly increased across the time period, regardless of the assay used, and remained statistically significant, even after correcting for potential loss in assay sensitivity, Dr. Gillison reported. Genotyping with the Inno-LiPA assay appeared to be the most precise, detecting more than a fourfold increase in HPV prevalence from 16.3% in 1984-1989 to 72.7% in 2000-2004.

Median survival was significantly better for patients with HPV-positive cancer at 131 months vs. 20 months for HPV-negative patients (log rank P value less than .001). HPV-positive cases on all assays had a significant reduction in hazard of death compared with HPV-negative cases after adjustment for age, sex, race, registry, calendar period, stage, surgery, chemotherapy, and radiotherapy.

Survival of HPV-positive cases increased over the study period but remained unchanged for HPV-negative cases. Consequently, survival of all oropharyngeal cancer cases improved over time, according to the results of the study, which was led by Dr. Amil Chaturvedi, an investigator with the division of cancer epidemiology and genetics at the National Cancer Institute, Rockville, Md.

Dr. Gillison and Dr. Chaturvedi reported no conflicts of interest. A coauthor disclosed consultancy, research funding, and honoraria from Merck.

CHICAGO – Human papillomavirus infection was firmly linked to the recent rise in oropharyngeal cancers in the United States, based on data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results program.

If current trends continue, the incidence of HPV-related oral cancers will soon surpass that of cervical cancers, senior author Dr. Maura Gillison reported at the annual meeting of the American Society of Clinical Oncology.

The incidence of HPV-positive oropharyngeal cancers increased 225% – from 0.8 per 100,000 to 2.8 per 100,000 – between 1988 and 2004, the researchers found. At the same time, the incidence rate for HPV-negative oropharyngeal cancers, which are strongly related to tobacco and alcohol use, declined by 50% – from 2.0 per 100,000 to 1.0 per 100,000.

Consequently, the overall incidence of oropharyngeal cancers increased 28%.

Even by the conservative estimate that 70% of oropharyngeal cancers in 2020 will be HPV positive, the annual number of HPV-positive oral squamous cell carcinomas (8,653 cases) is expected to surpass cervical cancers (7,726 cases). Further, the majority will occur among men (7,426 cases), said Dr. Gillison, a medical oncologist and the Jeg Coughlin Chair in Cancer Research at Ohio State University Comprehensive Cancer Center in Columbus.

Changes in sexual behavior among recent birth cohorts and increased oral HPV exposure probably influenced the increases in incidence and prevalence, Dr. Gillison speculated. Having a high lifetime number of sexual partners is a known risk factor for HPV infection.

Although the rise in oral cancers in the United States has been attributed to HPV infection, the empirical evidence to back the contention was uncovered prior to the SEER study. A previous study by Dr. Gillison and her colleagues helped to establish that HPV infection causes an epidemiologically and clinically different form of oral cancer. Their findings documented a major increase in the incidence of HPV-related oral cancers in the United States, particularly among young, white men, and that survival rates are significantly higher in patients with HPV-related oral cancers than in those with HPV-negative cancers (J. Clin. Oncol. 2008;26:612-9).

The evidence surrounding HPV-related oral cancers has been mounting, "but I don’t think there is a lot of awareness in the general medical community," Dr. Gillison said in an interview. Most of her head-and-neck cancer patients who are nonsmokers were referred to her after undergoing months of antibiotic therapy for presumed tonsillitis.

Screening the sexual partners of oropharyngeal cancer patients has been discussed, but there is no evidence to support the practice. The risk for oral cancer is fourfold higher in HPV-positive patients’ partners, but the absolute risk is low, Dr. Gillison said. Alternatively, there are now three or four case reports of husband-wife couples with HPV16-positive tonsillar cancer.

"Probably 80% of people have HPV exposures in their life and 99.1% clear the infections without consequence," she said. "So, whatever [stable sexual partners] have swapped in terms of infection, they’ve already swapped. Just because they suddenly found that one of them got cancer from it doesn’t mean the other one will."

The researchers called for more studies to evaluate the efficacy of HPV vaccines in preventing oral HPV infections.

Dr. Gillison worked for 3 years with Merck & Co., the maker of the HPV vaccine Gardasil, and commented that Merck will not likely pursue this indication. Merck was interested in studying the vaccine in prevention of oral cancers but saw the endeavor as too much of an uphill battle in part because oral cancers are not readily accessible visibly or through biopsy. Merck instead successfully opted to seek approval for the prevention of anal cancers, an indication that was approved in December 2010 for male and females 9-26 years old.

It was already approved in the same age groups for the prevention of cervical, vulvar, and vaginal cancer and of genital warts caused by HPV types 6, 11, 16, and 18 in females and for the prevention of genital warts caused by HPV types 6 and 11 in males.

Invited discussant Dr. Lisa Licitra of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, said that oral cancers are on the rise in Europe in both men and women and that a vaccine should be pursued. Data on oropharyngeal cancer from her institute did not find a greater contribution from men.

"A preventive vaccine is worth considering," she said. "In particular, when we consider the European data, I think that in this direction, action should be taken."

In their study, Dr. Gillison and her colleagues used four different assays to determine the HPV status for 271 oropharyngeal cancer cases collected from 1984 to 2004 by three population-based cancer registries of the National Cancer Institute’s Surveillance, Epidemiology, and End Results program in Hawaii, Iowa, and Los Angeles. Trends in HPV prevalence across four calendar periods were estimated using logistic regression.

The HPV prevalence in oropharyngeal cancer significantly increased across the time period, regardless of the assay used, and remained statistically significant, even after correcting for potential loss in assay sensitivity, Dr. Gillison reported. Genotyping with the Inno-LiPA assay appeared to be the most precise, detecting more than a fourfold increase in HPV prevalence from 16.3% in 1984-1989 to 72.7% in 2000-2004.

Median survival was significantly better for patients with HPV-positive cancer at 131 months vs. 20 months for HPV-negative patients (log rank P value less than .001). HPV-positive cases on all assays had a significant reduction in hazard of death compared with HPV-negative cases after adjustment for age, sex, race, registry, calendar period, stage, surgery, chemotherapy, and radiotherapy.

Survival of HPV-positive cases increased over the study period but remained unchanged for HPV-negative cases. Consequently, survival of all oropharyngeal cancer cases improved over time, according to the results of the study, which was led by Dr. Amil Chaturvedi, an investigator with the division of cancer epidemiology and genetics at the National Cancer Institute, Rockville, Md.

Dr. Gillison and Dr. Chaturvedi reported no conflicts of interest. A coauthor disclosed consultancy, research funding, and honoraria from Merck.

CHICAGO – Human papillomavirus infection was firmly linked to the recent rise in oropharyngeal cancers in the United States, based on data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results program.

If current trends continue, the incidence of HPV-related oral cancers will soon surpass that of cervical cancers, senior author Dr. Maura Gillison reported at the annual meeting of the American Society of Clinical Oncology.

The incidence of HPV-positive oropharyngeal cancers increased 225% – from 0.8 per 100,000 to 2.8 per 100,000 – between 1988 and 2004, the researchers found. At the same time, the incidence rate for HPV-negative oropharyngeal cancers, which are strongly related to tobacco and alcohol use, declined by 50% – from 2.0 per 100,000 to 1.0 per 100,000.

Consequently, the overall incidence of oropharyngeal cancers increased 28%.

Even by the conservative estimate that 70% of oropharyngeal cancers in 2020 will be HPV positive, the annual number of HPV-positive oral squamous cell carcinomas (8,653 cases) is expected to surpass cervical cancers (7,726 cases). Further, the majority will occur among men (7,426 cases), said Dr. Gillison, a medical oncologist and the Jeg Coughlin Chair in Cancer Research at Ohio State University Comprehensive Cancer Center in Columbus.

Changes in sexual behavior among recent birth cohorts and increased oral HPV exposure probably influenced the increases in incidence and prevalence, Dr. Gillison speculated. Having a high lifetime number of sexual partners is a known risk factor for HPV infection.

Although the rise in oral cancers in the United States has been attributed to HPV infection, the empirical evidence to back the contention was uncovered prior to the SEER study. A previous study by Dr. Gillison and her colleagues helped to establish that HPV infection causes an epidemiologically and clinically different form of oral cancer. Their findings documented a major increase in the incidence of HPV-related oral cancers in the United States, particularly among young, white men, and that survival rates are significantly higher in patients with HPV-related oral cancers than in those with HPV-negative cancers (J. Clin. Oncol. 2008;26:612-9).

The evidence surrounding HPV-related oral cancers has been mounting, "but I don’t think there is a lot of awareness in the general medical community," Dr. Gillison said in an interview. Most of her head-and-neck cancer patients who are nonsmokers were referred to her after undergoing months of antibiotic therapy for presumed tonsillitis.

Screening the sexual partners of oropharyngeal cancer patients has been discussed, but there is no evidence to support the practice. The risk for oral cancer is fourfold higher in HPV-positive patients’ partners, but the absolute risk is low, Dr. Gillison said. Alternatively, there are now three or four case reports of husband-wife couples with HPV16-positive tonsillar cancer.

"Probably 80% of people have HPV exposures in their life and 99.1% clear the infections without consequence," she said. "So, whatever [stable sexual partners] have swapped in terms of infection, they’ve already swapped. Just because they suddenly found that one of them got cancer from it doesn’t mean the other one will."

The researchers called for more studies to evaluate the efficacy of HPV vaccines in preventing oral HPV infections.

Dr. Gillison worked for 3 years with Merck & Co., the maker of the HPV vaccine Gardasil, and commented that Merck will not likely pursue this indication. Merck was interested in studying the vaccine in prevention of oral cancers but saw the endeavor as too much of an uphill battle in part because oral cancers are not readily accessible visibly or through biopsy. Merck instead successfully opted to seek approval for the prevention of anal cancers, an indication that was approved in December 2010 for male and females 9-26 years old.

It was already approved in the same age groups for the prevention of cervical, vulvar, and vaginal cancer and of genital warts caused by HPV types 6, 11, 16, and 18 in females and for the prevention of genital warts caused by HPV types 6 and 11 in males.

Invited discussant Dr. Lisa Licitra of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, said that oral cancers are on the rise in Europe in both men and women and that a vaccine should be pursued. Data on oropharyngeal cancer from her institute did not find a greater contribution from men.

"A preventive vaccine is worth considering," she said. "In particular, when we consider the European data, I think that in this direction, action should be taken."

In their study, Dr. Gillison and her colleagues used four different assays to determine the HPV status for 271 oropharyngeal cancer cases collected from 1984 to 2004 by three population-based cancer registries of the National Cancer Institute’s Surveillance, Epidemiology, and End Results program in Hawaii, Iowa, and Los Angeles. Trends in HPV prevalence across four calendar periods were estimated using logistic regression.

The HPV prevalence in oropharyngeal cancer significantly increased across the time period, regardless of the assay used, and remained statistically significant, even after correcting for potential loss in assay sensitivity, Dr. Gillison reported. Genotyping with the Inno-LiPA assay appeared to be the most precise, detecting more than a fourfold increase in HPV prevalence from 16.3% in 1984-1989 to 72.7% in 2000-2004.

Median survival was significantly better for patients with HPV-positive cancer at 131 months vs. 20 months for HPV-negative patients (log rank P value less than .001). HPV-positive cases on all assays had a significant reduction in hazard of death compared with HPV-negative cases after adjustment for age, sex, race, registry, calendar period, stage, surgery, chemotherapy, and radiotherapy.

Survival of HPV-positive cases increased over the study period but remained unchanged for HPV-negative cases. Consequently, survival of all oropharyngeal cancer cases improved over time, according to the results of the study, which was led by Dr. Amil Chaturvedi, an investigator with the division of cancer epidemiology and genetics at the National Cancer Institute, Rockville, Md.

Dr. Gillison and Dr. Chaturvedi reported no conflicts of interest. A coauthor disclosed consultancy, research funding, and honoraria from Merck.

CHICAGO – Human papillomavirus infection was firmly linked to the recent rise in oropharyngeal cancers in the United States, based on data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results program.

If current trends continue, the incidence of HPV-related oral cancers will soon surpass that of cervical cancers, senior author Dr. Maura Gillison reported at the annual meeting of the American Society of Clinical Oncology.

The incidence of HPV-positive oropharyngeal cancers increased 225% – from 0.8 per 100,000 to 2.8 per 100,000 – between 1988 and 2004, the researchers found. At the same time, the incidence rate for HPV-negative oropharyngeal cancers, which are strongly related to tobacco and alcohol use, declined by 50% – from 2.0 per 100,000 to 1.0 per 100,000.

Consequently, the overall incidence of oropharyngeal cancers increased 28%.

Even by the conservative estimate that 70% of oropharyngeal cancers in 2020 will be HPV positive, the annual number of HPV-positive oral squamous cell carcinomas (8,653 cases) is expected to surpass cervical cancers (7,726 cases). Further, the majority will occur among men (7,426 cases), said Dr. Gillison, a medical oncologist and the Jeg Coughlin Chair in Cancer Research at Ohio State University Comprehensive Cancer Center in Columbus.

Changes in sexual behavior among recent birth cohorts and increased oral HPV exposure probably influenced the increases in incidence and prevalence, Dr. Gillison speculated. Having a high lifetime number of sexual partners is a known risk factor for HPV infection.

Although the rise in oral cancers in the United States has been attributed to HPV infection, the empirical evidence to back the contention was uncovered prior to the SEER study. A previous study by Dr. Gillison and her colleagues helped to establish that HPV infection causes an epidemiologically and clinically different form of oral cancer. Their findings documented a major increase in the incidence of HPV-related oral cancers in the United States, particularly among young, white men, and that survival rates are significantly higher in patients with HPV-related oral cancers than in those with HPV-negative cancers (J. Clin. Oncol. 2008;26:612-9).

The evidence surrounding HPV-related oral cancers has been mounting, "but I don’t think there is a lot of awareness in the general medical community," Dr. Gillison said in an interview. Most of her head-and-neck cancer patients who are nonsmokers were referred to her after undergoing months of antibiotic therapy for presumed tonsillitis.

Screening the sexual partners of oropharyngeal cancer patients has been discussed, but there is no evidence to support the practice. The risk for oral cancer is fourfold higher in HPV-positive patients’ partners, but the absolute risk is low, Dr. Gillison said. Alternatively, there are now three or four case reports of husband-wife couples with HPV16-positive tonsillar cancer.

"Probably 80% of people have HPV exposures in their life and 99.1% clear the infections without consequence," she said. "So, whatever [stable sexual partners] have swapped in terms of infection, they’ve already swapped. Just because they suddenly found that one of them got cancer from it doesn’t mean the other one will."

The researchers called for more studies to evaluate the efficacy of HPV vaccines in preventing oral HPV infections.

Dr. Gillison worked for 3 years with Merck & Co., the maker of the HPV vaccine Gardasil, and commented that Merck will not likely pursue this indication. Merck was interested in studying the vaccine in prevention of oral cancers but saw the endeavor as too much of an uphill battle in part because oral cancers are not readily accessible visibly or through biopsy. Merck instead successfully opted to seek approval for the prevention of anal cancers, an indication that was approved in December 2010 for male and females 9-26 years old.

It was already approved in the same age groups for the prevention of cervical, vulvar, and vaginal cancer and of genital warts caused by HPV types 6, 11, 16, and 18 in females and for the prevention of genital warts caused by HPV types 6 and 11 in males.

Invited discussant Dr. Lisa Licitra of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, said that oral cancers are on the rise in Europe in both men and women and that a vaccine should be pursued. Data on oropharyngeal cancer from her institute did not find a greater contribution from men.

"A preventive vaccine is worth considering," she said. "In particular, when we consider the European data, I think that in this direction, action should be taken."

In their study, Dr. Gillison and her colleagues used four different assays to determine the HPV status for 271 oropharyngeal cancer cases collected from 1984 to 2004 by three population-based cancer registries of the National Cancer Institute’s Surveillance, Epidemiology, and End Results program in Hawaii, Iowa, and Los Angeles. Trends in HPV prevalence across four calendar periods were estimated using logistic regression.

The HPV prevalence in oropharyngeal cancer significantly increased across the time period, regardless of the assay used, and remained statistically significant, even after correcting for potential loss in assay sensitivity, Dr. Gillison reported. Genotyping with the Inno-LiPA assay appeared to be the most precise, detecting more than a fourfold increase in HPV prevalence from 16.3% in 1984-1989 to 72.7% in 2000-2004.

Median survival was significantly better for patients with HPV-positive cancer at 131 months vs. 20 months for HPV-negative patients (log rank P value less than .001). HPV-positive cases on all assays had a significant reduction in hazard of death compared with HPV-negative cases after adjustment for age, sex, race, registry, calendar period, stage, surgery, chemotherapy, and radiotherapy.

Survival of HPV-positive cases increased over the study period but remained unchanged for HPV-negative cases. Consequently, survival of all oropharyngeal cancer cases improved over time, according to the results of the study, which was led by Dr. Amil Chaturvedi, an investigator with the division of cancer epidemiology and genetics at the National Cancer Institute, Rockville, Md.

Dr. Gillison and Dr. Chaturvedi reported no conflicts of interest. A coauthor disclosed consultancy, research funding, and honoraria from Merck.

CHICAGO – Human papillomavirus infection was firmly linked to the recent rise in oropharyngeal cancers in the United States, based on data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results program.

If current trends continue, the incidence of HPV-related oral cancers will soon surpass that of cervical cancers, senior author Dr. Maura Gillison reported at the annual meeting of the American Society of Clinical Oncology.

The incidence of HPV-positive oropharyngeal cancers increased 225% – from 0.8 per 100,000 to 2.8 per 100,000 – between 1988 and 2004, the researchers found. At the same time, the incidence rate for HPV-negative oropharyngeal cancers, which are strongly related to tobacco and alcohol use, declined by 50% – from 2.0 per 100,000 to 1.0 per 100,000.

Consequently, the overall incidence of oropharyngeal cancers increased 28%.

Even by the conservative estimate that 70% of oropharyngeal cancers in 2020 will be HPV positive, the annual number of HPV-positive oral squamous cell carcinomas (8,653 cases) is expected to surpass cervical cancers (7,726 cases). Further, the majority will occur among men (7,426 cases), said Dr. Gillison, a medical oncologist and the Jeg Coughlin Chair in Cancer Research at Ohio State University Comprehensive Cancer Center in Columbus.

Changes in sexual behavior among recent birth cohorts and increased oral HPV exposure probably influenced the increases in incidence and prevalence, Dr. Gillison speculated. Having a high lifetime number of sexual partners is a known risk factor for HPV infection.

Although the rise in oral cancers in the United States has been attributed to HPV infection, the empirical evidence to back the contention was uncovered prior to the SEER study. A previous study by Dr. Gillison and her colleagues helped to establish that HPV infection causes an epidemiologically and clinically different form of oral cancer. Their findings documented a major increase in the incidence of HPV-related oral cancers in the United States, particularly among young, white men, and that survival rates are significantly higher in patients with HPV-related oral cancers than in those with HPV-negative cancers (J. Clin. Oncol. 2008;26:612-9).

The evidence surrounding HPV-related oral cancers has been mounting, "but I don’t think there is a lot of awareness in the general medical community," Dr. Gillison said in an interview. Most of her head-and-neck cancer patients who are nonsmokers were referred to her after undergoing months of antibiotic therapy for presumed tonsillitis.

Screening the sexual partners of oropharyngeal cancer patients has been discussed, but there is no evidence to support the practice. The risk for oral cancer is fourfold higher in HPV-positive patients’ partners, but the absolute risk is low, Dr. Gillison said. Alternatively, there are now three or four case reports of husband-wife couples with HPV16-positive tonsillar cancer.

"Probably 80% of people have HPV exposures in their life and 99.1% clear the infections without consequence," she said. "So, whatever [stable sexual partners] have swapped in terms of infection, they’ve already swapped. Just because they suddenly found that one of them got cancer from it doesn’t mean the other one will."

The researchers called for more studies to evaluate the efficacy of HPV vaccines in preventing oral HPV infections.

Dr. Gillison worked for 3 years with Merck & Co., the maker of the HPV vaccine Gardasil, and commented that Merck will not likely pursue this indication. Merck was interested in studying the vaccine in prevention of oral cancers but saw the endeavor as too much of an uphill battle in part because oral cancers are not readily accessible visibly or through biopsy. Merck instead successfully opted to seek approval for the prevention of anal cancers, an indication that was approved in December 2010 for male and females 9-26 years old.

It was already approved in the same age groups for the prevention of cervical, vulvar, and vaginal cancer and of genital warts caused by HPV types 6, 11, 16, and 18 in females and for the prevention of genital warts caused by HPV types 6 and 11 in males.

Invited discussant Dr. Lisa Licitra of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, said that oral cancers are on the rise in Europe in both men and women and that a vaccine should be pursued. Data on oropharyngeal cancer from her institute did not find a greater contribution from men.

"A preventive vaccine is worth considering," she said. "In particular, when we consider the European data, I think that in this direction, action should be taken."

In their study, Dr. Gillison and her colleagues used four different assays to determine the HPV status for 271 oropharyngeal cancer cases collected from 1984 to 2004 by three population-based cancer registries of the National Cancer Institute’s Surveillance, Epidemiology, and End Results program in Hawaii, Iowa, and Los Angeles. Trends in HPV prevalence across four calendar periods were estimated using logistic regression.

The HPV prevalence in oropharyngeal cancer significantly increased across the time period, regardless of the assay used, and remained statistically significant, even after correcting for potential loss in assay sensitivity, Dr. Gillison reported. Genotyping with the Inno-LiPA assay appeared to be the most precise, detecting more than a fourfold increase in HPV prevalence from 16.3% in 1984-1989 to 72.7% in 2000-2004.

Median survival was significantly better for patients with HPV-positive cancer at 131 months vs. 20 months for HPV-negative patients (log rank P value less than .001). HPV-positive cases on all assays had a significant reduction in hazard of death compared with HPV-negative cases after adjustment for age, sex, race, registry, calendar period, stage, surgery, chemotherapy, and radiotherapy.

Survival of HPV-positive cases increased over the study period but remained unchanged for HPV-negative cases. Consequently, survival of all oropharyngeal cancer cases improved over time, according to the results of the study, which was led by Dr. Amil Chaturvedi, an investigator with the division of cancer epidemiology and genetics at the National Cancer Institute, Rockville, Md.

Dr. Gillison and Dr. Chaturvedi reported no conflicts of interest. A coauthor disclosed consultancy, research funding, and honoraria from Merck.

CHICAGO – Human papillomavirus infection was firmly linked to the recent rise in oropharyngeal cancers in the United States, based on data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results program.

If current trends continue, the incidence of HPV-related oral cancers will soon surpass that of cervical cancers, senior author Dr. Maura Gillison reported at the annual meeting of the American Society of Clinical Oncology.

The incidence of HPV-positive oropharyngeal cancers increased 225% – from 0.8 per 100,000 to 2.8 per 100,000 – between 1988 and 2004, the researchers found. At the same time, the incidence rate for HPV-negative oropharyngeal cancers, which are strongly related to tobacco and alcohol use, declined by 50% – from 2.0 per 100,000 to 1.0 per 100,000.

Consequently, the overall incidence of oropharyngeal cancers increased 28%.

Even by the conservative estimate that 70% of oropharyngeal cancers in 2020 will be HPV positive, the annual number of HPV-positive oral squamous cell carcinomas (8,653 cases) is expected to surpass cervical cancers (7,726 cases). Further, the majority will occur among men (7,426 cases), said Dr. Gillison, a medical oncologist and the Jeg Coughlin Chair in Cancer Research at Ohio State University Comprehensive Cancer Center in Columbus.

Changes in sexual behavior among recent birth cohorts and increased oral HPV exposure probably influenced the increases in incidence and prevalence, Dr. Gillison speculated. Having a high lifetime number of sexual partners is a known risk factor for HPV infection.

Although the rise in oral cancers in the United States has been attributed to HPV infection, the empirical evidence to back the contention was uncovered prior to the SEER study. A previous study by Dr. Gillison and her colleagues helped to establish that HPV infection causes an epidemiologically and clinically different form of oral cancer. Their findings documented a major increase in the incidence of HPV-related oral cancers in the United States, particularly among young, white men, and that survival rates are significantly higher in patients with HPV-related oral cancers than in those with HPV-negative cancers (J. Clin. Oncol. 2008;26:612-9).

The evidence surrounding HPV-related oral cancers has been mounting, "but I don’t think there is a lot of awareness in the general medical community," Dr. Gillison said in an interview. Most of her head-and-neck cancer patients who are nonsmokers were referred to her after undergoing months of antibiotic therapy for presumed tonsillitis.

Screening the sexual partners of oropharyngeal cancer patients has been discussed, but there is no evidence to support the practice. The risk for oral cancer is fourfold higher in HPV-positive patients’ partners, but the absolute risk is low, Dr. Gillison said. Alternatively, there are now three or four case reports of husband-wife couples with HPV16-positive tonsillar cancer.

"Probably 80% of people have HPV exposures in their life and 99.1% clear the infections without consequence," she said. "So, whatever [stable sexual partners] have swapped in terms of infection, they’ve already swapped. Just because they suddenly found that one of them got cancer from it doesn’t mean the other one will."

The researchers called for more studies to evaluate the efficacy of HPV vaccines in preventing oral HPV infections.

Dr. Gillison worked for 3 years with Merck & Co., the maker of the HPV vaccine Gardasil, and commented that Merck will not likely pursue this indication. Merck was interested in studying the vaccine in prevention of oral cancers but saw the endeavor as too much of an uphill battle in part because oral cancers are not readily accessible visibly or through biopsy. Merck instead successfully opted to seek approval for the prevention of anal cancers, an indication that was approved in December 2010 for male and females 9-26 years old.

It was already approved in the same age groups for the prevention of cervical, vulvar, and vaginal cancer and of genital warts caused by HPV types 6, 11, 16, and 18 in females and for the prevention of genital warts caused by HPV types 6 and 11 in males.

Invited discussant Dr. Lisa Licitra of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, said that oral cancers are on the rise in Europe in both men and women and that a vaccine should be pursued. Data on oropharyngeal cancer from her institute did not find a greater contribution from men.

"A preventive vaccine is worth considering," she said. "In particular, when we consider the European data, I think that in this direction, action should be taken."

In their study, Dr. Gillison and her colleagues used four different assays to determine the HPV status for 271 oropharyngeal cancer cases collected from 1984 to 2004 by three population-based cancer registries of the National Cancer Institute’s Surveillance, Epidemiology, and End Results program in Hawaii, Iowa, and Los Angeles. Trends in HPV prevalence across four calendar periods were estimated using logistic regression.

The HPV prevalence in oropharyngeal cancer significantly increased across the time period, regardless of the assay used, and remained statistically significant, even after correcting for potential loss in assay sensitivity, Dr. Gillison reported. Genotyping with the Inno-LiPA assay appeared to be the most precise, detecting more than a fourfold increase in HPV prevalence from 16.3% in 1984-1989 to 72.7% in 2000-2004.

Median survival was significantly better for patients with HPV-positive cancer at 131 months vs. 20 months for HPV-negative patients (log rank P value less than .001). HPV-positive cases on all assays had a significant reduction in hazard of death compared with HPV-negative cases after adjustment for age, sex, race, registry, calendar period, stage, surgery, chemotherapy, and radiotherapy.

Survival of HPV-positive cases increased over the study period but remained unchanged for HPV-negative cases. Consequently, survival of all oropharyngeal cancer cases improved over time, according to the results of the study, which was led by Dr. Amil Chaturvedi, an investigator with the division of cancer epidemiology and genetics at the National Cancer Institute, Rockville, Md.

Dr. Gillison and Dr. Chaturvedi reported no conflicts of interest. A coauthor disclosed consultancy, research funding, and honoraria from Merck.

LONDON – Almost one-quarter of patients who had been given induction chemotherapy before radiotherapy for head and neck cancer experienced long-term swallowing difficulties, with another 15% experiencing voice disabilities that correlated with the mobility of the vocal cords.

Long-term data from the GORTEC (Groupe Oncologie Radiothérapie Tête et Cou) 2000-01 larynx preservation trial also show that approximately two-thirds of long-term head and neck cancer survivors experienced severe problems with sticky saliva and dry mouth, which were in turn linked to nutritional problems.

These findings, reported May 9 at the European Society for Therapeutic Radiation Oncology (ESTRO) Anniversary Conference, further confirm that studies looking at the effects of chemoradiotherapy on the larynx in head and neck cancer need to consider prospective assessment of laryngeal function, rather than just looking at anatomical preservation, according to a French radiation oncologist.

Dr. Gilles Calais of the Centre Hôpitalier Régional et Universitaire de Tours (France) presented data from a prospective analysis of 61 patients who had participated in the original 213-patient GORTEC 2000-01 trial. He also presented updated results from the trial using a recently developed composite end point.

"Larynx preservation can be achieved for most of our [head and neck] patients by using three different strategies: induction chemotherapy, concomitant [chemoradiotherapy], or alternating chemoradiotherapy," Dr. Calais observed. Indeed, larynx preservation is a possibility in approximately 80% of patients, he said.

However, anatomical preservation does not mean that laryngeal function is maintained, especially with respect to the ability to speak or to swallow normally. This realization recently resulted in the development of new end points for clinical trials that included both survival and laryngeal function. The new end points are laryngoesophageal dysfunction-free survival (LED-FS) and freedom from laryngoesophageal dysfunction (FF-LED).

"So the purpose of this study was to go back to our data of the GORTEC 2000-01 study and evaluate the results according to these new composite end points," Dr. Calais explained. "In parallel," he added, "we performed a prospective analysis of voice and swallowing function for long-term surviving patients."

Published in 2009, the GORTEC 2000-01 study showed that induction chemotherapy with TPF (docetaxel, cisplatin, and 5-fluorouracil) was superior to pf (cisplatin and 5-FU) in terms of 3-year larynx preservation rates (J. Natl. Cancer Inst. 2009;101:498-506). In all, 110 patients had been treated with TPF and 103 with PF, and the published larynx preservation rates were 70.3% and 57.5%, respectively. Anatomical preservation of the larynx was a possibly in 66 patients, and these patients were assessed for voice and swallowing function.

Recalculating survival curves according to the two new end points showed much lower overall values, compared with the anatomical-only end points, Dr. Calais noted. Considering all patients, the 5-year LED-FS was just 28% and the 5-year FF-LED was 50%.

Patients who were treated with the taxane-containing regimen fared better than those who received the cisplatin and 5-FU chemotherapy. The 5-year LED-FS rates were 36% in the TPF arm vs. 21% for the PF arm (P = .007). The 5-year FF-LED rates were 60% and 39%, respectively (P = .005).

"These data can be used as a reference for comparison with future larynx preservation studies," Dr. Calais said. He noted that it was important to bear in mind that the best treatment to preserve the larynx is not known, referring to the FF-LED rate of 60% with the TPF regimen.

"Of course, [the] patient’s quality of life measure[s used] should be conducted in every future larynx preservation study."

Dr. Calais declared no financial conflicts of interest.

LONDON – Almost one-quarter of patients who had been given induction chemotherapy before radiotherapy for head and neck cancer experienced long-term swallowing difficulties, with another 15% experiencing voice disabilities that correlated with the mobility of the vocal cords.

Long-term data from the GORTEC (Groupe Oncologie Radiothérapie Tête et Cou) 2000-01 larynx preservation trial also show that approximately two-thirds of long-term head and neck cancer survivors experienced severe problems with sticky saliva and dry mouth, which were in turn linked to nutritional problems.

These findings, reported May 9 at the European Society for Therapeutic Radiation Oncology (ESTRO) Anniversary Conference, further confirm that studies looking at the effects of chemoradiotherapy on the larynx in head and neck cancer need to consider prospective assessment of laryngeal function, rather than just looking at anatomical preservation, according to a French radiation oncologist.

Dr. Gilles Calais of the Centre Hôpitalier Régional et Universitaire de Tours (France) presented data from a prospective analysis of 61 patients who had participated in the original 213-patient GORTEC 2000-01 trial. He also presented updated results from the trial using a recently developed composite end point.

"Larynx preservation can be achieved for most of our [head and neck] patients by using three different strategies: induction chemotherapy, concomitant [chemoradiotherapy], or alternating chemoradiotherapy," Dr. Calais observed. Indeed, larynx preservation is a possibility in approximately 80% of patients, he said.

However, anatomical preservation does not mean that laryngeal function is maintained, especially with respect to the ability to speak or to swallow normally. This realization recently resulted in the development of new end points for clinical trials that included both survival and laryngeal function. The new end points are laryngoesophageal dysfunction-free survival (LED-FS) and freedom from laryngoesophageal dysfunction (FF-LED).

"So the purpose of this study was to go back to our data of the GORTEC 2000-01 study and evaluate the results according to these new composite end points," Dr. Calais explained. "In parallel," he added, "we performed a prospective analysis of voice and swallowing function for long-term surviving patients."

Published in 2009, the GORTEC 2000-01 study showed that induction chemotherapy with TPF (docetaxel, cisplatin, and 5-fluorouracil) was superior to pf (cisplatin and 5-FU) in terms of 3-year larynx preservation rates (J. Natl. Cancer Inst. 2009;101:498-506). In all, 110 patients had been treated with TPF and 103 with PF, and the published larynx preservation rates were 70.3% and 57.5%, respectively. Anatomical preservation of the larynx was a possibly in 66 patients, and these patients were assessed for voice and swallowing function.

Recalculating survival curves according to the two new end points showed much lower overall values, compared with the anatomical-only end points, Dr. Calais noted. Considering all patients, the 5-year LED-FS was just 28% and the 5-year FF-LED was 50%.

Patients who were treated with the taxane-containing regimen fared better than those who received the cisplatin and 5-FU chemotherapy. The 5-year LED-FS rates were 36% in the TPF arm vs. 21% for the PF arm (P = .007). The 5-year FF-LED rates were 60% and 39%, respectively (P = .005).

"These data can be used as a reference for comparison with future larynx preservation studies," Dr. Calais said. He noted that it was important to bear in mind that the best treatment to preserve the larynx is not known, referring to the FF-LED rate of 60% with the TPF regimen.

"Of course, [the] patient’s quality of life measure[s used] should be conducted in every future larynx preservation study."

Dr. Calais declared no financial conflicts of interest.

LONDON – Almost one-quarter of patients who had been given induction chemotherapy before radiotherapy for head and neck cancer experienced long-term swallowing difficulties, with another 15% experiencing voice disabilities that correlated with the mobility of the vocal cords.

Long-term data from the GORTEC (Groupe Oncologie Radiothérapie Tête et Cou) 2000-01 larynx preservation trial also show that approximately two-thirds of long-term head and neck cancer survivors experienced severe problems with sticky saliva and dry mouth, which were in turn linked to nutritional problems.

These findings, reported May 9 at the European Society for Therapeutic Radiation Oncology (ESTRO) Anniversary Conference, further confirm that studies looking at the effects of chemoradiotherapy on the larynx in head and neck cancer need to consider prospective assessment of laryngeal function, rather than just looking at anatomical preservation, according to a French radiation oncologist.

Dr. Gilles Calais of the Centre Hôpitalier Régional et Universitaire de Tours (France) presented data from a prospective analysis of 61 patients who had participated in the original 213-patient GORTEC 2000-01 trial. He also presented updated results from the trial using a recently developed composite end point.

"Larynx preservation can be achieved for most of our [head and neck] patients by using three different strategies: induction chemotherapy, concomitant [chemoradiotherapy], or alternating chemoradiotherapy," Dr. Calais observed. Indeed, larynx preservation is a possibility in approximately 80% of patients, he said.

However, anatomical preservation does not mean that laryngeal function is maintained, especially with respect to the ability to speak or to swallow normally. This realization recently resulted in the development of new end points for clinical trials that included both survival and laryngeal function. The new end points are laryngoesophageal dysfunction-free survival (LED-FS) and freedom from laryngoesophageal dysfunction (FF-LED).

"So the purpose of this study was to go back to our data of the GORTEC 2000-01 study and evaluate the results according to these new composite end points," Dr. Calais explained. "In parallel," he added, "we performed a prospective analysis of voice and swallowing function for long-term surviving patients."

Published in 2009, the GORTEC 2000-01 study showed that induction chemotherapy with TPF (docetaxel, cisplatin, and 5-fluorouracil) was superior to pf (cisplatin and 5-FU) in terms of 3-year larynx preservation rates (J. Natl. Cancer Inst. 2009;101:498-506). In all, 110 patients had been treated with TPF and 103 with PF, and the published larynx preservation rates were 70.3% and 57.5%, respectively. Anatomical preservation of the larynx was a possibly in 66 patients, and these patients were assessed for voice and swallowing function.

Recalculating survival curves according to the two new end points showed much lower overall values, compared with the anatomical-only end points, Dr. Calais noted. Considering all patients, the 5-year LED-FS was just 28% and the 5-year FF-LED was 50%.

Patients who were treated with the taxane-containing regimen fared better than those who received the cisplatin and 5-FU chemotherapy. The 5-year LED-FS rates were 36% in the TPF arm vs. 21% for the PF arm (P = .007). The 5-year FF-LED rates were 60% and 39%, respectively (P = .005).

"These data can be used as a reference for comparison with future larynx preservation studies," Dr. Calais said. He noted that it was important to bear in mind that the best treatment to preserve the larynx is not known, referring to the FF-LED rate of 60% with the TPF regimen.

"Of course, [the] patient’s quality of life measure[s used] should be conducted in every future larynx preservation study."

Dr. Calais declared no financial conflicts of interest.

LONDON – Expression of the epidermal growth factor receptor predicts whether patients with laryngeal cancer will benefit from hypoxia modification in addition to accelerated radiotherapy.

Study findings reported May 9 at the European Society for Therapeutic Radiation Oncology (ESTRO) Anniversary Conference showed that low expression was associated with higher disease-specific survival and locoregional control than was high expression in patients who received ARCON (accelerated radiotherapy with carbogen and nicotinamide).

EGFR expression is prognostic for patients who are treated with conventional fractionated radiotherapy, but did not predict response in patients undergoing just AR (accelerated radiotherapy) without hypoxia modification.

"EGFR can activate different downstream signaling pathways [in the tumor cell] that – once activated – can influence tumor cell survival, proliferation, [and] migration," all of which can contribute to tumor progression, said Monique Nijkamp, a Ph.D. student in the radiation oncology department of St. Radboud University Medical Centre in Nijmegen, the Netherlands.

High expression has already been linked to worse outcome in patients who were treated with radiotherapy for head and neck cancer (Cancer Res. 2002;62:7350-6). Ms. Nijkamp said that EGFR could be activated by ionizing radiation, and could account for resistance to radiotherapy in some treated individuals.

Hypothesizing that ARCON may help to overcome this resistance, Ms. Nikamp and coworkers examined 272 biopsy samples taken from 345 patients who had been treated with accelerated radiotherapy, with or without hypoxia modification, in a phase III study.

Preliminary results of the study were reported last September at the ESTRO 29 meeting in Barcelona. They showed that ARCON significantly improved regional – but not locoregional – tumor control, compared with AR alone. All of the patients in the trial had advanced-stage laryngeal cancer.

The latest findings suggest that patients with high expression may not gain any extra benefit from the addition of hypoxia modification. Indeed, although not statistically significant, better 5-year locoregional control (88% vs. 71%) and disease-specific survival (91% vs. 78%) were seen in patients with low EGFR expression than in those with high EGFR expression who were treated with ARCON.

Ms. Nijkamp suggested that perhaps high EGFR–expressing tumors were rapidly activating downstream signaling pathways that negated the effects of hypoxia modification. No difference in outcomes was found according to EGFR expression in the AR alone arm.

"There is concern over the methodologies used to measure EGFR, and this could have a large bearing on what conclusions can be drawn from studies," said Dr. Nick Slevin, who was invited to comment on the findings.

"From the literature and from this study, it appears that high EGFR laryngeal cancers benefit from accelerated radiotherapy, but that low EGFR tumors do not," added Dr. Slevin, a consultant clinical oncologist at the Christie NHS Foundation Trust and the University of Manchester (England).

"I think it’s a fair summary to also say that high-EGFR tumors benefit from AR but not from CON [carbogen and nicotinamide] and that low-EGFR tumors benefit from the CON but not the AR. ... So I’m not sure ARCON is the right approach for all tumors."

Other approaches to hypoxia modification for low EGFR–expressing tumors (such as oral nimorazole) may overcome the logistic difficulties of delivering carbogen and nicotinamide, he added.

The study was supported by the Dutch Cancer Society. Ms. Nijkamp and Dr. Slevin declared they had no financial conflicts of interest.

LONDON – Expression of the epidermal growth factor receptor predicts whether patients with laryngeal cancer will benefit from hypoxia modification in addition to accelerated radiotherapy.

Study findings reported May 9 at the European Society for Therapeutic Radiation Oncology (ESTRO) Anniversary Conference showed that low expression was associated with higher disease-specific survival and locoregional control than was high expression in patients who received ARCON (accelerated radiotherapy with carbogen and nicotinamide).

EGFR expression is prognostic for patients who are treated with conventional fractionated radiotherapy, but did not predict response in patients undergoing just AR (accelerated radiotherapy) without hypoxia modification.

"EGFR can activate different downstream signaling pathways [in the tumor cell] that – once activated – can influence tumor cell survival, proliferation, [and] migration," all of which can contribute to tumor progression, said Monique Nijkamp, a Ph.D. student in the radiation oncology department of St. Radboud University Medical Centre in Nijmegen, the Netherlands.

High expression has already been linked to worse outcome in patients who were treated with radiotherapy for head and neck cancer (Cancer Res. 2002;62:7350-6). Ms. Nijkamp said that EGFR could be activated by ionizing radiation, and could account for resistance to radiotherapy in some treated individuals.

Hypothesizing that ARCON may help to overcome this resistance, Ms. Nikamp and coworkers examined 272 biopsy samples taken from 345 patients who had been treated with accelerated radiotherapy, with or without hypoxia modification, in a phase III study.

Preliminary results of the study were reported last September at the ESTRO 29 meeting in Barcelona. They showed that ARCON significantly improved regional – but not locoregional – tumor control, compared with AR alone. All of the patients in the trial had advanced-stage laryngeal cancer.

The latest findings suggest that patients with high expression may not gain any extra benefit from the addition of hypoxia modification. Indeed, although not statistically significant, better 5-year locoregional control (88% vs. 71%) and disease-specific survival (91% vs. 78%) were seen in patients with low EGFR expression than in those with high EGFR expression who were treated with ARCON.

Ms. Nijkamp suggested that perhaps high EGFR–expressing tumors were rapidly activating downstream signaling pathways that negated the effects of hypoxia modification. No difference in outcomes was found according to EGFR expression in the AR alone arm.

"There is concern over the methodologies used to measure EGFR, and this could have a large bearing on what conclusions can be drawn from studies," said Dr. Nick Slevin, who was invited to comment on the findings.

"From the literature and from this study, it appears that high EGFR laryngeal cancers benefit from accelerated radiotherapy, but that low EGFR tumors do not," added Dr. Slevin, a consultant clinical oncologist at the Christie NHS Foundation Trust and the University of Manchester (England).

"I think it’s a fair summary to also say that high-EGFR tumors benefit from AR but not from CON [carbogen and nicotinamide] and that low-EGFR tumors benefit from the CON but not the AR. ... So I’m not sure ARCON is the right approach for all tumors."

Other approaches to hypoxia modification for low EGFR–expressing tumors (such as oral nimorazole) may overcome the logistic difficulties of delivering carbogen and nicotinamide, he added.

The study was supported by the Dutch Cancer Society. Ms. Nijkamp and Dr. Slevin declared they had no financial conflicts of interest.

LONDON – Expression of the epidermal growth factor receptor predicts whether patients with laryngeal cancer will benefit from hypoxia modification in addition to accelerated radiotherapy.

Study findings reported May 9 at the European Society for Therapeutic Radiation Oncology (ESTRO) Anniversary Conference showed that low expression was associated with higher disease-specific survival and locoregional control than was high expression in patients who received ARCON (accelerated radiotherapy with carbogen and nicotinamide).

EGFR expression is prognostic for patients who are treated with conventional fractionated radiotherapy, but did not predict response in patients undergoing just AR (accelerated radiotherapy) without hypoxia modification.

"EGFR can activate different downstream signaling pathways [in the tumor cell] that – once activated – can influence tumor cell survival, proliferation, [and] migration," all of which can contribute to tumor progression, said Monique Nijkamp, a Ph.D. student in the radiation oncology department of St. Radboud University Medical Centre in Nijmegen, the Netherlands.

High expression has already been linked to worse outcome in patients who were treated with radiotherapy for head and neck cancer (Cancer Res. 2002;62:7350-6). Ms. Nijkamp said that EGFR could be activated by ionizing radiation, and could account for resistance to radiotherapy in some treated individuals.

Hypothesizing that ARCON may help to overcome this resistance, Ms. Nikamp and coworkers examined 272 biopsy samples taken from 345 patients who had been treated with accelerated radiotherapy, with or without hypoxia modification, in a phase III study.

Preliminary results of the study were reported last September at the ESTRO 29 meeting in Barcelona. They showed that ARCON significantly improved regional – but not locoregional – tumor control, compared with AR alone. All of the patients in the trial had advanced-stage laryngeal cancer.

The latest findings suggest that patients with high expression may not gain any extra benefit from the addition of hypoxia modification. Indeed, although not statistically significant, better 5-year locoregional control (88% vs. 71%) and disease-specific survival (91% vs. 78%) were seen in patients with low EGFR expression than in those with high EGFR expression who were treated with ARCON.

Ms. Nijkamp suggested that perhaps high EGFR–expressing tumors were rapidly activating downstream signaling pathways that negated the effects of hypoxia modification. No difference in outcomes was found according to EGFR expression in the AR alone arm.

"There is concern over the methodologies used to measure EGFR, and this could have a large bearing on what conclusions can be drawn from studies," said Dr. Nick Slevin, who was invited to comment on the findings.

"From the literature and from this study, it appears that high EGFR laryngeal cancers benefit from accelerated radiotherapy, but that low EGFR tumors do not," added Dr. Slevin, a consultant clinical oncologist at the Christie NHS Foundation Trust and the University of Manchester (England).

"I think it’s a fair summary to also say that high-EGFR tumors benefit from AR but not from CON [carbogen and nicotinamide] and that low-EGFR tumors benefit from the CON but not the AR. ... So I’m not sure ARCON is the right approach for all tumors."

Other approaches to hypoxia modification for low EGFR–expressing tumors (such as oral nimorazole) may overcome the logistic difficulties of delivering carbogen and nicotinamide, he added.

The study was supported by the Dutch Cancer Society. Ms. Nijkamp and Dr. Slevin declared they had no financial conflicts of interest.