- Email: [email protected]
Anaplastic thyroid cancer: Rare, fatal, and neglected
Anaplastic thyroid cancer: Rare, fatal, and neglected Electron Kebebew, MD, Bethesda, MD
From the Endocrine Oncology Branch of the National Cancer Institute, Bethesda, MD
THYROID CANCER IS UNIQUE in that the different histologic subtypes exhibit the full spectrum of cancer behavior. Small (#1 cm), localized papillary thyroid cancers are common and are associated with almost a near-normal life expectancy after thyroidectomy. On the other hand, anaplastic thyroid cancer is rare, with an incidence of 1–2 cases per million people per year and is almost uniformly lethal.1 Approximately 10% of patients with anaplastic thyroid cancer present with only local disease; multimodal therapy (surgery, chemotherapy, and radiation) is therefore often necessary and may be associated with a better outcome in the majority of patients with advanced disease.1,2 Unfortunately, there has been no significant improvement in survival of patients with anaplastic thyroid cancer in nearly 6 decades. In most experimental investigations of new therapeutic agents for thyroid cancer, anaplastic thyroid cancer has also been relatively neglected, with most studies focused on locally advanced/metastatic differentiated thyroid cancer and other histologies. For example, of the >50 clinical trials available to patients with thyroid cancer, evaluating various tyrosine kinase inhibitors and other agents, only 8 include anaplastic thyroid cancer histology and only 2 are focused on anaplastic thyroid cancer.3,4 This is remarkable given that most deaths related to thyroid cancer are caused by anaplastic thyroid cancer. Sosa et al5 report on the influence of surgical resection using data from a multi-institution, randomized, controlled trial comparing carboplatin/ paclitaxel with and without fosbretabulin in patients with anaplastic thyroid cancer.5 The trial Accepted for publication August 29, 2012. Reprint requests: Electron Kebebew, MD, Endocrine Oncology Branch, National Cancer Institute, Building 10-CRC, Room 3-3940, 10 Center Drive, MSC 1201, Bethesda, MD 20892. E-mail: [email protected]. Surgery 2012;152:1088-9. 0039-6060/$ - see front matter Published by Mosby, Inc. http://dx.doi.org/10.1016/j.surg.2012.08.059
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was terminated early because of insufficient accrual after 80 patients were enrolled and most patients (90%) had stage IVC disease (distant metastasis). Forty-four patients (55%) had surgical resection before enrolling in the trial for systemic disease. The investigators found a trend in higher median survival (8.2 months) in patients who had cancer-directed surgery before receiving carboplatin/paclitaxel with fosbretabulin compared to those who did not have an operation and received carboplatin/paclitaxel (median survival, 4 months; P = .25). While this study is the largest randomized study of anaplastic thyroid cancer to date, it was not powered to address the impact of surgical resection on patient outcome with systemic chemotherapy, and the majority of patients had metastatic disease. These findings, although not conclusive, support a multimodal therapeutic approach in patients with anaplastic thyroid cancer. Resection of locoregional anaplastic thyroid cancer---when it can be performed with gross or microscopic negative margins---should be performed in the presence or absence of distant disease because it may reduce the risk that a patient will die from asphyxiation or bleeding from the great vessels caused by locoregional tumor invasion. Our understanding of the molecular pathogenesis of anaplastic thyroid cancer has improved, and the relative frequency of mutations in genes such as BRAF, RAS, CTNNB1, PIK3CA, TP53, AXIN1, PTEN, and APC has been characterized.6 The most prevalent of these genetic alterations is in AXIN1 (82%), followed by TP53 (55%), CTNNB1 (38%), and BRAF (26%).6 These data could have important clinical ramifications in the design of future therapeutic trials because compounds that target specific driver mutations, such as BRAF, have already shown remarkable tumor activity in recent clinical trials for other types of cancers and in preclinical studies of anaplastic thyroid cancer.7-9 The authors are to be congratulated for performing a randomized trial in anaplastic thyroid cancer and to acknowledge the limitations of their study.5 The trend observed on the impact of surgical resection on median survival is important and is a
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significant contribution to the limited and low level of evidence data available that multimodal therapy may be warranted in patients with stage IVC anaplastic thyroid cancer. An increase in collaborative and multi-institution translational and clinical research is gravely needed for anaplastic thyroid cancer, a rare, lethal, and neglected malignancy. REFERENCES 1. Kebebew E, Greenspan FS, Clark OH, Woeber KA, McMillan A. Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors. Cancer 2005;103:1330-5. 2. McIver B, Hay ID, Giuffrida DF, Dvorak CE, Grant CS, Thompson GB, et al. Anaplastic thyroid carcinoma: a 50-year experience at a single institution. Surgery 2001;130:1028-34. 3. Harris PJ, Bible KC. Emerging therapeutics for advanced thyroid malignancies: rationale and targeted approaches. Expert Opin Investig Drugs 2011;20:1357-75. 4. ClinicalTrials.gov web site. Open studies of thyroid cancer. Available from: http://clinicaltrials.gov/ct2/results?term=thyroid+ cancer&recr=Open&rslt=&type=Intr&cond=anaplastic&intr=
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&outc=&spons=&lead=&id=&state1=&cntry1=&state2=&cntry2= &state3=&cntry3=&locn=&gndr=&phase=0&phase=1&phase=2 &rcv_s=&rcv_e=&lup_s=&lup_e=. Sosa J, Balkissoon J, Lu S, et al. Thyroidectomy followed by fosbretabulin (CA4P) combination regimen appears to suggest improvement in patient survival in anaplastic thyroid cancer. Surgery 2012;152:1078-87. Smallridge RC, Marlow LA, Copland JA. Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies. Endocr Relat Cancer 2009;16:17-44. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 2012;366: 707-14. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364: 2507-16. Nehs MA, Nucera C, Nagarkatti SS, Sadow PM, MoralesGarcia D, Hodin RA, et al. Late intervention with antiBRAF(V600E) therapy induces tumor regression in an orthotopic mouse model of human anaplastic thyroid cancer. Endocrinology 2012;153:985-94.
From the Endocrine Oncology Branch of the National Cancer Institute, Bethesda, MD
THYROID CANCER IS UNIQUE in that the different histologic subtypes exhibit the full spectrum of cancer behavior. Small (#1 cm), localized papillary thyroid cancers are common and are associated with almost a near-normal life expectancy after thyroidectomy. On the other hand, anaplastic thyroid cancer is rare, with an incidence of 1–2 cases per million people per year and is almost uniformly lethal.1 Approximately 10% of patients with anaplastic thyroid cancer present with only local disease; multimodal therapy (surgery, chemotherapy, and radiation) is therefore often necessary and may be associated with a better outcome in the majority of patients with advanced disease.1,2 Unfortunately, there has been no significant improvement in survival of patients with anaplastic thyroid cancer in nearly 6 decades. In most experimental investigations of new therapeutic agents for thyroid cancer, anaplastic thyroid cancer has also been relatively neglected, with most studies focused on locally advanced/metastatic differentiated thyroid cancer and other histologies. For example, of the >50 clinical trials available to patients with thyroid cancer, evaluating various tyrosine kinase inhibitors and other agents, only 8 include anaplastic thyroid cancer histology and only 2 are focused on anaplastic thyroid cancer.3,4 This is remarkable given that most deaths related to thyroid cancer are caused by anaplastic thyroid cancer. Sosa et al5 report on the influence of surgical resection using data from a multi-institution, randomized, controlled trial comparing carboplatin/ paclitaxel with and without fosbretabulin in patients with anaplastic thyroid cancer.5 The trial Accepted for publication August 29, 2012. Reprint requests: Electron Kebebew, MD, Endocrine Oncology Branch, National Cancer Institute, Building 10-CRC, Room 3-3940, 10 Center Drive, MSC 1201, Bethesda, MD 20892. E-mail: [email protected]. Surgery 2012;152:1088-9. 0039-6060/$ - see front matter Published by Mosby, Inc. http://dx.doi.org/10.1016/j.surg.2012.08.059
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was terminated early because of insufficient accrual after 80 patients were enrolled and most patients (90%) had stage IVC disease (distant metastasis). Forty-four patients (55%) had surgical resection before enrolling in the trial for systemic disease. The investigators found a trend in higher median survival (8.2 months) in patients who had cancer-directed surgery before receiving carboplatin/paclitaxel with fosbretabulin compared to those who did not have an operation and received carboplatin/paclitaxel (median survival, 4 months; P = .25). While this study is the largest randomized study of anaplastic thyroid cancer to date, it was not powered to address the impact of surgical resection on patient outcome with systemic chemotherapy, and the majority of patients had metastatic disease. These findings, although not conclusive, support a multimodal therapeutic approach in patients with anaplastic thyroid cancer. Resection of locoregional anaplastic thyroid cancer---when it can be performed with gross or microscopic negative margins---should be performed in the presence or absence of distant disease because it may reduce the risk that a patient will die from asphyxiation or bleeding from the great vessels caused by locoregional tumor invasion. Our understanding of the molecular pathogenesis of anaplastic thyroid cancer has improved, and the relative frequency of mutations in genes such as BRAF, RAS, CTNNB1, PIK3CA, TP53, AXIN1, PTEN, and APC has been characterized.6 The most prevalent of these genetic alterations is in AXIN1 (82%), followed by TP53 (55%), CTNNB1 (38%), and BRAF (26%).6 These data could have important clinical ramifications in the design of future therapeutic trials because compounds that target specific driver mutations, such as BRAF, have already shown remarkable tumor activity in recent clinical trials for other types of cancers and in preclinical studies of anaplastic thyroid cancer.7-9 The authors are to be congratulated for performing a randomized trial in anaplastic thyroid cancer and to acknowledge the limitations of their study.5 The trend observed on the impact of surgical resection on median survival is important and is a
Kebebew 1089
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significant contribution to the limited and low level of evidence data available that multimodal therapy may be warranted in patients with stage IVC anaplastic thyroid cancer. An increase in collaborative and multi-institution translational and clinical research is gravely needed for anaplastic thyroid cancer, a rare, lethal, and neglected malignancy. REFERENCES 1. Kebebew E, Greenspan FS, Clark OH, Woeber KA, McMillan A. Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors. Cancer 2005;103:1330-5. 2. McIver B, Hay ID, Giuffrida DF, Dvorak CE, Grant CS, Thompson GB, et al. Anaplastic thyroid carcinoma: a 50-year experience at a single institution. Surgery 2001;130:1028-34. 3. Harris PJ, Bible KC. Emerging therapeutics for advanced thyroid malignancies: rationale and targeted approaches. Expert Opin Investig Drugs 2011;20:1357-75. 4. ClinicalTrials.gov web site. Open studies of thyroid cancer. Available from: http://clinicaltrials.gov/ct2/results?term=thyroid+ cancer&recr=Open&rslt=&type=Intr&cond=anaplastic&intr=
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&outc=&spons=&lead=&id=&state1=&cntry1=&state2=&cntry2= &state3=&cntry3=&locn=&gndr=&phase=0&phase=1&phase=2 &rcv_s=&rcv_e=&lup_s=&lup_e=. Sosa J, Balkissoon J, Lu S, et al. Thyroidectomy followed by fosbretabulin (CA4P) combination regimen appears to suggest improvement in patient survival in anaplastic thyroid cancer. Surgery 2012;152:1078-87. Smallridge RC, Marlow LA, Copland JA. Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies. Endocr Relat Cancer 2009;16:17-44. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 2012;366: 707-14. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364: 2507-16. Nehs MA, Nucera C, Nagarkatti SS, Sadow PM, MoralesGarcia D, Hodin RA, et al. Late intervention with antiBRAF(V600E) therapy induces tumor regression in an orthotopic mouse model of human anaplastic thyroid cancer. Endocrinology 2012;153:985-94.