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Emerging therapies for thyroid carcinoma
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The Surgeon, Journal of the Royal Colleges of Surgeons of Edinburgh and Ireland www.thesurgeon.net
Review
Emerging therapies for thyroid carcinoma S. Walsh*, R. Prichard, A.D.K. Hill Department of Surgery, RCSI Smurfitt Building, Beaumont Hospital, Dublin 9, Ireland
article info
abstract
Article history:
Thyroid carcinoma is the most commonly diagnosed endocrine malignancy. Its incidence
Received 20 March 2011
is currently rising worldwide. The discovery of genetic mutations associated with the
Received in revised form
development of thyroid cancer, such as BRAF and RET, has lead to the development of new
1 August 2011
drugs which target the pathways which they influence. Despite recent advances, the
Accepted 17 August 2011
prognosis of anaplastic thyroid carcinoma is still unfavourable. In this review we look at
Available online 9 September 2011
emerging novel therapies for the treatment of well-differentiated and medullary thyroid carcinoma, and advances and future directions in the management of anaplastic thyroid
Keywords: Thyroid carcinoma Tyrosine kinase inhibitors
carcinoma. ª 2011 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.
Papillary Medullary Anaplastic BRAF RET Vandetanib Sunitinib Sorafenib Imatinib Motesanib
Introduction Thyroid carcinoma is the commonest endocrine malignancy, with an overall estimated incidence of 7.7 per 100,000.1 The last two decades have seen a worldwide rise in the incidence,2 with papillary carcinoma showing the greatest proportional increase over time.3 Thyroid carcinomas comprise a heterogenous group of tumours with different clinical and pathological characteristics and can be loosely divided into three main
subgroups. Differentiated thyroid carcinomas include papillary, follicular and Hu¨rthle cell carcinomas. These tumours arise from follicular thyroid cells and have similarities in their favourable clinical course and the principles of their management.4 Medullary thyroid carcinoma originates from parafollicular C-cells. However, one quarter of medullary carcinomas are caused by point mutations in the RET oncogene and are associated with familial syndromes, including multiple endocrine neoplasia type 2A and type 2B.5 Anaplastic
* Corresponding author. E-mail address: [email protected] (S. Walsh). 1479-666X/$ e see front matter ª 2011 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.surge.2011.08.004
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carcinoma, the majority of which arise de novo with a small proportion arising from well-differentiated thyroid cancers, responds disappointingly to conventional therapies and has an extremely poor overall prognosis.6 In general the treatment of thyroid tumours comprises surgical resection, radioactive iodine and thyroid hormone suppressive therapy.7 Overall prognosis is excellent with a 98% 10-year survival for differentiated thyroid carcinoma.8 However when patients develop metastatic disease, systemic chemotherapy is of limited benefit with poor overall response rates and little increase in overall survival rates.9 For patients with poorly responsive differentiated thyroid carcinoma or metastatic medullary carcinoma novel therapeutic options are desperately needed to improve disease outcomes. Multiple novel therapies targeting angiogenesis have been recently developed and are currently in clinical trials assessing their efficacy. Anaplastic carcinoma almost forms a separate entity with an overall 1 year survival rate of 20%.6 Surgical intervention is largely aimed at providing local control and has little impact on overall survival, while the majority are insensitive to radioactive iodine.10 Therefore, new developments are predominantly aimed at neoadjuvant treatment with a combination of systemic chemotherapy and radiotherapy. The aim of this review is discuss the biological mutations underpinning advanced thyroid carcinoma and to focus on the emerging novel therapies for its treatment. Secondly, an update on the current advances in the management of patients with anaplastic thyroid carcinoma will be provided.
Targeting cell signalling pathways Tyrosine kinase inhibitors Protein kinases are amongst the most promising new targets for the treatment of cancer. They act by regulating cellular signal transduction pathways, thereby influencing cell growth, survival and differentiation. The identification of the dysregulation and upregulation of various protein kinases, and the pathways in which they are involved, has led to the development of tyrosine kinase inhibitors. In 2002, imatinib (Gleevec) was introduced into routine clinical practice for the treatment of gastrointestinal stromal tumours. Imatinib was also found to be highly effective in the treatment of chronic myeloid leukaemia.11 The addition the tyrosine kinase inhibitor lapatinib to the treatment of breast carcinoma which overexpresses the HER2 oncogene has significantly improved the prognosis of these patients.12 The success of these tyrosine kinase inhibitors has led to increased research into the effect on tyrosine kinase inhibition on a vast range of solid tumours, including thyroid carcinoma.
Thyroid carcinoma mutations Recent endeavours to elicit the pathogenesis of thyroid carcinoma have revealed several genetic mutations which lead to its development including aberrations of BRAF and RET.
BRAF Several intracellular signalling pathways, including the PI3K/ AKT cell signalling pathway and the MAPK (mitogen activated protein kinase) cell signalling cascade have been shown to be integral to the development and progression of thyroid carcinoma.13 Among the three forms of Raf kinases, BRAF (the gene for the B-type Raf kinase), with its gene located on chromosome 7, is the most potent activator of the MAPK signalling pathway. BRAF activating point mutations are clustered in exons 11 and 15 of the gene.14 The most common genetic alteration in thyroid carcinoma is the oncogenic T1799A transversion mutation of BRAF.14 This aberrancy, which was discovered in 2008, is observed in approximately 44% of papillary thyroid carcinoma and 24% of anaplastic thyroid carcinoma.14 Raf is a key component of the MAPK signalling cascade, of which there are several inhibitors. The MEK inhibitor, CI-1040, has been shown to inhibit the proliferation and growth of thyroid cancer cells in vitro.15 This effect seemed to be BRAF mutation or RAS mutation selective. Thyroid cancer cell lines containing either RET or RAF mutations were found to be highly sensitive to two RAF kinase inhibitors, AAL-881 and LBT-613.16 AZD6244 is an inhibitor of MAPK ERK, which is down stream of RAF, inhibited the MEKERK pathway across a spectrum of thyroid cancer cells, and was also most effective in BRAF mutated cell lines.17
RET The RET (REarranged during Transcription) receptor protein is a tyrosine kinase influencing cell survival.18 The RET oncogene is located on chromosome 10q11.2.19 After dimerization, RET activates several signal transduction pathways, including the MAPK signalling cascade and the PI3K/AKT cell signalling pathway, leading to increased cell growth, survival and proliferation.20 Point mutations in the RET proto-oncogene are responsible for almost all inherited and almost half of all sporadic medullary thyroid carcinomas.21 Exposure to radiation is a major risk factor for the development of RET associated papillary thyroid carcinoma.19 Currently there is no tyrosine kinase inhibitor specific to RET available, but there are several multi-targeted tyrosine kinase inhibitors which have demonstrated significant activity against RET, including vandetanib (ZD6474), sorafenib (BAY 43-9006), motesanib, imatenib and sunitinib.
Clinical evidence for tyrosine kinase inhibitors in thyroid carcinoma Vandetanib Vandetanib (ZD6474) is an orally available tyrosine kinase inhibitor, which targets vascular endothelial growth factor receptor (VEGR), epidermal growth factor receptor (EGFR) and RET signalling.22 Genetic alterations of RET have been implicated in the pathophysiology of medullary thyroid carcinoma. Upregulation of VEGF in thyroid carcinoma in comparison with benign thyroid tissue was first observed in 1997.23 Increased expression of EGFR has been observed in follicular, medullary and anaplastic thyroid cancer.24e26 The initial phase II clinical trials performed in thirty patients with advanced or unresectable hereditary medullary thyroid
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cancer demonstrated good response to 300 mg vandetanib daily, with minimal adverse events.27 Further clinical trials showed the over half of patients with advanced hereditary MTC achieved disease stability after receiving only 100 mg vandetanib daily.28 The results of ZETA, the first phase III multi-centre study evaluating oral once-daily vandetanib 300 mg in 331 patients with unresectable, locally advanced or metastatic hereditary or sporadic medullary thyroid cancer, have recently been released.29 The investigators looked at progression free survival, objective response rate and disease control rate. Over half of the patients enrolled were positive for RET mutation. A response rate of 45% was reported as well as a significant decrease in calcitonin and CEA biomarkers. These results are promising although limited by the advanced disease of the patients enrolled.
Sorafenib Sorafenib (BAY 43-9006) is a multi-kinase inhibitor which targets BRAF, VEGFR, KIT (a stem cell growth factor protooncogene involved in cell survival and differentiation) and platelet-derived growth factor receptor (PDGFR), and has been demonstrated to strongly inhibit RET kinase in vitro.30 The original phase II clinical trial, in which 400 mg of sorafenib was administered twice daily to 21 patients with metastatic medullary carcinoma showed that 87% of the patients with sporadic MTC achieved stable disease.31 In a similar trial, all 5 patients treated with sorafenib exhibited partial response.32 In both of these trials the authors reported side-effects which included hand and foot syndrome (HFS), fatigue and diarrhea. Hand and foot syndrome, characterized by a painful palmarplantar rash, is a cutaneous side-effect associated with various chemotherapy agents. Sorafenib has emerged as a leading cause of HFS, with 10e62% of patients treated with it reporting the side-effect.33 A more recent study has shown that patients with metastatic papillary thyroid carcinoma also respond to treatment with sorafenib, suggesting that the therapeutic use of sorafenib may not be limited to the treatment of medullary thyroid carcinoma.34 In this study, the partial response rate was 33% and the stable disease rate, 44%.
Imatinib Imatinib (Gleevec) is a tyrosine kinase inhibitor which inhibits RET, PDGFR and KIT, and has revolutionized the treatment of chronic myeloid leukaemia. Early cell-line studies showed that treatment with imatinib significantly inhibited growth in anaplastic p-53 mutated thyroid carcinoma cell lines, but not in p-53 mutated papillary thyroid carcinoma cell lines.35 Further in vivo studies demonstrated additive effects between imatinib and gefitinib, an inhibitor of HER1, or endothelial growth factor receptor, when used to treat anaplastic thyroid carcinoma xenografts in nude mice.36 However a phase II clinical trial testing the use of imatinib in medullary thyroid carcinoma yielded disappointing results.37 Less than a quarter of the patients achieved stable disease and there was no evidence of partial response. Furthermore, patients with hypothyroidism who were being treated with imatinib developed increased levothyroxine requirements.38 In contrast, another trial testing imatinib in a similar cohort of patients reported that the drug was well tolerated, although disease stability was only transient.39
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Sunitinib Sunitinib is a small molecule inhibitor targeting similar protein kinases to sorafenibdVEGFR, PDGFR, KIT and RET. It has been shown to downregulate the MEK/ERK and SAPK/JNK cell signalling pathways in papillary thyroid carcinoma.40 Phase I clinical trials showed acceptable safety profiles and partial response to sunitinib in conjunction with capecitabine in patients with advanced thyroid carcinoma.41 Subsequently a phase II clinical trial treated 33 patients with either welldifferentiated thyroid carcinoma, or medullary thyroid carcinoma with sunitinib.42 One patient had complete response, 28% had a partial response and 46% exhibited disease stability. The side-effect profile was similar to that of sorafenib, and included hand and foot syndrome, neutropaenia and fatigue. The first results of the THYSU trial were recently released.43 Patients with iodine-refractive advanced thyroid cancer were treated with 50 mg daily for 4 weeks, every 6 weeks. Of the 15 patients eligible for evaluation, one had a partial response and twelve demonstrated disease stability. The final results are yet to be released. These papers suggest that sunitinib is a promising treatment for thyroid carcinoma. However, it is important to bear in mind that sunitinb causes an increase in levothyrroxine requirements.44 This warrants caution when treating a cohort of patients who may have undergone thyroid surgery as part of their cancer treatment.
Motesanib Motesanib, like sorafenib and sunitinib, is a tyrosine kinase inhibitor targeting RET, VEGFR, PDGFR and KIT. It is orally available, facilitating easy administration. Motesanib was tested in a cohort of 93 patients with advanced thyroid carcinoma, comprising 61% papillary thyroid carcinoma.45 A response rate of 14% and disease stability rate of 67% was observed. A phase II clinical trial in which motesanib was given to patients with advanced, progressive or metastatic medullary carcinoma reported an impressive disease stability rate of 81%, and significant decreases in tumour markers.46 Changes in serum placental growth factor and soluble VEGF two weeks after commencement of treatment have been identified as potential predictors of response to motesanib.47 In view of the impressive response rates, favourable safety profile and availability of potential predictors of response motesanib may in the future play a role in the treatment of both differentiated and medullary thyroid carcinoma.
Other emerging therapies There are several other therapeutic agents undergoing investigation for their use in thyroid carcinoma. Src is a protooncogene involved in signalling and is thus involved in the control of cell proliferation, cell differentiation, migration, angiogenesis, and survival. Src is thus thought to play a key role in tumour formation and progression.48e50 Four out of five thyroid cancer cell lines showed good sensitivity to inhibition of Src with AZD0530.51 Further investigation is warranted before progression to clinical trials. Bortezomib effectively inhibited thyroid tumour growth in vivo and in vitro.52 This finding prompted the commencement of two clinical trials, one testing its use in iodine refractory metastatic thyroid cancer (NCT00104871), and the other testing its use in
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conjunction with vandetanib in the treatment of metastatic medullary thyroid carcinoma (NCT00923247). A key down stream component in the PI3K pathway is the serine/threonine kinase known as mTOR, the human target of rapamycin. mTOR is thus a critical regulator of tumour formation and progression. Consistent with its role in tumour formation and progression, targeted therapy against mTOR has been shown to decrease tumour growth in model systems.53e55 Indeed, several agents that inhibit mTor are currently in clinical trials for the treatment of multiple cancer types.56e58 In vitro studies have shown that anaplastic and medullary thyroid cancer cell lines are sensitive to treatment with everolimus (RAD001), a novel inhibitor of mTor.59,60 In vitro studies revealed that while everolimus blocked tumour growth, it did not slow disease progression.61 Thus the recommendation was to combine everolimus with other therapies which will inhibit metastasis. There are currently several clinical trials recruiting patients with advanced thyroid carcinoma, to test everolimus either alone, or in combination with sorafenib (NCT01263951, NCT01118065, NCT01164176).
Anaplastic thyroid carcinoma Anaplastic thyroid carcinoma accounts for merely 2e5% of all thyroid cancer.62 Due to their aggressive nature, they are classified as T4 and Stage IV, regardless of the actual tumour burden. Research into the treatment of anaplastic thyroid carcinoma is deficient due to the rarity of the tumour and the rapid progression of the disease. As a result survival rates are low (20% at one year) and this has remained virtually static in the past fifty years.63 However a recent study of 75 patients with anaplastic thyroid carcinoma showed remission in 89% of those who received surgical therapy and chemoradiation. These patients also had a longer median survival.64 A retrospective analysis of 5 patients demonstrated that a combination of radiation and docetaxel was effective for the treatment of anaplastic thyroid cancer.65 In this cohort, two patients achieved complete response, and two patients partial response. A study by Foote et al also reported improved survival rates of 70% at 1 year and 60% at 2 years following aggressive multimodal therapy for stage IV anaplastic thyroid carcinoma.66 Aggressive multimodal therapy constituted surgery, if feasible, intensity-modulated radiation therapy and radiosensitising adjuvant chemotherapy involving four cycles of docetaxel and doxorubicin. A Serbian study reported a clinical benefit of 50% from treatment with radiotherapy followed by doxorubicin and cisplatin.67 A series of 50 patients treated in Hong Kong further demonstrated that patients with anaplastic thyroid carcinoma benefit from an aggressive multidisciplinary approach, combining surgery, radiotherapy and chemotherapy.68 A recent study examining the effect of imatinib on patients with advanced anaplastic thyroid carcinoma reported that of the 8 patients included for analysis, 2 exhibited partial response and 4 achieved disease stability.69 Preclinical data indicates that the main role for this drug lies in the treatment of anaplastic thyroid carcinoma. The main challenges in the search for new treatments for anaplastic thyroid carcinoma
are the rarity of this tumour and its aggressive nature, leading to difficulty in recruiting patients for clinical trials. There is clearly a need for a large multi-centred clinical trial testing the use of imatinib in metastatic anaplastic thyroid carcinoma. There are two phase II clinical trials in the recruitment phase, testing the use of sorafenib alone, and bevacizimab with doxorubicin, in advanced anaplastic thyroid carcinoma (NCT00126568, NCT00804830).
Conclusion The treatment of well-differentiated and medullary thyroid carcinomas has recently seen many exciting advances, with new targeted drugs achieving promising results in phase III clinical trials. However these advances have yet to become applicable to anaplastic thyroid carcinoma, which still carries a dismal prognosis in contrast with other subtypes of thyroid carcinoma. Preclinical studies have yielded promising results in the response of anaplastic thyroid cancer to a number of targeted therapies. However, the difficulty in recruiting these patients, who frequently have advanced disease at presentation, to participate in clinical trials has resulted in these drugs failing to be adequately tested clinically. Collaboration between cancer centres worldwide is imperative in recruiting sufficient cases of anaplastic thyroid cancer to prove the efficacy of new drugs in the treatment of this rare, but lethal cancer.
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The Surgeon, Journal of the Royal Colleges of Surgeons of Edinburgh and Ireland www.thesurgeon.net
Review
Emerging therapies for thyroid carcinoma S. Walsh*, R. Prichard, A.D.K. Hill Department of Surgery, RCSI Smurfitt Building, Beaumont Hospital, Dublin 9, Ireland
article info
abstract
Article history:
Thyroid carcinoma is the most commonly diagnosed endocrine malignancy. Its incidence
Received 20 March 2011
is currently rising worldwide. The discovery of genetic mutations associated with the
Received in revised form
development of thyroid cancer, such as BRAF and RET, has lead to the development of new
1 August 2011
drugs which target the pathways which they influence. Despite recent advances, the
Accepted 17 August 2011
prognosis of anaplastic thyroid carcinoma is still unfavourable. In this review we look at
Available online 9 September 2011
emerging novel therapies for the treatment of well-differentiated and medullary thyroid carcinoma, and advances and future directions in the management of anaplastic thyroid
Keywords: Thyroid carcinoma Tyrosine kinase inhibitors
carcinoma. ª 2011 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.
Papillary Medullary Anaplastic BRAF RET Vandetanib Sunitinib Sorafenib Imatinib Motesanib
Introduction Thyroid carcinoma is the commonest endocrine malignancy, with an overall estimated incidence of 7.7 per 100,000.1 The last two decades have seen a worldwide rise in the incidence,2 with papillary carcinoma showing the greatest proportional increase over time.3 Thyroid carcinomas comprise a heterogenous group of tumours with different clinical and pathological characteristics and can be loosely divided into three main
subgroups. Differentiated thyroid carcinomas include papillary, follicular and Hu¨rthle cell carcinomas. These tumours arise from follicular thyroid cells and have similarities in their favourable clinical course and the principles of their management.4 Medullary thyroid carcinoma originates from parafollicular C-cells. However, one quarter of medullary carcinomas are caused by point mutations in the RET oncogene and are associated with familial syndromes, including multiple endocrine neoplasia type 2A and type 2B.5 Anaplastic
* Corresponding author. E-mail address: [email protected] (S. Walsh). 1479-666X/$ e see front matter ª 2011 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.surge.2011.08.004
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carcinoma, the majority of which arise de novo with a small proportion arising from well-differentiated thyroid cancers, responds disappointingly to conventional therapies and has an extremely poor overall prognosis.6 In general the treatment of thyroid tumours comprises surgical resection, radioactive iodine and thyroid hormone suppressive therapy.7 Overall prognosis is excellent with a 98% 10-year survival for differentiated thyroid carcinoma.8 However when patients develop metastatic disease, systemic chemotherapy is of limited benefit with poor overall response rates and little increase in overall survival rates.9 For patients with poorly responsive differentiated thyroid carcinoma or metastatic medullary carcinoma novel therapeutic options are desperately needed to improve disease outcomes. Multiple novel therapies targeting angiogenesis have been recently developed and are currently in clinical trials assessing their efficacy. Anaplastic carcinoma almost forms a separate entity with an overall 1 year survival rate of 20%.6 Surgical intervention is largely aimed at providing local control and has little impact on overall survival, while the majority are insensitive to radioactive iodine.10 Therefore, new developments are predominantly aimed at neoadjuvant treatment with a combination of systemic chemotherapy and radiotherapy. The aim of this review is discuss the biological mutations underpinning advanced thyroid carcinoma and to focus on the emerging novel therapies for its treatment. Secondly, an update on the current advances in the management of patients with anaplastic thyroid carcinoma will be provided.
Targeting cell signalling pathways Tyrosine kinase inhibitors Protein kinases are amongst the most promising new targets for the treatment of cancer. They act by regulating cellular signal transduction pathways, thereby influencing cell growth, survival and differentiation. The identification of the dysregulation and upregulation of various protein kinases, and the pathways in which they are involved, has led to the development of tyrosine kinase inhibitors. In 2002, imatinib (Gleevec) was introduced into routine clinical practice for the treatment of gastrointestinal stromal tumours. Imatinib was also found to be highly effective in the treatment of chronic myeloid leukaemia.11 The addition the tyrosine kinase inhibitor lapatinib to the treatment of breast carcinoma which overexpresses the HER2 oncogene has significantly improved the prognosis of these patients.12 The success of these tyrosine kinase inhibitors has led to increased research into the effect on tyrosine kinase inhibition on a vast range of solid tumours, including thyroid carcinoma.
Thyroid carcinoma mutations Recent endeavours to elicit the pathogenesis of thyroid carcinoma have revealed several genetic mutations which lead to its development including aberrations of BRAF and RET.
BRAF Several intracellular signalling pathways, including the PI3K/ AKT cell signalling pathway and the MAPK (mitogen activated protein kinase) cell signalling cascade have been shown to be integral to the development and progression of thyroid carcinoma.13 Among the three forms of Raf kinases, BRAF (the gene for the B-type Raf kinase), with its gene located on chromosome 7, is the most potent activator of the MAPK signalling pathway. BRAF activating point mutations are clustered in exons 11 and 15 of the gene.14 The most common genetic alteration in thyroid carcinoma is the oncogenic T1799A transversion mutation of BRAF.14 This aberrancy, which was discovered in 2008, is observed in approximately 44% of papillary thyroid carcinoma and 24% of anaplastic thyroid carcinoma.14 Raf is a key component of the MAPK signalling cascade, of which there are several inhibitors. The MEK inhibitor, CI-1040, has been shown to inhibit the proliferation and growth of thyroid cancer cells in vitro.15 This effect seemed to be BRAF mutation or RAS mutation selective. Thyroid cancer cell lines containing either RET or RAF mutations were found to be highly sensitive to two RAF kinase inhibitors, AAL-881 and LBT-613.16 AZD6244 is an inhibitor of MAPK ERK, which is down stream of RAF, inhibited the MEKERK pathway across a spectrum of thyroid cancer cells, and was also most effective in BRAF mutated cell lines.17
RET The RET (REarranged during Transcription) receptor protein is a tyrosine kinase influencing cell survival.18 The RET oncogene is located on chromosome 10q11.2.19 After dimerization, RET activates several signal transduction pathways, including the MAPK signalling cascade and the PI3K/AKT cell signalling pathway, leading to increased cell growth, survival and proliferation.20 Point mutations in the RET proto-oncogene are responsible for almost all inherited and almost half of all sporadic medullary thyroid carcinomas.21 Exposure to radiation is a major risk factor for the development of RET associated papillary thyroid carcinoma.19 Currently there is no tyrosine kinase inhibitor specific to RET available, but there are several multi-targeted tyrosine kinase inhibitors which have demonstrated significant activity against RET, including vandetanib (ZD6474), sorafenib (BAY 43-9006), motesanib, imatenib and sunitinib.
Clinical evidence for tyrosine kinase inhibitors in thyroid carcinoma Vandetanib Vandetanib (ZD6474) is an orally available tyrosine kinase inhibitor, which targets vascular endothelial growth factor receptor (VEGR), epidermal growth factor receptor (EGFR) and RET signalling.22 Genetic alterations of RET have been implicated in the pathophysiology of medullary thyroid carcinoma. Upregulation of VEGF in thyroid carcinoma in comparison with benign thyroid tissue was first observed in 1997.23 Increased expression of EGFR has been observed in follicular, medullary and anaplastic thyroid cancer.24e26 The initial phase II clinical trials performed in thirty patients with advanced or unresectable hereditary medullary thyroid
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cancer demonstrated good response to 300 mg vandetanib daily, with minimal adverse events.27 Further clinical trials showed the over half of patients with advanced hereditary MTC achieved disease stability after receiving only 100 mg vandetanib daily.28 The results of ZETA, the first phase III multi-centre study evaluating oral once-daily vandetanib 300 mg in 331 patients with unresectable, locally advanced or metastatic hereditary or sporadic medullary thyroid cancer, have recently been released.29 The investigators looked at progression free survival, objective response rate and disease control rate. Over half of the patients enrolled were positive for RET mutation. A response rate of 45% was reported as well as a significant decrease in calcitonin and CEA biomarkers. These results are promising although limited by the advanced disease of the patients enrolled.
Sorafenib Sorafenib (BAY 43-9006) is a multi-kinase inhibitor which targets BRAF, VEGFR, KIT (a stem cell growth factor protooncogene involved in cell survival and differentiation) and platelet-derived growth factor receptor (PDGFR), and has been demonstrated to strongly inhibit RET kinase in vitro.30 The original phase II clinical trial, in which 400 mg of sorafenib was administered twice daily to 21 patients with metastatic medullary carcinoma showed that 87% of the patients with sporadic MTC achieved stable disease.31 In a similar trial, all 5 patients treated with sorafenib exhibited partial response.32 In both of these trials the authors reported side-effects which included hand and foot syndrome (HFS), fatigue and diarrhea. Hand and foot syndrome, characterized by a painful palmarplantar rash, is a cutaneous side-effect associated with various chemotherapy agents. Sorafenib has emerged as a leading cause of HFS, with 10e62% of patients treated with it reporting the side-effect.33 A more recent study has shown that patients with metastatic papillary thyroid carcinoma also respond to treatment with sorafenib, suggesting that the therapeutic use of sorafenib may not be limited to the treatment of medullary thyroid carcinoma.34 In this study, the partial response rate was 33% and the stable disease rate, 44%.
Imatinib Imatinib (Gleevec) is a tyrosine kinase inhibitor which inhibits RET, PDGFR and KIT, and has revolutionized the treatment of chronic myeloid leukaemia. Early cell-line studies showed that treatment with imatinib significantly inhibited growth in anaplastic p-53 mutated thyroid carcinoma cell lines, but not in p-53 mutated papillary thyroid carcinoma cell lines.35 Further in vivo studies demonstrated additive effects between imatinib and gefitinib, an inhibitor of HER1, or endothelial growth factor receptor, when used to treat anaplastic thyroid carcinoma xenografts in nude mice.36 However a phase II clinical trial testing the use of imatinib in medullary thyroid carcinoma yielded disappointing results.37 Less than a quarter of the patients achieved stable disease and there was no evidence of partial response. Furthermore, patients with hypothyroidism who were being treated with imatinib developed increased levothyroxine requirements.38 In contrast, another trial testing imatinib in a similar cohort of patients reported that the drug was well tolerated, although disease stability was only transient.39
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Sunitinib Sunitinib is a small molecule inhibitor targeting similar protein kinases to sorafenibdVEGFR, PDGFR, KIT and RET. It has been shown to downregulate the MEK/ERK and SAPK/JNK cell signalling pathways in papillary thyroid carcinoma.40 Phase I clinical trials showed acceptable safety profiles and partial response to sunitinib in conjunction with capecitabine in patients with advanced thyroid carcinoma.41 Subsequently a phase II clinical trial treated 33 patients with either welldifferentiated thyroid carcinoma, or medullary thyroid carcinoma with sunitinib.42 One patient had complete response, 28% had a partial response and 46% exhibited disease stability. The side-effect profile was similar to that of sorafenib, and included hand and foot syndrome, neutropaenia and fatigue. The first results of the THYSU trial were recently released.43 Patients with iodine-refractive advanced thyroid cancer were treated with 50 mg daily for 4 weeks, every 6 weeks. Of the 15 patients eligible for evaluation, one had a partial response and twelve demonstrated disease stability. The final results are yet to be released. These papers suggest that sunitinib is a promising treatment for thyroid carcinoma. However, it is important to bear in mind that sunitinb causes an increase in levothyrroxine requirements.44 This warrants caution when treating a cohort of patients who may have undergone thyroid surgery as part of their cancer treatment.
Motesanib Motesanib, like sorafenib and sunitinib, is a tyrosine kinase inhibitor targeting RET, VEGFR, PDGFR and KIT. It is orally available, facilitating easy administration. Motesanib was tested in a cohort of 93 patients with advanced thyroid carcinoma, comprising 61% papillary thyroid carcinoma.45 A response rate of 14% and disease stability rate of 67% was observed. A phase II clinical trial in which motesanib was given to patients with advanced, progressive or metastatic medullary carcinoma reported an impressive disease stability rate of 81%, and significant decreases in tumour markers.46 Changes in serum placental growth factor and soluble VEGF two weeks after commencement of treatment have been identified as potential predictors of response to motesanib.47 In view of the impressive response rates, favourable safety profile and availability of potential predictors of response motesanib may in the future play a role in the treatment of both differentiated and medullary thyroid carcinoma.
Other emerging therapies There are several other therapeutic agents undergoing investigation for their use in thyroid carcinoma. Src is a protooncogene involved in signalling and is thus involved in the control of cell proliferation, cell differentiation, migration, angiogenesis, and survival. Src is thus thought to play a key role in tumour formation and progression.48e50 Four out of five thyroid cancer cell lines showed good sensitivity to inhibition of Src with AZD0530.51 Further investigation is warranted before progression to clinical trials. Bortezomib effectively inhibited thyroid tumour growth in vivo and in vitro.52 This finding prompted the commencement of two clinical trials, one testing its use in iodine refractory metastatic thyroid cancer (NCT00104871), and the other testing its use in
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conjunction with vandetanib in the treatment of metastatic medullary thyroid carcinoma (NCT00923247). A key down stream component in the PI3K pathway is the serine/threonine kinase known as mTOR, the human target of rapamycin. mTOR is thus a critical regulator of tumour formation and progression. Consistent with its role in tumour formation and progression, targeted therapy against mTOR has been shown to decrease tumour growth in model systems.53e55 Indeed, several agents that inhibit mTor are currently in clinical trials for the treatment of multiple cancer types.56e58 In vitro studies have shown that anaplastic and medullary thyroid cancer cell lines are sensitive to treatment with everolimus (RAD001), a novel inhibitor of mTor.59,60 In vitro studies revealed that while everolimus blocked tumour growth, it did not slow disease progression.61 Thus the recommendation was to combine everolimus with other therapies which will inhibit metastasis. There are currently several clinical trials recruiting patients with advanced thyroid carcinoma, to test everolimus either alone, or in combination with sorafenib (NCT01263951, NCT01118065, NCT01164176).
Anaplastic thyroid carcinoma Anaplastic thyroid carcinoma accounts for merely 2e5% of all thyroid cancer.62 Due to their aggressive nature, they are classified as T4 and Stage IV, regardless of the actual tumour burden. Research into the treatment of anaplastic thyroid carcinoma is deficient due to the rarity of the tumour and the rapid progression of the disease. As a result survival rates are low (20% at one year) and this has remained virtually static in the past fifty years.63 However a recent study of 75 patients with anaplastic thyroid carcinoma showed remission in 89% of those who received surgical therapy and chemoradiation. These patients also had a longer median survival.64 A retrospective analysis of 5 patients demonstrated that a combination of radiation and docetaxel was effective for the treatment of anaplastic thyroid cancer.65 In this cohort, two patients achieved complete response, and two patients partial response. A study by Foote et al also reported improved survival rates of 70% at 1 year and 60% at 2 years following aggressive multimodal therapy for stage IV anaplastic thyroid carcinoma.66 Aggressive multimodal therapy constituted surgery, if feasible, intensity-modulated radiation therapy and radiosensitising adjuvant chemotherapy involving four cycles of docetaxel and doxorubicin. A Serbian study reported a clinical benefit of 50% from treatment with radiotherapy followed by doxorubicin and cisplatin.67 A series of 50 patients treated in Hong Kong further demonstrated that patients with anaplastic thyroid carcinoma benefit from an aggressive multidisciplinary approach, combining surgery, radiotherapy and chemotherapy.68 A recent study examining the effect of imatinib on patients with advanced anaplastic thyroid carcinoma reported that of the 8 patients included for analysis, 2 exhibited partial response and 4 achieved disease stability.69 Preclinical data indicates that the main role for this drug lies in the treatment of anaplastic thyroid carcinoma. The main challenges in the search for new treatments for anaplastic thyroid carcinoma
are the rarity of this tumour and its aggressive nature, leading to difficulty in recruiting patients for clinical trials. There is clearly a need for a large multi-centred clinical trial testing the use of imatinib in metastatic anaplastic thyroid carcinoma. There are two phase II clinical trials in the recruitment phase, testing the use of sorafenib alone, and bevacizimab with doxorubicin, in advanced anaplastic thyroid carcinoma (NCT00126568, NCT00804830).
Conclusion The treatment of well-differentiated and medullary thyroid carcinomas has recently seen many exciting advances, with new targeted drugs achieving promising results in phase III clinical trials. However these advances have yet to become applicable to anaplastic thyroid carcinoma, which still carries a dismal prognosis in contrast with other subtypes of thyroid carcinoma. Preclinical studies have yielded promising results in the response of anaplastic thyroid cancer to a number of targeted therapies. However, the difficulty in recruiting these patients, who frequently have advanced disease at presentation, to participate in clinical trials has resulted in these drugs failing to be adequately tested clinically. Collaboration between cancer centres worldwide is imperative in recruiting sufficient cases of anaplastic thyroid cancer to prove the efficacy of new drugs in the treatment of this rare, but lethal cancer.
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