Managing Radioactive Iodine-Refractory Thyroid Cancer
Managing Radioactive Iodine-Refractory Thyroid Cancer
Published literature was reviewed to understand advances in the use of targeted therapies for RAI-refractory DTC. A PubMed search was conducted using the search terms "radioactive iodine-refractory, differentiated thyroid cancer, and treatment" restricted to a 2000–2012 timeframe, English language, and humans. Relevant articles were also identified from the bibliographies of selected references and clinical trials were identified at http://www.clinicaltrials.gov/. Individual cases were reviewed from our own clinical practice to identify and present examples of RAI-refractory disease and its progression.
As new treatment options emerge, it is becoming increasingly important to recognize the point at which RAI treatment is no longer of benefit to a patient. Generally speaking, we recommend that the definition of RAI-refractory DTC be based on clinical evidence or on imaging data showing at least 1 lesion that does not take up RAI (detailed in Table 1) and thus encompasses both truly refractory disease as well as resistant disease. Of course, the practitioner must be certain that RAI refractoriness is truly present and that decreased RAI uptake is not due to excess iodine intake in the diet, iodine supplement use, or prior procedures involving the administration of iodine-containing dye.
Variations in the definition of RAI-refractory disease persist in practice and in clinical trial design, and a need exists for the establishment of common criteria. Movement toward a consensus definition of RAI-refractory DTC will require coordination across medical specialties as it will influence the transition of treatment from a primarily endocrinologist-driven regimen to one usually driven by a medical oncologist.
For patients with RAI-refractory tumors, conventional cytotoxic chemotherapy has produced disappointing response rates (5–17% partial response [PR]) and significant toxicity in patients with advanced thyroid cancer . Based on research implicating several major pathways in the pathogenesis of this tumor type (Fig. 1), a number of targeted systemic therapies are currently under development. For symptomatic, nonresectable, RAI-refractory metastases that have been treated or cannot be treated with EBRT, National Comprehensive Cancer Network and American Thyroid Association guidelines recommend consideration of participation in a clinical trial or the use of small-molecule tyrosine kinase inhibitors (TKIs) ( Table 2 ).
Thyroid malignancies are highly vascularized; elevated serum vascular endothelial growth factor (VEGF), a major driver of tumor vascularization, has been associated with larger tumor size and poorer prognosis in DTC. Inhibition of VEGF-mediated vascularization is a proven treatment approach in many cancers, and most TKIs under investigation in DTC target angiogenesis and VEGF signaling ( Table 3 ).
In addition, as illustrated in Figure 1, activating genetic alterations in the RET/RAS/BRAF and PI3K/Akt/mTOR pathways frequently occur in PTC and FTC, respectively. Studies evaluating a genetic testing panel of BRAF and RAS point mutations and RET/PTC, PAX8/PPARγ, and TRK rearrangements found that any mutation was a strong predictor of malignancy in thyroid nodules irrespective of the cytologic diagnosis. Many new agents under study for DTC target one or more signaling steps in these pathways in addition to angiogenesis ( Table 3 ). Most are TKIs, with the exception of selumetinib, a serine/threonine kinase inhibitor of MEK1, 2.
(Enlarge Image)
Figure 1.
Signaling pathways implicated in papillary and follicular thyroid cancer. The approximate prevalence rates of genetic alterations in key pathway components are indicated (gray shading). Genetic variations include point mutations, genetic rearrangements, and increased gene copy number. The reported prevalence of genetic changes varies and may reflect inter- and intra-tumoral variation, geographic differences among patients, and differences in analytical methods (17–19,27,60–69).
In single-arm Phase 2 studies ( Table 3 ), objective response rates for systemic therapies ranged from 3 to 50%. Although complete responses are uncommon, clinical benefit rates (objective response + stable disease) range from 68 to 96%. Median progression-free survival (PFS) is generally longer than 1 year. Compared with conventional doxorubicin-based regimens, the clinical activity of kinase inhibitors represents a considerable improvement, offering an important therapeutic option for patients with metastatic, RAI-refractory disease.
It should be noted in this context that Response Evaluation Criteria in Solid Tumors (RECIST) criteria are not well suited for measuring response to targeted therapies. RECIST criteria were developed based on historical chemotherapeutic agents that worked primarily through cytotoxic mechanisms. Because kinase inhibitors do not exhibit classic cytotoxic activity, the RECIST criteria do not account for changes in tumor morphology, tumor status based on imaging studies, or immune-related responses following treatment with targeted agents. Recognition of the shortcomings of the RECIST v.1.0 criteria led to an update (RECIST v.1.1) that takes into account the value of imaging studies, such as CT (computed tomography) and FDG-PET ([18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography), in the anatomical assessment of tumor burden.
Sorafenib is the first targeted agent to be evaluated in a Phase 3 trial for RAI-refractory DTC. In the multinational DECISION trial (n = 417), sorafenib significantly extended PFS (primary trial endpoint) over placebo. In this trial, RAI-refractory disease was defined as a target lesion with no iodine uptake on a post-RAI scan performed under conditions of a low iodine diet and adequate TSH elevation or recombinant TSH stimulation. However, patients with some uptake were eligible if 1) they had undergone a single RAI treatment (≥100 mCi) in the previous 16 months and had progression of the target lesion despite RAI treatment; 2) they had undergone multiple RAI treatments, with at least 1 RAI treatment >16 months ago, and had disease progression after each of 2 RAI treatments (≥100 mCi each) administered within 16 months of each other; or 3) had received a cumulative RAI dose of ≥600 mCi. Patients must have shown progression by RECIST within the previous 14 months.
Lenvatinib is also being evaluated in a multicenter Phase 3 trial. In this trial, RAI-refractory disease is defined by at least 1 of the following: 1) 1 or more measurable lesions that do not demonstrate iodine uptake on any radioiodine scan; 2) 1 or more measurable lesions that have progressed by RECIST 1.1 criteria within 12 months of iodine 131 (I-131) therapy, despite demonstration of radioiodine avidity at the time of that treatment by pre- or posttreatment scanning; or 3) cumulative activity of I-131 of >600 mCi, with the last dose administered at least 6 months prior to study entry.
It is interesting to note that these 2 trials used different definitions of disease progression and RAI-refractory disease, further underscoring the need for consensus criteria.
Once a tumor has been established to be RAI-refractory, the decision whether to start a TKI should be based on clinical presentation of the patient, as well as imaging studies. Because most patients are asymptomatic even with metastatic disease and at present there is no evidence to suggest that earlier treatment with kinase inhibitors confers a clinical advantage over later treatment, systemic therapy should be used in patients with advanced symptomatic disease, relatively large tumor burden, and demonstrable disease progression. A multidisciplinary, multiregional panel of experts recently recommended that progressive disease should be defined by growth of lesions using RECIST rather than relying solely on an increase in tumor markers (e.g., thyroglobulin [Tg]). In our practice, the size (and change in size) of metastatic disease, intensity of standardized uptake value (SUV) activity on PET scan, volumetric doubling time (VDT), and symptoms are all taken into account. To assess for rapidly progressive disease, we use VDT based on structural imaging. A VDT of less than 1 year is consistent with more rapidly aggressive disease. If the VDT is less than 6 months, we would recommend initiation of a TKI. If the VDT is between 6 months and 1 year, the decision should be based on clinical judgment with close monitoring and repeat evaluations every 3 to 6 months.
Shared decision making with patients regarding treatment initiation is of critical importance. The side effects of targeted therapies can be significant to an otherwise asymptomatic patient, and health care providers should be well educated in managing possible side effects to maximize the likelihood that a patient can sustain an optimal long-term treatment regimen. In addition, although many of these drugs have increased PFS, none have yet demonstrated an impact on overall survival. However, it should be noted that the crossover design of current Phase 3 trials will likely hinder the ability to discern a survival advantage.
The following 4 cases illustrate the diverse ways in which RAI-unresponsive DTC may manifest and the challenges an endocrinologist might face in determining optimal timing for initiation of TKI therapy in these patients. Patients 1 and 2 represent the most common clinical scenarios.
This patient is a relatively young male whose tumor did not respond to RAI from the outset (and is thus considered refractory), despite being a well-differentiated papillary cancer with Hürthle cell features. His rapidly aggressive course is uncommon in thyroid cancer and was the rationale for enrollment in a TKI trial.
Additional novel approaches that are currently under investigation target molecules in a variety of pathways (Table 4). Findings that hypermethylation of tumor suppressor gene promoters and altered histone acetylation are associated with progression of thyroid cancer form the basis for exploring the activities of DNA-demethylation agents (e.g., decitabine) and histone deacetylase inhibitors (e.g., panobinostat, romidepsin, valproic acid, vorinostat) in DTC. Clinical studies to date, however, have shown unremarkable activity and/or unexpected severe adverse events with these compounds in thyroid cancer (Table 4). Whether these compounds will show greater activity in combination with other treatment modalities remains to be determined.
The immunomodulatory drugs thalidomide and lenalidomide have demonstrated antiangiogenic properties. Because thyroid cancer is associated with hypervascularization, compounds that inhibit angiogenesis may be active against this tumor type. Thus far, Phase 2 clinical studies show considerable clinical benefit of thalidomide and lenalidomide in patients with RAI-refractory DTC. Interestingly, RAI unresponsiveness was defined according to different criteria in the thalidomide Phase 2 study than in either of the Phase 3 studies of TKIs mentioned above.
In addition to single-agent studies, a number of combination regimens are currently under investigation in advanced DTC, including many that aim to disrupt multiple signaling pathways simultaneously. This approach may result in more complete growth inhibition and may be more likely to circumvent resistance mechanisms. Studies of combination regimens of targeted therapy and RAI treatment are also underway, which could provide insight into the benefit, if any, of earlier treatment with targeted therapy. Notably, a pilot study in 12 RAI-refractory patients showed that short-term therapy (4 weeks) with the mitogen activated protein (MAP) kinase inhibitor selumetinib led to a clinically meaningful increase in iodine uptake, with 8 of 12 patients reaching the dosimetry threshold for RAI therapy. Among these, 5 had a partial response and 3 had stable disease following radioiodine treatment (Table 4). The concept of using agents to enhance or restore uptake of iodine is not new. However, results using these agents have thus far been mixed. It will be of interest to see whether this approach can provide meaningful long-term benefit in the refractory patient (as in patients #2, #3, and #4 above).
The number of clinical studies currently ongoing in thyroid cancer belies the challenges that investigators face in conducting studies. First, enrollment of sufficient numbers of patients to execute Phase 2 and 3 studies is difficult. Although this problem is somewhat ameliorated by conducting multicenter studies, it remains a formidable issue that hampers forward progress in the evaluation of effective therapies for thyroid cancer.
Methods
Published literature was reviewed to understand advances in the use of targeted therapies for RAI-refractory DTC. A PubMed search was conducted using the search terms "radioactive iodine-refractory, differentiated thyroid cancer, and treatment" restricted to a 2000–2012 timeframe, English language, and humans. Relevant articles were also identified from the bibliographies of selected references and clinical trials were identified at http://www.clinicaltrials.gov/. Individual cases were reviewed from our own clinical practice to identify and present examples of RAI-refractory disease and its progression.
Criteria for Characterizing RAI-refractory DTC
As new treatment options emerge, it is becoming increasingly important to recognize the point at which RAI treatment is no longer of benefit to a patient. Generally speaking, we recommend that the definition of RAI-refractory DTC be based on clinical evidence or on imaging data showing at least 1 lesion that does not take up RAI (detailed in Table 1) and thus encompasses both truly refractory disease as well as resistant disease. Of course, the practitioner must be certain that RAI refractoriness is truly present and that decreased RAI uptake is not due to excess iodine intake in the diet, iodine supplement use, or prior procedures involving the administration of iodine-containing dye.
Variations in the definition of RAI-refractory disease persist in practice and in clinical trial design, and a need exists for the establishment of common criteria. Movement toward a consensus definition of RAI-refractory DTC will require coordination across medical specialties as it will influence the transition of treatment from a primarily endocrinologist-driven regimen to one usually driven by a medical oncologist.
The Advent of Targeted Kinase Inhibitors in Systemic Treatment of RAI-refractory DTC
For patients with RAI-refractory tumors, conventional cytotoxic chemotherapy has produced disappointing response rates (5–17% partial response [PR]) and significant toxicity in patients with advanced thyroid cancer . Based on research implicating several major pathways in the pathogenesis of this tumor type (Fig. 1), a number of targeted systemic therapies are currently under development. For symptomatic, nonresectable, RAI-refractory metastases that have been treated or cannot be treated with EBRT, National Comprehensive Cancer Network and American Thyroid Association guidelines recommend consideration of participation in a clinical trial or the use of small-molecule tyrosine kinase inhibitors (TKIs) ( Table 2 ).
Thyroid malignancies are highly vascularized; elevated serum vascular endothelial growth factor (VEGF), a major driver of tumor vascularization, has been associated with larger tumor size and poorer prognosis in DTC. Inhibition of VEGF-mediated vascularization is a proven treatment approach in many cancers, and most TKIs under investigation in DTC target angiogenesis and VEGF signaling ( Table 3 ).
In addition, as illustrated in Figure 1, activating genetic alterations in the RET/RAS/BRAF and PI3K/Akt/mTOR pathways frequently occur in PTC and FTC, respectively. Studies evaluating a genetic testing panel of BRAF and RAS point mutations and RET/PTC, PAX8/PPARγ, and TRK rearrangements found that any mutation was a strong predictor of malignancy in thyroid nodules irrespective of the cytologic diagnosis. Many new agents under study for DTC target one or more signaling steps in these pathways in addition to angiogenesis ( Table 3 ). Most are TKIs, with the exception of selumetinib, a serine/threonine kinase inhibitor of MEK1, 2.
(Enlarge Image)
Figure 1.
Signaling pathways implicated in papillary and follicular thyroid cancer. The approximate prevalence rates of genetic alterations in key pathway components are indicated (gray shading). Genetic variations include point mutations, genetic rearrangements, and increased gene copy number. The reported prevalence of genetic changes varies and may reflect inter- and intra-tumoral variation, geographic differences among patients, and differences in analytical methods (17–19,27,60–69).
In single-arm Phase 2 studies ( Table 3 ), objective response rates for systemic therapies ranged from 3 to 50%. Although complete responses are uncommon, clinical benefit rates (objective response + stable disease) range from 68 to 96%. Median progression-free survival (PFS) is generally longer than 1 year. Compared with conventional doxorubicin-based regimens, the clinical activity of kinase inhibitors represents a considerable improvement, offering an important therapeutic option for patients with metastatic, RAI-refractory disease.
It should be noted in this context that Response Evaluation Criteria in Solid Tumors (RECIST) criteria are not well suited for measuring response to targeted therapies. RECIST criteria were developed based on historical chemotherapeutic agents that worked primarily through cytotoxic mechanisms. Because kinase inhibitors do not exhibit classic cytotoxic activity, the RECIST criteria do not account for changes in tumor morphology, tumor status based on imaging studies, or immune-related responses following treatment with targeted agents. Recognition of the shortcomings of the RECIST v.1.0 criteria led to an update (RECIST v.1.1) that takes into account the value of imaging studies, such as CT (computed tomography) and FDG-PET ([18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography), in the anatomical assessment of tumor burden.
Sorafenib is the first targeted agent to be evaluated in a Phase 3 trial for RAI-refractory DTC. In the multinational DECISION trial (n = 417), sorafenib significantly extended PFS (primary trial endpoint) over placebo. In this trial, RAI-refractory disease was defined as a target lesion with no iodine uptake on a post-RAI scan performed under conditions of a low iodine diet and adequate TSH elevation or recombinant TSH stimulation. However, patients with some uptake were eligible if 1) they had undergone a single RAI treatment (≥100 mCi) in the previous 16 months and had progression of the target lesion despite RAI treatment; 2) they had undergone multiple RAI treatments, with at least 1 RAI treatment >16 months ago, and had disease progression after each of 2 RAI treatments (≥100 mCi each) administered within 16 months of each other; or 3) had received a cumulative RAI dose of ≥600 mCi. Patients must have shown progression by RECIST within the previous 14 months.
Lenvatinib is also being evaluated in a multicenter Phase 3 trial. In this trial, RAI-refractory disease is defined by at least 1 of the following: 1) 1 or more measurable lesions that do not demonstrate iodine uptake on any radioiodine scan; 2) 1 or more measurable lesions that have progressed by RECIST 1.1 criteria within 12 months of iodine 131 (I-131) therapy, despite demonstration of radioiodine avidity at the time of that treatment by pre- or posttreatment scanning; or 3) cumulative activity of I-131 of >600 mCi, with the last dose administered at least 6 months prior to study entry.
It is interesting to note that these 2 trials used different definitions of disease progression and RAI-refractory disease, further underscoring the need for consensus criteria.
The Decision of Whether and When to Treat with Targeted Inhibitors
Once a tumor has been established to be RAI-refractory, the decision whether to start a TKI should be based on clinical presentation of the patient, as well as imaging studies. Because most patients are asymptomatic even with metastatic disease and at present there is no evidence to suggest that earlier treatment with kinase inhibitors confers a clinical advantage over later treatment, systemic therapy should be used in patients with advanced symptomatic disease, relatively large tumor burden, and demonstrable disease progression. A multidisciplinary, multiregional panel of experts recently recommended that progressive disease should be defined by growth of lesions using RECIST rather than relying solely on an increase in tumor markers (e.g., thyroglobulin [Tg]). In our practice, the size (and change in size) of metastatic disease, intensity of standardized uptake value (SUV) activity on PET scan, volumetric doubling time (VDT), and symptoms are all taken into account. To assess for rapidly progressive disease, we use VDT based on structural imaging. A VDT of less than 1 year is consistent with more rapidly aggressive disease. If the VDT is less than 6 months, we would recommend initiation of a TKI. If the VDT is between 6 months and 1 year, the decision should be based on clinical judgment with close monitoring and repeat evaluations every 3 to 6 months.
Shared decision making with patients regarding treatment initiation is of critical importance. The side effects of targeted therapies can be significant to an otherwise asymptomatic patient, and health care providers should be well educated in managing possible side effects to maximize the likelihood that a patient can sustain an optimal long-term treatment regimen. In addition, although many of these drugs have increased PFS, none have yet demonstrated an impact on overall survival. However, it should be noted that the crossover design of current Phase 3 trials will likely hinder the ability to discern a survival advantage.
Case Studies
The following 4 cases illustrate the diverse ways in which RAI-unresponsive DTC may manifest and the challenges an endocrinologist might face in determining optimal timing for initiation of TKI therapy in these patients. Patients 1 and 2 represent the most common clinical scenarios.
A 66-year-old male presented in 2005 with a diagnosis of metastatic FTC by a right femur biopsy that demonstrated cells of thyroid derivation. Subsequent to the diagnosis of bone metastasis, thyroidectomy was performed, and the surgical pathology showed a 5-cm follicular thyroid tumor with intravascular and capsular invasion with no extrathyroidal extension. The patient received 198 mCi of I-131 after appropriate withdrawal of thyroid hormone, and the 7-day posttreatment scan revealed iodine uptake in the thyroid bed, right femur, and lungs. Two additional treatments of high-dose I-131 were given over the next 3 years for a total dose of ~700 mCi. Posttreatment scans demonstrated persistent iodine avidity in the metastatic lesions in the lung and right femur, and although some lesions decreased in size, other lesions progressively increased. The VDT of his lung lesions from June 2011 to June 2012 was 1.7 years. The VDT from June 2012 to June 2013 was 0.88 years. His Tg level has gone from 142 in June 2011 to 179 in June 2012 to 262 in June 2013. He remains asymptomatic.
This patient has persistent iodine-avid metastatic thyroid cancer despite multiple high-dose RAI treatments and his tumor is therefore considered RAI resistant. Because the VDT on recent imaging is now less than 1 year, our plan is to restage him again in 6 months to determine the rapidity of progression. The patient is a candidate for a TKI, and he is amenable to systemic treatment if there is further shortening of the VDT at his next follow-up.
A 65-year-old male was diagnosed with locally invasive PTC at age 46. Total thyroidectomy and nodal dissection revealed a 9-cm paratracheal mass extending to the superior mediastinum in addition to multifocal PTC, left recurrent laryngeal nerve involvement, and jugular lymph node metastases. He received a total of 458 mCi in 3 separate treatments over 3 years and posttherapy whole-body scans demonstrated continued iodine uptake in the neck. He underwent a second surgery for recurrence followed by another 150 mCi I-131 with lithium pretreatment. The posttreatment whole-body scan continued to show uptake limited to the neck, albeit less intense. He then underwent EBRT with 5,580 cGy with a resulting fall in the Tg level. Eleven years after his initial diagnosis of thyroid cancer, CT imaging of the chest identified innumerable lung nodules consistent with metastatic disease. On retrospective review of prior imaging studies, 1- and 2-mm lung nodules had been present, which increased in size. Initially, the lung metastases did not demonstrate FDG uptake on PET scan likely due to the small size. However, after another 2 years, the lung nodules measured up to 7 mm, and PET scanning showed FDG uptake. Now 20 years since diagnosis, the lung metastases continue to grow in number and size up to 2.5 cm with increasing intensity (SUV) on PET/CT, and his serum Tg is progressively increasing. The VDT of this patient's lung metastases is greater than 1 year, but he has progressive disease. A new 1.4-cm highly PET-positive lesion (SUV 40) was seen on PET scan in July 2013 and is concerning for dedifferentiation. He remains clinically asymptomatic.
Similar to patient 1, this patient's tumor is considered RAI resistant, having displayed emergence of posttreatment lesions with minimal to no RAI uptake. Although we would consider this patient a candidate for a TKI, he has not yet wanted to enroll in a clinical trial because he is clinically asymptomatic. Evaluation by a thoracic surgeon is imminent to discuss resection of the new lesion.
A 48-year-old female was noted to have a left lobe thyroid nodule during an evaluation for voice hoarseness. Biopsy of the nodule confirmed thyroid carcinoma. Thyroidectomy revealed PTC that enveloped the left recurrent laryngeal nerve and invaded the cricopharyngeal muscle and lateral pharynx. Furthermore, deep jugular lymph nodes were involved. She received postoperative RAI treatment (100 mCi) followed by EBRT with 5,500 rads to the neck and upper chest. She received a second dose of RAI and both posttreatment whole-body scans showed uptake in the neck only. Two years after her initial diagnosis, pulmonary nodules were seen on chest x-ray. A low-dose diagnostic iodine scan was negative. Pulmonary lung metastasis due to PTC was confirmed by biopsy of the lung nodules. Over the next 5 years, her lung metastasis remained relatively stable while demonstrating FDG uptake on PET scan and negative uptake on iodine scan. Because serum Tg continued to rise, one final empiric high dose of I-131 (198 mCi) was administered. Pretreatment with retinoic acid and lithium was used in an effort to increase iodine uptake; however, the 7-day whole-body scan showed no uptake. As the lung metastases continued to grow, she became progressively symptomatic from increased tumor burden, which was confirmed by worsening obstructive ventilatory defects noted on pulmonary function testing. She was enrolled in a Phase 2 clinical trial evaluating sorafenib. Her disease progressed and she succumbed to thyroid cancer at the age of 67, 19 years after her initial diagnosis.
This patient's tumor failed to take up I-131 and is therefore considered RAI refractory. A TKI was initiated for clinically symptomatic disease.
A 55-year-old male diagnosed with thyroid cancer at age 49 underwent a total thyroidectomy as initial management. Pathology demonstrated multifocal PTC, Hürthle cell and follicular variants, and focal tall cell features. There was minimal extrathyroidal extension and 1 of 2 central compartment lymph nodes was positive for metastatic papillary carcinoma. Two months after surgery, he received 153.1 mCi of RAI after thyroid hormone withdrawal and his 7-day posttreatment scan showed uptake in the anterior neck. No uptake was noted in the lateral neck, mediastinum, or lung regions. Six months later a palpable mass was noted in his neck despite thyroid hormone suppression and undetectable Tg. He underwent a CT scan of the neck and chest, which showed a 2.5-cm midline mass in the lower neck and upper mediastinum, as well as multiple lymph nodes suspicious for metastatic disease. A biopsy confirmed persistent thyroid cancer, and he underwent a right-sided modified neck dissection (levels II, III, IV, and VI), as well as an upper mediastinal dissection. Three months after the neck dissection, with a suppressed TSH, Tg antibodies (which had previously been undetectable) were now elevated at 100 units/mL, and a PET/CT scan demonstrated several lesions in his neck and chest with intense FDG uptake. A low-dose diagnostic iodine scan showed no uptake. He underwent another surgery to remove gross disease in the neck, followed by EBRT. This patient has developed multiple skeletal metastases, and his lung metastases continue to increase in size. From July 2011 to November 2011, the VDT was 3.57 months and this worsened to 1.8 months by June 2012. He was enrolled in a Phase 3 placebo-controlled, crossover clinical trial using lenvatinib.
This patient is a relatively young male whose tumor did not respond to RAI from the outset (and is thus considered refractory), despite being a well-differentiated papillary cancer with Hürthle cell features. His rapidly aggressive course is uncommon in thyroid cancer and was the rationale for enrollment in a TKI trial.
Future Directions: Additional Targets and Combination Regimens
Additional novel approaches that are currently under investigation target molecules in a variety of pathways (Table 4). Findings that hypermethylation of tumor suppressor gene promoters and altered histone acetylation are associated with progression of thyroid cancer form the basis for exploring the activities of DNA-demethylation agents (e.g., decitabine) and histone deacetylase inhibitors (e.g., panobinostat, romidepsin, valproic acid, vorinostat) in DTC. Clinical studies to date, however, have shown unremarkable activity and/or unexpected severe adverse events with these compounds in thyroid cancer (Table 4). Whether these compounds will show greater activity in combination with other treatment modalities remains to be determined.
The immunomodulatory drugs thalidomide and lenalidomide have demonstrated antiangiogenic properties. Because thyroid cancer is associated with hypervascularization, compounds that inhibit angiogenesis may be active against this tumor type. Thus far, Phase 2 clinical studies show considerable clinical benefit of thalidomide and lenalidomide in patients with RAI-refractory DTC. Interestingly, RAI unresponsiveness was defined according to different criteria in the thalidomide Phase 2 study than in either of the Phase 3 studies of TKIs mentioned above.
In addition to single-agent studies, a number of combination regimens are currently under investigation in advanced DTC, including many that aim to disrupt multiple signaling pathways simultaneously. This approach may result in more complete growth inhibition and may be more likely to circumvent resistance mechanisms. Studies of combination regimens of targeted therapy and RAI treatment are also underway, which could provide insight into the benefit, if any, of earlier treatment with targeted therapy. Notably, a pilot study in 12 RAI-refractory patients showed that short-term therapy (4 weeks) with the mitogen activated protein (MAP) kinase inhibitor selumetinib led to a clinically meaningful increase in iodine uptake, with 8 of 12 patients reaching the dosimetry threshold for RAI therapy. Among these, 5 had a partial response and 3 had stable disease following radioiodine treatment (Table 4). The concept of using agents to enhance or restore uptake of iodine is not new. However, results using these agents have thus far been mixed. It will be of interest to see whether this approach can provide meaningful long-term benefit in the refractory patient (as in patients #2, #3, and #4 above).
The number of clinical studies currently ongoing in thyroid cancer belies the challenges that investigators face in conducting studies. First, enrollment of sufficient numbers of patients to execute Phase 2 and 3 studies is difficult. Although this problem is somewhat ameliorated by conducting multicenter studies, it remains a formidable issue that hampers forward progress in the evaluation of effective therapies for thyroid cancer.