S P E C I A L
F E A T U R E E d i t o r i a l
Second-Line Treatment for Advanced Thyroid Cancer: An Indication in Need of Randomized Clinical Trials Aaron B. Cohen and Marcia S. Brose Department of Medicine (A.B.C., M.S.B.) and Department of Otorhinolaryngology, Head and Neck Surgery (M.S.B.), Abramson Cancer Center at University of Pennsylvania, Philadelphia, Pennsylvania 19104
T
he incidence of thyroid cancer has grown over the last three decades, and in the United States, it has increased more than any other cancer (1, 2). Differentiated thyroid cancer (DTC) is the most common of all thyroid cancers, accounting for approximately 90% of cases, and includes papillary, follicular, and hu¨rthle cell histologies (3). Although most patients with DTC have a favorable prognosis with standard treatments, including surgery, radioactive iodine (RAI), and TSH suppression, 10 –15% of patients will develop disease refractory to RAI therapy (4, 5). These patients have a median overall survival of 2.5 to 3.5 years (6, 7). For decades, standard therapy for RAI-refractory DTC consisted of cytotoxic chemotherapy with doxorubicin, with unsatisfactory results and side effects (8). The discovery of oncogenic v-raf murine sarcoma viral oncogene homolog B (BRAF) mutations in papillary thyroid cancer in 2003 and the recognition that thyroid cancers are also highly vascular paved the way for the use of sorafenib in metastatic RAI-refractory DTC. A serine-threonine kinase inhibitor, sorafenib, has been found to have multiple targets including VEGFR1–3, platelet derived growth factor receptor beta (PDGFR), V-Raf-1 murine Leukemia viral oncogene homolog (RAF-1), and BRAF (9). Its activity in DTC, first shown in phase II studies, resulted in the design and execution of DECISION: a double-blind, randomized, placebo-controlled phase III trial evaluating the efficacy and safety of sorafenib in patients with locally advanced or metastatic RAI-refractory DTC (10 –12). DECISION was important in helping to define patients with RAI-refractory DTC that were in need of systemic therapy in addition to determining the benefit of
sorafenib. Patients were eligible if they met criteria for RAI-refractory disease, defined either as: 1) Having received a total lifetime dose of greater than or equal to 600mCi, 2) The presence of progressing lesions that were RAI non-Avid, or 3) The presence of lesions that had progressed in the period immediately after a therapeutic dose of RAI (12). Furthermore, patients needed to have met RECIST (Response Evaluation Criteria In Solid Tumors) criteria for progressive disease in the year before going on study, which included progression of target lesions by 20% or the development of new lesions (12). The study met its primary endpoint; the median progression free survival (PFS) in the sorafenib arm was 10.8 months, compared to 5.8 months in the placebo arm (hazard ratio, 0.587; P ⬍ .0001) (12). In November of 2013, based on the data from DECISION, sorafenib became the first multikinase inhibitor (MKI) to be approved by the Food and Drug Administration for the treatment of RAI-refractory progressive DTC. This was practice changing; patients now had a tolerable systemic therapy to manage progressive, RAI-refractory disease. However, the median PFS for patients who receive sorafenib in the first-line setting is 10.8 months (12), leaving open the question of which therapies to consider in the second-line setting. This is especially important because most patients who stop treatment because of disease progression or the development of intolerable or unmanageable adverse events often maintain a good performance status and are candidates for subsequent therapy. In this issue of the JCEM, Dadu et al (13) report results of their retrospective analysis examining the efficacy of second-line therapy in patients with metastatic, RAI-refractory DTC previously treated with sorafenib.
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received May 6, 2014. Accepted May 8, 2014.
Abbreviations: BRAF, v-raf murine sarcoma viral oncogene homolog B; DTC, differentiated thyroid cancer; MKI, multikinase inhibitor; PFS, progression free survival; RAI, radioactive iodine; PDGFR, platelet derived growth factor receptor beta; TKI, tyrosine-kinase inhibitor; VEGFR, vascular endothelial growth factory receptors.
For article see page 2086
doi: 10.1210/jc.2014-2236
J Clin Endocrinol Metab, June 2014, 99(6):1995–1997
jcem.endojournals.org
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 18 February 2015. at 05:38 For personal use only. No other uses without permission. . All rights reserved.
1995
1996
Cohen and Brose
Second-Line Treatment of Advanced, RAI-Refractory DTC
Patients proceeding to a second-line treatment after progression on sorafenib reflect common practice in which kinase inhibitors are given in a sequential fashion. It is reassuring that the median overall survival observed for patients treated with sequential therapy is longer than that observed for those treated with sorafenib alone (58.4 vs 28.8 mo). Furthermore, the reported partial response rate of 41% is encouraging because many patients require tumor responses to relieve symptoms (13). However, before we accept these results at face value, we need to appreciate the strong possibility that these results are a “self-fulfilling prophecy” and are due in part to selection bias. Patients who receive sorafenib alone (group 1) are more likely to do poorly, whether it is due to progressive disease or comorbidities precluding subsequent therapy. They are far more likely to be sicker than those who go on to “salvage therapy,” (group 2) because those patients are more likely to tolerate additional systemic therapy. Consequently, patients who are eligible for subsequent therapy are likely to have a better overall survival without any intervention when compared to those who receive sorafenib alone. It is also unclear why almost one-third (11 of 39) of the patients in the “sorafenib only” group were included in this analysis when they had yet to fail sorafenib or discontinue it due to intolerance. This too may have swayed the results, given the shorter follow-up period for patients in group 1. We must also note that the PFS on sorafenib observed in this series (7.2 mo) wassignificantlyshorterthanthatseenintheDECISIONstudy. As the authors suggest, this is likely due to the presence of sicker patients, or a poorer baseline prognosis (with perhaps greater transformation to poorly differentiated histology), or poorer control of sorafenib-related toxicity. The use of sequential MKIs for the treatment of RAIrefractory DTC has its precedent in chronic myelogenous leukemia (14) and solid tumors, most notably gastrointestinal stromal tumor (15, 16). At this time, there are at least seven multikinase agents, in addition to sorafenib, that have shown activity in phase II trials (17). Several of the early phase II trials of MKIs for DTC have also enrolled patients with a history of prior systemic exposure to kinase inhibitors (18 –20). However, relatively little data are available on how these patients fared compared to their treatment-naive counterparts. More recently, a study evaluating the role of lenvatinib after previous vascular endothelial growth factory receptors (VEGFR) VEGFR-directed therapy demonstrated a response rate of 41% compared to 54% for patients with no prior VEGFR therapy (21), documenting activity for lenvatinib in both the first-line and second-line setting (21). Additionally, vemurafenib, a kinase inhibitor that targets papillary thyroid cancers harboring the BRAFV600E mutation, has been shown to achieve a partial response rate of 26% in patients
J Clin Endocrinol Metab, June 2014, 99(6):1995–1997
heavily pretreated with tyrosine-kinase inhibitors (TKIs) compared to 35% in patients who were MKI-naive (22). Not surprisingly, PFS and response rate to lenvatinib and vemurafenib studies in the second line were less impressive compared to the treatment naive group (21, 22), suggesting that subsequent treatment with MKIs may reflect the law of diminishing returns. In 2014, the optimal strategy and sequencing of various TKIs is unclear; prospective randomized trials will be needed to determine the most effective means of sequencing these agents. Finally, the use of MKIs in the salvage setting (as commonly defined as progression within 6 mo of starting therapy), after failure of response to sorafenib, has not been well studied because only a small percentage of patients have progressive disease as their best response, and no studies to date have reported results in this small population. Patients discontinue sorafenib (or most MKIs for that matter) for two main reasons: toxicity and progression. To prevent premature discontinuation due to toxicity and to maximize therapeutic benefit, further research and education are needed to maximize the therapeutic benefit of sorafenib and prevent early suspension of therapy due to otherwise manageable toxicities. Patients with thyroid cancer on average receive treatment much longer than patients with renal cell carcinoma or hepatocellular carcinoma and may encounter different, more persistent challenges with sorafenib; toxicities may be exacerbated by duration of therapy and interaction with the underlying disease, as well as other medications. Recent guidance on how best to manage toxicities related to chronic use of sorafenib was recently published (23). Patients who require second-line therapy due to disease progression constitute a discrete treatment population and likely differ from those who discontinue sorafenib while responding due to toxicity. As a result, going forward, sequencing studies will need to account for the reasons second-line treatment is initiated. Is it progressive decease or toxicity? Under these circumstances, very different considerations exist. For the former, it is imperative to examine mechanisms of resistance and their bearing on second-line activity. For the latter, it is crucial to determine the degree to which toxicities and mechanisms of intolerance may be shared by the second-line agents. From a practical perspective, progression can affect single or multiple metastatic sites. In cases of an isolated site of progression in otherwise responsive disease, patients may benefit from local ablative treatment to the progressing site (either surgery or external beam radiation) and then continue treatment with sorafenib. This approach has been adopted in advanced nonsmall cell lung cancer patients with EGFR mutations who develop oligoprogression on erlotinib or other EGFR tyrosine kinase inhibitors
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 18 February 2015. at 05:38 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2014-2236
(24). Understanding the mechanisms of resistance on the molecular level will allow for more informed clinical trial design going forward. Dadu et al (13) are to be commended for their efforts to raise our awareness of the key issues regarding treatment after use of sorafenib and the clear demonstration that second-line therapy can work in patients with thyroid cancer. However, due to the inherent limitations of a retrospective analysis, we will need to await prospective clinical trials to determine the proper sequencing and dosing of the active agents available. To this end, the current treatment paradigm for metastatic renal cell carcinoma, which starts with sunitinib and pazopanib (and temsirolimus for poor-risk patients) in the first-line setting, followed by axitinib and everolimus (25) in the second-line setting, was the result of multiple prospective trials. Similar efforts are required for DTC. Because a large proportion of DTC patients will be candidates for second- and third-line therapy, the most important conclusion we can draw is that at the end of first-line treatment with sorafenib, as much as possible, patients should ideally be enrolled into clinical trials.
jcem.endojournals.org
7.
8.
9.
10. 11. 12.
13.
14.
15.
Acknowledgments Address all correspondence and requests for reprints to: Marcia Brose, MD, PhD, Department of Otorhinolaryngology, Head and Neck Surgery, Abramson Cancer Center, University of Pennsylvania, Clinical Research Building, Room 127, 415 Curie Boulevard, Philadelphia, PA 19104. E-mail: [email protected]. Disclosure Summary: M.S.B. has served as a consultant and received grant money from Bayer/Onyx, AstraZeneca, Eisai, and Exelixis and from Novartis, Loxo, Roche/Genetech (ie no consultant fees). A.B.C. has nothing to declare.
16.
17.
18.
19.
20.
References 1. Howlader N, Noone AM, Krapcho M, et al; National Cancer Institute. SEER Cancer Statistics Review, 1975–2011. http://seer. cancer.gov/csr/1975_2011/. Based on November 2013 SEER data submission. Published April 2014. 2. Chen AY, Jemal A, Ward EM. Increasing incidence of differentiated thyroid cancer in the United States, 1988 –2005. Cancer. 2009;115: 3801–3807. 3. Busaidy NL, Cabanillas ME. Differentiated thyroid cancer: management of patients with radioiodine nonresponsive disease. J Thyroid Res. 2012;2012:618985. 4. Xing M, Haugen BR, Schlumberger M. Progress in molecular-based management of differentiated thyroid cancer. Lancet. 2013; 381(9871):1058 –1069. 5. Pacini F, Ito Y, Luster M, Pitoia F, Robinson B, Wirth L. Radioactive iodine-refractory differentiated thyroid cancer: unmet needs and future directions. Expert Rev Endocrinol Metab. 2012;7:541–554. 6. Durante C, Haddy N, Baudin E, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thy-
21.
22.
23.
24.
25.
1997
roid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab. 2006;91:2892–2899. Robbins RJ, Larson SM. The value of positron emission tomography (PET) in the management of patients with thyroid cancer. Best Pract Res Clin Endocrinol Metab. 2008;22(6):1047–1059. Matuszczyk A, Petersenn S, Bockisch A, et al. Chemotherapy with doxorubicin in progressive medullary and thyroid carcinoma of the follicular epithelium. Horm Metab Res. 2008;40:210 –213. Wilhelm SM, Carter C, Tang L, et al. BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099 –7109. Gupta-Abramson V, Troxel AB, Nellore A, et al. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol. 2008;26:4714–4719. Kloos RT, Ringel MD, Knopp MV, et al. Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol. 2009;27(10):1675–1684. Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial [published online April 24, 2014]. Lancet. doi: 10.1016/01406736(14)60421-9. Dadu R, Devine C, Hernandez M, et al. Role of salvage targeted therapy in differentiated thyroid cancer patients who fail first-line sorafenib. J Clin Endocrinol Metab. 2014;99:2086 –2094. Bauer RC, Sänger J, Peschel C, Duyster J, von Bubnoff N. Sequential inhibitor therapy in CML: in vitro simulation elucidates the pattern of resistance mutations after second- and third-line treatment. Clin Cancer Res. 2013;19(11):2962–2972. Gramza AW, Corless CL, Heinrich MC. Resistance to tyrosine kinase inhibitors in gastrointestinal stromal tumors. Clin Cancer Res. 2009;15(24):7510 –7518. Felici A, Bria E, Tortora G, Cognetti F, Milella M. Sequential therapy in metastatic clear cell renal carcinoma: TKI-TKI vs TKImTOR. Expert Rev Anticancer Ther. 2012;12(12):1545–1557. Kapiteijn E, Schneider TC, Morreau H, Gelderblom H, Nortier JW, Smit JW. New treatment modalities in advanced thyroid cancer. Ann Oncol. 2012;23(1):10 –18. Bible KC, Suman VJ, Molina JR, et al. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study. Lancet Oncol. 2010;11:962–972. Leboulleux S, Bastholt L, Krause T, et al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol. 2012;13:897–905. Carr LL, Mankoff DA, Goulart BH, et al. Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin Cancer Res. 2010;16(21): 5260 –5268. Sherman SI, Jarzab B, Cabanillas ME, et al. A phase II trial of the multitargeted kinase inhibitor E7080 in advanced radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). J Clin Oncol. 2011;29(suppl):5503. Brose MS, Cabanillas ME, Cohen EE, et al. An open-label, multicenter phase 2 study of the BRAF inhibitor vemurafenib in patients with metastatic or unresectable papillary thyroid cancer (PTC) positive for the BRAF V600 mutation and resistant to radioactive iodine. Eur J Cancer. 2011;47(suppl 2):28. Brose MS, Frenette CT, Keefe SM, Stein SM. Management of sorafenib-related adverse events: a clinician’s perspective. Semin Oncol. 2014;41(suppl 2):S1–S16. Yu HA, Sima CS, Huang J, et al. Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFRmutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors. J Thorac Oncol. 2013; 8(3):346 –351. Motzer RJ, Jonasch E, Agarwal N, et al. Kidney cancer, version 2.2014. J Natl Compr Canc Netw. 2014;12(2):175–182.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 18 February 2015. at 05:38 For personal use only. No other uses without permission. . All rights reserved.
F E A T U R E E d i t o r i a l
Second-Line Treatment for Advanced Thyroid Cancer: An Indication in Need of Randomized Clinical Trials Aaron B. Cohen and Marcia S. Brose Department of Medicine (A.B.C., M.S.B.) and Department of Otorhinolaryngology, Head and Neck Surgery (M.S.B.), Abramson Cancer Center at University of Pennsylvania, Philadelphia, Pennsylvania 19104
T
he incidence of thyroid cancer has grown over the last three decades, and in the United States, it has increased more than any other cancer (1, 2). Differentiated thyroid cancer (DTC) is the most common of all thyroid cancers, accounting for approximately 90% of cases, and includes papillary, follicular, and hu¨rthle cell histologies (3). Although most patients with DTC have a favorable prognosis with standard treatments, including surgery, radioactive iodine (RAI), and TSH suppression, 10 –15% of patients will develop disease refractory to RAI therapy (4, 5). These patients have a median overall survival of 2.5 to 3.5 years (6, 7). For decades, standard therapy for RAI-refractory DTC consisted of cytotoxic chemotherapy with doxorubicin, with unsatisfactory results and side effects (8). The discovery of oncogenic v-raf murine sarcoma viral oncogene homolog B (BRAF) mutations in papillary thyroid cancer in 2003 and the recognition that thyroid cancers are also highly vascular paved the way for the use of sorafenib in metastatic RAI-refractory DTC. A serine-threonine kinase inhibitor, sorafenib, has been found to have multiple targets including VEGFR1–3, platelet derived growth factor receptor beta (PDGFR), V-Raf-1 murine Leukemia viral oncogene homolog (RAF-1), and BRAF (9). Its activity in DTC, first shown in phase II studies, resulted in the design and execution of DECISION: a double-blind, randomized, placebo-controlled phase III trial evaluating the efficacy and safety of sorafenib in patients with locally advanced or metastatic RAI-refractory DTC (10 –12). DECISION was important in helping to define patients with RAI-refractory DTC that were in need of systemic therapy in addition to determining the benefit of
sorafenib. Patients were eligible if they met criteria for RAI-refractory disease, defined either as: 1) Having received a total lifetime dose of greater than or equal to 600mCi, 2) The presence of progressing lesions that were RAI non-Avid, or 3) The presence of lesions that had progressed in the period immediately after a therapeutic dose of RAI (12). Furthermore, patients needed to have met RECIST (Response Evaluation Criteria In Solid Tumors) criteria for progressive disease in the year before going on study, which included progression of target lesions by 20% or the development of new lesions (12). The study met its primary endpoint; the median progression free survival (PFS) in the sorafenib arm was 10.8 months, compared to 5.8 months in the placebo arm (hazard ratio, 0.587; P ⬍ .0001) (12). In November of 2013, based on the data from DECISION, sorafenib became the first multikinase inhibitor (MKI) to be approved by the Food and Drug Administration for the treatment of RAI-refractory progressive DTC. This was practice changing; patients now had a tolerable systemic therapy to manage progressive, RAI-refractory disease. However, the median PFS for patients who receive sorafenib in the first-line setting is 10.8 months (12), leaving open the question of which therapies to consider in the second-line setting. This is especially important because most patients who stop treatment because of disease progression or the development of intolerable or unmanageable adverse events often maintain a good performance status and are candidates for subsequent therapy. In this issue of the JCEM, Dadu et al (13) report results of their retrospective analysis examining the efficacy of second-line therapy in patients with metastatic, RAI-refractory DTC previously treated with sorafenib.
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received May 6, 2014. Accepted May 8, 2014.
Abbreviations: BRAF, v-raf murine sarcoma viral oncogene homolog B; DTC, differentiated thyroid cancer; MKI, multikinase inhibitor; PFS, progression free survival; RAI, radioactive iodine; PDGFR, platelet derived growth factor receptor beta; TKI, tyrosine-kinase inhibitor; VEGFR, vascular endothelial growth factory receptors.
For article see page 2086
doi: 10.1210/jc.2014-2236
J Clin Endocrinol Metab, June 2014, 99(6):1995–1997
jcem.endojournals.org
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 18 February 2015. at 05:38 For personal use only. No other uses without permission. . All rights reserved.
1995
1996
Cohen and Brose
Second-Line Treatment of Advanced, RAI-Refractory DTC
Patients proceeding to a second-line treatment after progression on sorafenib reflect common practice in which kinase inhibitors are given in a sequential fashion. It is reassuring that the median overall survival observed for patients treated with sequential therapy is longer than that observed for those treated with sorafenib alone (58.4 vs 28.8 mo). Furthermore, the reported partial response rate of 41% is encouraging because many patients require tumor responses to relieve symptoms (13). However, before we accept these results at face value, we need to appreciate the strong possibility that these results are a “self-fulfilling prophecy” and are due in part to selection bias. Patients who receive sorafenib alone (group 1) are more likely to do poorly, whether it is due to progressive disease or comorbidities precluding subsequent therapy. They are far more likely to be sicker than those who go on to “salvage therapy,” (group 2) because those patients are more likely to tolerate additional systemic therapy. Consequently, patients who are eligible for subsequent therapy are likely to have a better overall survival without any intervention when compared to those who receive sorafenib alone. It is also unclear why almost one-third (11 of 39) of the patients in the “sorafenib only” group were included in this analysis when they had yet to fail sorafenib or discontinue it due to intolerance. This too may have swayed the results, given the shorter follow-up period for patients in group 1. We must also note that the PFS on sorafenib observed in this series (7.2 mo) wassignificantlyshorterthanthatseenintheDECISIONstudy. As the authors suggest, this is likely due to the presence of sicker patients, or a poorer baseline prognosis (with perhaps greater transformation to poorly differentiated histology), or poorer control of sorafenib-related toxicity. The use of sequential MKIs for the treatment of RAIrefractory DTC has its precedent in chronic myelogenous leukemia (14) and solid tumors, most notably gastrointestinal stromal tumor (15, 16). At this time, there are at least seven multikinase agents, in addition to sorafenib, that have shown activity in phase II trials (17). Several of the early phase II trials of MKIs for DTC have also enrolled patients with a history of prior systemic exposure to kinase inhibitors (18 –20). However, relatively little data are available on how these patients fared compared to their treatment-naive counterparts. More recently, a study evaluating the role of lenvatinib after previous vascular endothelial growth factory receptors (VEGFR) VEGFR-directed therapy demonstrated a response rate of 41% compared to 54% for patients with no prior VEGFR therapy (21), documenting activity for lenvatinib in both the first-line and second-line setting (21). Additionally, vemurafenib, a kinase inhibitor that targets papillary thyroid cancers harboring the BRAFV600E mutation, has been shown to achieve a partial response rate of 26% in patients
J Clin Endocrinol Metab, June 2014, 99(6):1995–1997
heavily pretreated with tyrosine-kinase inhibitors (TKIs) compared to 35% in patients who were MKI-naive (22). Not surprisingly, PFS and response rate to lenvatinib and vemurafenib studies in the second line were less impressive compared to the treatment naive group (21, 22), suggesting that subsequent treatment with MKIs may reflect the law of diminishing returns. In 2014, the optimal strategy and sequencing of various TKIs is unclear; prospective randomized trials will be needed to determine the most effective means of sequencing these agents. Finally, the use of MKIs in the salvage setting (as commonly defined as progression within 6 mo of starting therapy), after failure of response to sorafenib, has not been well studied because only a small percentage of patients have progressive disease as their best response, and no studies to date have reported results in this small population. Patients discontinue sorafenib (or most MKIs for that matter) for two main reasons: toxicity and progression. To prevent premature discontinuation due to toxicity and to maximize therapeutic benefit, further research and education are needed to maximize the therapeutic benefit of sorafenib and prevent early suspension of therapy due to otherwise manageable toxicities. Patients with thyroid cancer on average receive treatment much longer than patients with renal cell carcinoma or hepatocellular carcinoma and may encounter different, more persistent challenges with sorafenib; toxicities may be exacerbated by duration of therapy and interaction with the underlying disease, as well as other medications. Recent guidance on how best to manage toxicities related to chronic use of sorafenib was recently published (23). Patients who require second-line therapy due to disease progression constitute a discrete treatment population and likely differ from those who discontinue sorafenib while responding due to toxicity. As a result, going forward, sequencing studies will need to account for the reasons second-line treatment is initiated. Is it progressive decease or toxicity? Under these circumstances, very different considerations exist. For the former, it is imperative to examine mechanisms of resistance and their bearing on second-line activity. For the latter, it is crucial to determine the degree to which toxicities and mechanisms of intolerance may be shared by the second-line agents. From a practical perspective, progression can affect single or multiple metastatic sites. In cases of an isolated site of progression in otherwise responsive disease, patients may benefit from local ablative treatment to the progressing site (either surgery or external beam radiation) and then continue treatment with sorafenib. This approach has been adopted in advanced nonsmall cell lung cancer patients with EGFR mutations who develop oligoprogression on erlotinib or other EGFR tyrosine kinase inhibitors
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 18 February 2015. at 05:38 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2014-2236
(24). Understanding the mechanisms of resistance on the molecular level will allow for more informed clinical trial design going forward. Dadu et al (13) are to be commended for their efforts to raise our awareness of the key issues regarding treatment after use of sorafenib and the clear demonstration that second-line therapy can work in patients with thyroid cancer. However, due to the inherent limitations of a retrospective analysis, we will need to await prospective clinical trials to determine the proper sequencing and dosing of the active agents available. To this end, the current treatment paradigm for metastatic renal cell carcinoma, which starts with sunitinib and pazopanib (and temsirolimus for poor-risk patients) in the first-line setting, followed by axitinib and everolimus (25) in the second-line setting, was the result of multiple prospective trials. Similar efforts are required for DTC. Because a large proportion of DTC patients will be candidates for second- and third-line therapy, the most important conclusion we can draw is that at the end of first-line treatment with sorafenib, as much as possible, patients should ideally be enrolled into clinical trials.
jcem.endojournals.org
7.
8.
9.
10. 11. 12.
13.
14.
15.
Acknowledgments Address all correspondence and requests for reprints to: Marcia Brose, MD, PhD, Department of Otorhinolaryngology, Head and Neck Surgery, Abramson Cancer Center, University of Pennsylvania, Clinical Research Building, Room 127, 415 Curie Boulevard, Philadelphia, PA 19104. E-mail: [email protected]. Disclosure Summary: M.S.B. has served as a consultant and received grant money from Bayer/Onyx, AstraZeneca, Eisai, and Exelixis and from Novartis, Loxo, Roche/Genetech (ie no consultant fees). A.B.C. has nothing to declare.
16.
17.
18.
19.
20.
References 1. Howlader N, Noone AM, Krapcho M, et al; National Cancer Institute. SEER Cancer Statistics Review, 1975–2011. http://seer. cancer.gov/csr/1975_2011/. Based on November 2013 SEER data submission. Published April 2014. 2. Chen AY, Jemal A, Ward EM. Increasing incidence of differentiated thyroid cancer in the United States, 1988 –2005. Cancer. 2009;115: 3801–3807. 3. Busaidy NL, Cabanillas ME. Differentiated thyroid cancer: management of patients with radioiodine nonresponsive disease. J Thyroid Res. 2012;2012:618985. 4. Xing M, Haugen BR, Schlumberger M. Progress in molecular-based management of differentiated thyroid cancer. Lancet. 2013; 381(9871):1058 –1069. 5. Pacini F, Ito Y, Luster M, Pitoia F, Robinson B, Wirth L. Radioactive iodine-refractory differentiated thyroid cancer: unmet needs and future directions. Expert Rev Endocrinol Metab. 2012;7:541–554. 6. Durante C, Haddy N, Baudin E, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thy-
21.
22.
23.
24.
25.
1997
roid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab. 2006;91:2892–2899. Robbins RJ, Larson SM. The value of positron emission tomography (PET) in the management of patients with thyroid cancer. Best Pract Res Clin Endocrinol Metab. 2008;22(6):1047–1059. Matuszczyk A, Petersenn S, Bockisch A, et al. Chemotherapy with doxorubicin in progressive medullary and thyroid carcinoma of the follicular epithelium. Horm Metab Res. 2008;40:210 –213. Wilhelm SM, Carter C, Tang L, et al. BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099 –7109. Gupta-Abramson V, Troxel AB, Nellore A, et al. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol. 2008;26:4714–4719. Kloos RT, Ringel MD, Knopp MV, et al. Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol. 2009;27(10):1675–1684. Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial [published online April 24, 2014]. Lancet. doi: 10.1016/01406736(14)60421-9. Dadu R, Devine C, Hernandez M, et al. Role of salvage targeted therapy in differentiated thyroid cancer patients who fail first-line sorafenib. J Clin Endocrinol Metab. 2014;99:2086 –2094. Bauer RC, Sänger J, Peschel C, Duyster J, von Bubnoff N. Sequential inhibitor therapy in CML: in vitro simulation elucidates the pattern of resistance mutations after second- and third-line treatment. Clin Cancer Res. 2013;19(11):2962–2972. Gramza AW, Corless CL, Heinrich MC. Resistance to tyrosine kinase inhibitors in gastrointestinal stromal tumors. Clin Cancer Res. 2009;15(24):7510 –7518. Felici A, Bria E, Tortora G, Cognetti F, Milella M. Sequential therapy in metastatic clear cell renal carcinoma: TKI-TKI vs TKImTOR. Expert Rev Anticancer Ther. 2012;12(12):1545–1557. Kapiteijn E, Schneider TC, Morreau H, Gelderblom H, Nortier JW, Smit JW. New treatment modalities in advanced thyroid cancer. Ann Oncol. 2012;23(1):10 –18. Bible KC, Suman VJ, Molina JR, et al. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study. Lancet Oncol. 2010;11:962–972. Leboulleux S, Bastholt L, Krause T, et al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol. 2012;13:897–905. Carr LL, Mankoff DA, Goulart BH, et al. Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin Cancer Res. 2010;16(21): 5260 –5268. Sherman SI, Jarzab B, Cabanillas ME, et al. A phase II trial of the multitargeted kinase inhibitor E7080 in advanced radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). J Clin Oncol. 2011;29(suppl):5503. Brose MS, Cabanillas ME, Cohen EE, et al. An open-label, multicenter phase 2 study of the BRAF inhibitor vemurafenib in patients with metastatic or unresectable papillary thyroid cancer (PTC) positive for the BRAF V600 mutation and resistant to radioactive iodine. Eur J Cancer. 2011;47(suppl 2):28. Brose MS, Frenette CT, Keefe SM, Stein SM. Management of sorafenib-related adverse events: a clinician’s perspective. Semin Oncol. 2014;41(suppl 2):S1–S16. Yu HA, Sima CS, Huang J, et al. Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFRmutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors. J Thorac Oncol. 2013; 8(3):346 –351. Motzer RJ, Jonasch E, Agarwal N, et al. Kidney cancer, version 2.2014. J Natl Compr Canc Netw. 2014;12(2):175–182.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 18 February 2015. at 05:38 For personal use only. No other uses without permission. . All rights reserved.
