Original Article
Motesanib Diphosphate in Progressive Differentiated Thyroid Cancer
N Engl J Med 2008; 359:31-42July 3, 2008
- Abstract
Background
The expression of vascular endothelial growth factor (VEGF) is characteristic of differentiated thyroid cancer and is associated with aggressive tumor behavior and a poor clinical outcome. Motesanib diphosphate (AMG 706) is a novel oral inhibitor of VEGF receptors, platelet-derived growth-factor receptor, and KIT.
Methods
In an open-label, single-group, phase 2 study, we treated 93 patients who had progressive, locally advanced or metastatic, radioiodine-resistant differentiated thyroid cancer with 125 mg of motesanib diphosphate, administered orally once daily. The primary end point was an objective response as assessed by an independent radiographic review. Additional end points included the duration of the response, progression-free survival, safety, and changes in serum thyroglobulin concentration.
Results
Of the 93 patients, 57 (61%) had papillary thyroid carcinoma. The objective response rate was 14%. Stable disease was achieved in 67% of the patients, and stable disease was maintained for 24 weeks or longer in 35%; 8% had progressive disease as the best response. The Kaplan–Meier estimate of the median duration of the response was 32 weeks (the lower limit of the 95% confidence interval [CI] was 24; the upper limit could not be estimated because of an insufficient number of events); the estimate of median progression-free survival was 40 weeks (95% CI, 32 to 50). Among the 75 patients in whom thyroglobulin analysis was performed, 81% had decreased serum thyroglobulin concentrations during treatment, as compared with baseline levels. The most common treatment-related adverse events were diarrhea (in 59% of the patients), hypertension (56%), fatigue (46%), and weight loss (40%).
Conclusions
Motesanib diphosphate can induce partial responses in patients with advanced or metastatic differentiated thyroid cancer that is progressive. (ClinicalTrials.gov number, NCT00121628.)
Media in This Article
Figure 1
Maximum Percent Change from Baseline in the Sum of the Longest Diameters (SLD) of Target Lesions.Figure 2
Kaplan−Meier Analysis of Progression-free Survival and Overall Survival.Article Activity
- Article
Thyroid cancers are classified histologically into four groups: papillary, follicular, medullary, and undifferentiated or anaplastic thyroid carcinomas.1 Papillary and follicular carcinomas (including the Hürthle-cell variant) are collectively known as differentiated thyroid cancers,1,2 and they account for approximately 95% of incident cases.3 Initial treatment typically involves total thyroidectomy followed by long-term administration of levothyroxine at doses that suppress thyrotropin; adjuvant radioiodine (131I) is often administered as well.2-4 This regimen is usually effective, but the 10-year recurrence rate is 20 to 30% among patients who are older, among patients with tumors larger than 4 cm in diameter, and among patients in whom the tumor extends beyond the thyroid or in whom extensive lymph-node metastases develop.4 There is no effective treatment for radioiodine-resistant metastatic disease; the 10-year survival rate in these cases is less than 15%.5
Increased expression of vascular endothelial growth factor (VEGF), a potent angiogenesis stimulator, is characteristic of differentiated thyroid cancers6,7 and is associated with increased growth, progression, and invasiveness of the tumor and with decreased recurrence-free survival.4,8-10 For this reason, an inhibitor of angiogenesis may be effective when initial therapy fails.11 Motesanib diphosphate (Amgen) is an oral inhibitor of the tyrosine kinases of VEGF receptors 1, 2, and 3; platelet-derived growth-factor receptor; and KIT.12 In a phase 1 study, treatment with 125 mg of motesanib diphosphate once daily resulted in antitumor activity in patients with advanced solid cancers, including five patients with differentiated thyroid cancer.13 In the present study, we investigated the efficacy and tolerability of motesanib diphosphate in progressive, locally advanced or metastatic differentiated thyroid cancer.
Methods
Patients
We included in the study adults who had histologically confirmed, locally advanced or metastatic differentiated thyroid cancer and documented evidence of disease progression (based on two sets of radiographic images) according to the Response Evaluation Criteria in Solid Tumors (RECIST),14 as assessed by the investigator, within 6 months before entry into the study. A rising serum thyroglobulin level alone was not sufficient evidence of disease progression before enrollment. Other key inclusion criteria were the presence of at least one lesion that was defined as measurable according to the RECIST guidelines and that was not amenable to surgical resection or external-beam radiation therapy or was refractory to radioiodine; the absence of untreated brain metastases; an Eastern Cooperative Oncology Group performance status score of 0 to 2; and adequate hepatic, renal, and cardiac function. Patients were ineligible if they had ever received treatment with VEGF-receptor inhibitors or if they had received nonhormonal anticancer therapy within 30 days before the start of the study. The protocol was approved by each center's independent ethics committee or institutional review board, and all patients provided written informed consent before enrollment.
Study Design and End Points
This phase 2, open-label study involving a cohort of patients with differentiated thyroid cancer was conducted at 42 centers in 10 countries. A parallel cohort included similar patients with metastatic medullary thyroid cancer; data from this cohort were not included in the analysis reported here. The primary end point was an objective response according to RECIST, as assessed by a centralized, independent review. Additional end points included the duration of response, progression-free survival, the time to response, and overall survival; adverse events; pharmacokinetic characteristics; and changes in the serum thyroglobulin concentration.
Patients received 125 mg of motesanib diphosphate orally once daily for up to 48 weeks or until there was evidence of unacceptable toxicity or disease progression. Treatment was offered beyond 48 weeks in an extension study if a clinical benefit was observed. Therapy was withheld if a treatment-related grade 3 adverse event that could not be controlled with supportive care, any related grade 4 adverse event, or symptomatic hypertension occurred. Treatment could be resumed at a dose of 100 mg per day, if toxicity was reduced to a grade of 1 or less for nonhematologic toxicity or to a grade of 2 or less for hematologic toxicity, or at a dose of 75 mg per day after a second interruption of treatment that was related to toxicity.
Adverse events were classified according to the Medical Dictionary for Regulatory Activities, and severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Patients had regular assessments of blood pressure (weekly until week 6, then every other week until week 16, and every 4 weeks thereafter), blood chemical profiles, blood counts, and urine protein levels. Free thyroxine and thyrotropin levels were measured at baseline and monthly thereafter.
Assessment of Tumor Response
Computed tomographic or magnetic resonance imaging scans of the neck, chest, and abdomen were obtained at 8-week intervals and when progression of the disease was suspected. An objective response (complete or partial response according to RECIST) was assessed by a centralized, independent review, with confirmation by repeat imaging studies at least 4 weeks later. A bone scintigram that showed no new osseous metastases (as compared with the findings at study entry) was also required to define an objective response in patients with follicular or Hürthle-cell carcinoma. The designation of stable disease required a single assessment of either stable disease or an unconfirmed objective response 47 days or more after the first administration of the drug.
Pharmacokinetics
Plasma samples to assess pharmacokinetics were collected from nine patients 15 minutes, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours after the administration of the drug on day 1 of the study. To assess trough concentrations of motesanib after long-term administration, plasma was collected before the daily dose at 4-week intervals during the first 24 weeks of the study. Plasma motesanib concentrations were measured by means of liquid chromatography coupled with tandem mass spectroscopy (CEDRA Clinical Research).
Thyroglobulin Analyses and Tumor Genotyping
Blood samples were collected at baseline and at 4-week intervals, and serum thyroglobulin measurements were performed with the use of the Access 2 automated immunochemiluminometric assay (Beckman Coulter). Intraassay coefficients of variation were 3.3%, 1.7%, and 1.9% at 0.76, 7.0, and 106 ng per milliliter, respectively; interassay coefficients of variation over the 9-month period of measurement were 4.8%, 4.7%, and 5.0% at 0.75, 7.3, and 106 ng per milliliter, respectively.
Tumor DNA from 33 patients was centrally screened for mutations in RET, B-type Raf kinase (BRAF), HRAS, KRAS, NRAS, and phosphatidylinositol-3-kinase, catalytic, alpha polypeptide (PIK3CA), and for rearrangements of RET-PTC1, RET-PTC3, and PAX8-peroxisome proliferator–activated receptor gamma 1 (PPARγ1). A detailed description of the methods is included in the Supplementary Appendix (available with the full text of this article at www.nejm.org).
Statistical Analysis
We planned to enroll at least 80 patients to achieve a two-sided 95% confidence interval of 12 to 30% for the rate of an objective response, assuming an observed rate of 20%. All patients who received one dose or more of motesanib diphosphate were included in the efficacy and safety analyses. The overall tumor response was derived from multiple time-point responses as assessed by an independent radiographic review. The duration of the tumor response was the interval between the first, subsequently confirmed, objective response and evidence of progressive disease. The time to the response was the time from the first administration of the study drug to the initially documented (and subsequently confirmed) response. Progression-free survival was the time from the first administration of the drug to the date of radiographic evidence of disease progression or death. The duration of the response, progression-free survival, and overall survival were described with Kaplan−Meier estimates and 95% confidence intervals. The thyroglobulin analysis subgroup included all patients for whom baseline and one or more post-baseline measurements of thyroglobulin were available and who did not have detectable antithyroglobulin antibodies.
Amgen designed the study, in collaboration with the study cochairs, Drs. Sherman and Schlumberger. The academic authors had complete access to the study data and decided, with Amgen's support, to publish the study. Employees of Amgen collected and managed the data and performed the statistical analysis. An independent panel of radiologists from RadPharm, a commercial imaging laboratory, reviewed all radiographic assessments. Amgen and the study cochairs interpreted the data. The manuscript was written by the study cochairs, with assistance from Complete Healthcare Communications and Amgen and with contributions from all of the coauthors. The study cochairs attest to the completeness and accuracy of the data.
Results
Patients
Between July 29, 2005, and March 13, 2006, a total of 93 patients with differentiated thyroid cancer were enrolled in the study. All of the patients received one dose or more of motesanib diphosphate. A total of 32 patients completed 48 weeks of treatment. The remaining patients discontinued the drug because of disease progression (35 patients), adverse events (12), death (5), withdrawal of consent (1), an administrative decision (1), a protocol deviation (1), or the patient's request (6). The median length of treatment for all patients was 35 weeks (range, 0.4 to 56), and the median follow-up was 50 weeks (range, 1 to 77).
The most common histologic subtype was papillary thyroid carcinoma. At study entry, almost all of the patients had metastases, usually with multiple sites of disease, including lung (87%), lymph nodes (72%), and liver (26%). Disease progression according to RECIST within 6 months before study day 1 was documented in all patients by the investigator. Seventeen percent of the patients had previously received systemic chemotherapy (Table 1Table 1
Demographic and Baseline Characteristics of the Patients.).Table 1 summarizes the results of tumor genotyping, which are shown in detail in Table 3 in the Supplementary Appendix. Of 25 patients with papillary thyroid carcinoma, 10 had tumors carrying the mutant BRAF V600E oncogene, and 4 had mutations in RAS genes (HRAS and KRAS in 1 patient each and NRAS in 2 patients).
Efficacy
The primary end point of a confirmed objective response was achieved in 13 patients (14%; 95% confidence interval [CI], 7.7 to 22.7), all of whom had partial responses; the median time to the response was 15 weeks (95% CI, 8 to 27) (Table 2Table 2
Tumor Response According to RECIST and Independent Review.). Stable disease was observed in 62 patients (67%), with durable stable disease (i.e., disease that was stable for 24 weeks or more) in 33 patients (35%). Nine patients (10%) had unconfirmed partial responses that were classified as stable disease. Overall, 49% of the patients had either a confirmed partial response or durable stable disease. Disease progression was the best observed response in seven patients (8%). In 69 patients (74%), tumor measurements decreased from the baseline measurements (Figure 1Figure 1Maximum Percent Change from Baseline in the Sum of the Longest Diameters (SLD) of Target Lesions.).Of the 13 patients with an objective response, 4 had disease that subsequently progressed while the patients were taking the study medication. The Kaplan–Meier estimate of the median duration of a response was 32 weeks (the lower limit of the 95% CI was 24; the upper limit could not be estimated because of an insufficient number of events). The estimated median progression-free survival was 40 weeks (95% CI, 32 to 50) (Figure 2AFigure 2
Kaplan−Meier Analysis of Progression-free Survival and Overall Survival.). The median overall survival was not estimable; the estimate of the survival rate at 12 months was 73% (95% CI, 63 to 83) (Figure 2B).There was no significant difference in the rate of the objective response between patients with the papillary or follicular variant of papillary carcinoma (57 patients) and those with the follicular or Hürthle-cell type (36 patients) (12% and 17%, respectively; P=0.56). We found no association between the presence or absence of the BRAF V600E mutation (10 and 15 patients, respectively) and the clinical outcome. Six of the 10 patients whose tumor contained the BRAF mutation had either a confirmed partial response or durable stable disease, as compared with 5 of the 15 patients without the mutation (Table 3 in the Supplementary Appendix).
Safety
A total of 87 patients (94%) had at least one treatment-related adverse event during the course of the study (Table 3Table 3
Treatment-Related Adverse Events and Related Adverse Events of Interest in the 93 Patients.). Twelve patients (13%) discontinued treatment owing to adverse events. The most commonly reported events were diarrhea, hypertension, fatigue, and weight loss; patients with hypertension were treated with antihypertensive medication, and those with diarrhea, fatigue, or weight loss received supportive care. Grade 3 events were reported in 51 patients (55%); 5 patients had a total of eight treatment-related grade 4 events (hypocalcemia in 2 patients and hyperuricemia, hypokalemia, cerebral hemorrhage, confusion, agitation, and oliguria in 1 patient each). There were two treatment-related deaths; both were due to pulmonary hemorrhage and occurred in patients in whom the disease had progressed. Several treatment-related events of interest (previously observed with anti-VEGF or anti-VEGF receptor therapies) were noted (Table 3). Increased thyrotropin concentrations, hypothyroidism, or both were reported in 22% of the patients. Five patients (5%) had cholecystitis (grade 2 in three patients and grade 3 in two patients). Two patients had treatment-related cardiac disorders; one had bradycardia, palpitations, and tachycardia, and one had myocardial ischemia (grade 2 in both patients).Pharmacokinetics
Motesanib was rapidly absorbed, with a median time to the maximal plasma concentration (Cmax) of 1.0 hour; the terminal half-life was approximately 6.7 hours. The mean (±SD) motesanib Cmax value (787±526 ng per milliliter [2.10±1.41 μmol per liter]) and area under the plasma concentration–time curve (AUC0-24, 3.99±1.42 μg × hour per milliliter [10.7±3.79 μmol × hour per liter]) were similar to those observed for the 125-mg dose in another study of motesanib as monotherapy for solid tumors.13 Between weeks 4 and 24, the median trough plasma concentration (Cmin), measured in 9 to 23 patients at different time points, ranged from 8.50 to 26.3 ng per milliliter (22.7 to 70.3 nmol per liter) and was consistently above the IC50 value (4 ng per milliliter [10 nmol per liter]) for inhibition of the proliferation of human umbilical-vein endothelial cells in vitro.12
Thyroglobulin Analyses
Of the 75 patients in whom thyroglobulin analysis was performed, 61 (81%) had serum thyroglobulin concentrations that decreased from baseline during the study. In 34 patients (45%) the decrease was 50% or more, and that decrease was sustained for 24 weeks or more in 11 patients (15%). A correlation was observed between a decrease from baseline of 50% or more in thyroglobulin concentration and a decrease from baseline of 30% or more in the sum of the longest diameter of target tumor lesions (Spearman's rank correlation coefficient, 0.472; P<0.001).
Discussion
The treatment for progressive, advanced or metastatic differentiated thyroid cancer has been limited to surgery, radioiodine therapy, external-beam radiation therapy, or a combination of these treatments. In patients with radioiodine-resistant disease, cytotoxic chemotherapy yields low response rates of short duration, is often associated with considerable toxicity, and does not prolong survival.15-17 Recently, angiogenesis has been explored as a target for the treatment of advanced thyroid cancer. A study of thalidomide, which has several actions, including the inhibition of angiogenesis, showed that 5 of 28 patients with a variety of thyroid cancers had unconfirmed partial responses on the basis of criteria other than RECIST.18
We found that 13 of 93 patients with progressive, radioiodine-resistant, locally advanced or metastatic differentiated thyroid cancer who received 125 mg of motesanib diphosphate once daily had a partial response. Of these 93 patients, 87 had at least one adverse event, and 51 had a grade 3 adverse event. The response to motesanib diphosphate, which inhibits multiple signaling pathways that are involved in differentiated thyroid tumorigenesis, including VEGF and platelet-derived growth-factor receptors,12 suggests that inhibiting angiogenesis in differentiated thyroid cancer may be clinically useful. Recent preliminary data suggest that other inhibitors of VEGF receptors have efficacy in advanced thyroid cancer.19,20 In a single-institution trial of sorafenib, the confirmed partial response rate among 58 patients with metastatic papillary thyroid carcinoma was 3%.20 In our study of 93 patients with progressive differentiated thyroid cancer, the proportion of patients who had stable disease (67%), the proportion who had durable stable disease (35%) and the median progression-free survival (40 weeks [95% CI, 32 to 50]) all suggest clinically meaningful tumor control. In contrast, no partial or complete responses were seen in a phase 2 study of gefitinib, an inhibitor of the epidermal growth factor receptor, among 18 patients with advanced differentiated thyroid cancer, and the progression-free survival time was only 3.7 months (95% CI, 1.8 to 5.7).21
Changes in the thyroglobulin concentration are used to monitor residual tumor volume, recurrent or metastatic tumor growth, or both in patients with differentiated thyroid cancer.22,23 The decrease in serum thyroglobulin levels that we found in most patients and its correlation with the tumor response are consistent with the findings previously reported for radioiodine therapy.24 The magnitude of this effect was probably underestimated because thyrotropin promotes thyroglobulin secretion, and treatment with motesanib diphosphate caused increased serum concentrations of thyrotropin.
We attempted to correlate the tumor genotype and clinical response in differentiated thyroid cancer, but the number of tumors available to be studied was too small to draw conclusions about an association of responsiveness with BRAF mutations that influence the VEGF-signaling pathway.25
Two adverse events related to motesanib diphosphate treatment are worth mentioning. Hypothyroidism, an increase in the thyrotropin concentration, or both occurred in 22% of the patients and have recently been reported during treatment with the multikinase inhibitors sunitinib,26 imatinib,27 and possibly sorafenib.28 In athyreotic patients (patients whose thyroids were surgically resected), motesanib diphosphate may induce alterations in the absorption or metabolism of thyroxine instead of affecting thyroid hormone synthesis, a mechanism that is implicated in sunitinib-induced hypothyroidism.26 Given these multiple effects on thyroid function, we suggest close monitoring of thyrotropin levels and adjustments in the dose of levothyroxine, as appropriate, in patients who are receiving multikinase inhibitors. In five patients in our study (5%), cholecystitis developed, a complication that has not previously been reported in association with antiangiogenic therapy. These five patients presented with classic symptoms (right-upper-quadrant pain and fever) and had a response to medical or surgical treatment (or both), including cholecystectomy. This incidence of cholecystitis is higher than expected on the basis of other studies of motesanib diphosphate; however, the cause is unknown and the relation to motesanib diphosphate is under investigation.
The key limitation of this trial was the lack of randomization with a control group. Because the study group specifically included patients with advanced differentiated thyroid cancer, traditional comparator therapies, such as cytotoxic chemotherapy, were inappropriate owing to their ineffectiveness and toxicity. However, we believe that the large number of patients enrolled in this study allowed a reasonable estimate of clinical benefit.
In conclusion, motesanib diphosphate may be an effective treatment in some patients with progressive, metastatic, radioiodine-resistant differentiated thyroid cancer. However, a broader applicability of treatment that inhibits angiogenesis in thyroid cancer needs to be established in further studies.
Addendum
Therapy with the multikinase inhibitor sorafenib has been reported to yield a 26% partial response rate in patients with metastatic differentiated thyroid carcinoma.29
Presented in part at the annual meeting of the American Society of Clinical Oncology, Chicago, June 1 to 5, 2007; and at the annual meeting of the European Thyroid Association, Leipzig, Germany, September 1 to 5, 2007.
Supported by Amgen.
Dr. Sherman reports receiving consulting fees from Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Enzon, Exelixis, and Genzyme, honoraria and lecture fees from Abbott and Genzyme, and grant support from Amgen, Genzyme, and AstraZeneca, and serving on an advisory committee for AstraZeneca and Abbott; Dr. Wirth, lecture fees from Sanofi-Aventis; Dr. Droz, lecture fees from AstraZeneca and consulting and lecture fees from Sanofi-Aventis; Dr. Bastholt, consulting and lecture fees from AstraZeneca, Pfizer, and Schering-Plough; Dr. Martins, honoraria and lecture fees from Genentech and Eli Lilly and grant support from Amgen, Genentech, Eli Lilly, Infinity, Pfizer, ImClone, Dana–Farber, Novartis, and Exelixis, and serving on advisory committees or review panels for Genentech; Dr. Licitra, consulting fees from GlaxoSmithKline, consulting and lecture fees from Merck, and grant support and consulting and lecture fees from Associazione Italiana Ricerca Cancro (AIRC); Dr. Schlumberger, consulting and lecture fees from AstraZeneca, Exelixis, and Genzyme and grant support from AstraZeneca, Genzyme, and Amgen; and Mr. Eschenberg and Drs. Sun, Juan, and Stepan being employees of and having equity ownership and stock options in Amgen. No other potential conflict of interest relevant to this article was reported.
We thank Carole Spencer, Ph.D., for measurement of thyroglobulin and analysis and discussion of the results; Jennifer Britton and Monica MacDonald for study management; Ali Hassan, Ph.D., whose work was funded by Amgen, and Beate D. Quednau, Ph.D. (Amgen), for assistance in drafting the manuscript; and David Reese, M.D., for discussion of the study results and critical review of the manuscript.
Source Information
From the University of Texas M.D. Anderson Cancer Center, Houston (S.I.S.); Dana−Farber Cancer Institute, Boston (L.J.W.); Centre Léon Bérard, Lyon, France (J.-P.D.); Medical School Bern, Bern, Switzerland (M.H.); Odense University Hospital, Odense, Denmark (L.B.); University of Washington, Seattle (R.G.M.); Istituto Nazionale dei Tumori, Milan (L.L.); Amgen, Thousand Oaks, CA (M.J.E., Y.-N.S., T.J., D.E.S.); and Institut Gustave Roussy, University Paris Sud, Villejuif, France (M.J.S.).
Address reprint requests to Dr. Sherman at the Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas M.D. Anderson Cancer Center, Unit 435, 1515 Holcombe Blvd., P.O. Box 301402, Houston, TX 77230-1402, or at sisherma@mdanderson.org.
Additional investigators who participated in this study are listed in the Appendix.
Appendix
In addition to the authors, the following investigators participated in the study: University Hospital for Nuclear Medicine and Endocrinology, Klagenfurt, Austria — P. Lind; University Hospital for Nuclear Medicine and Endocrinology, Salzburg, Austria — C. Pirich; University Hospital St. Luc, Brussels — C. Daumerie; Institut Gustave Roussy, Villejuif, France — E. Baudin; Institut Bergonié, Bordeaux, France — B.N. Bui; Centre Hospitalier Universitaire (CHU) de la Timone, Marseille, France — B. Conte-Devolx; CHU Angers, Angers, France — V. Rohmer; Institut Jean Godinot, Reims, France — C. Schvartz; Belgyogyaszati Hospital, Budapest, Hungary — I. Szabolcs, K. Racz; University Hospital, Florence, Italy — M.L. Brandi; University Hospital, Pisa, Italy — A. Pinchera, R. Elisei; Hospital S. Luigi Gonzaga, Orbassano, Italy — F. Orlandi; University Hospital, Siena, Italy — F. Pacini; Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland — B. Jarzab; Oddzial Clinic of Endocrinology, Poznan, Poland — J. Sowinski; Sahlgrenska University Hospital, Göteborg, Sweden — S. Jansson; Karolinska University Hospital, Stockholm — G. Lundell, A. Hallqvist; University Hospital, Geneva — C. Meier, J. Philippe; University of Pittsburgh Cancer Institute, Pittsburgh — S. Agarwala; Henry Ford Health System, Detroit — H. Ali; Mission International Medical Group, Mission Viejo, CA — J. Barrera; Center for Cancer and Blood Disorders, Bethesda, MD — R. Boccia; Cleveland Clinic Foundation, Cleveland — R. Bukowski; Washington Hospital Center, Washington, DC — K. Burman; University of California, San Francisco, San Francisco — O. Clark; Dartmouth–Hitchcock Medical Center, Lebanon, NH — T. Davis; University of Texas M.D. Anderson Cancer Center, Houston — A. Hoff, N. Sarlis; Lakeland Regional Cancer Center, Lakeland, FL — J. Jakub; Providence St. Joseph Medical Center, Burbank, CA — R. Mena; University of Cincinnati Barrett Cancer Center, Cincinnati — Z. Nahleh; Premiere Oncology Medical Corporation, Santa Monica, CA — L. Rosen; Cancer Center of the Carolinas, Greenville, SC — J. Stephenson; Sparrow Regional Cancer Center, Lansing, MI — G. Srkalovic; Pacific Shores Medical Group, Long Beach, CA — N. Tchekmedyian.
- References
References
1
DeLellis RA . Pathology and genetics of thyroid carcinoma. J Surg Oncol 2006;94:662-669
CrossRef | Web of Science | Medline2
Schlumberger MJ . Papillary and follicular thyroid carcinoma. N Engl J Med 1998;338:297-306
Full Text | Web of Science | Medline3
Hundahl SA ,Fleming ID ,Fremgen AM ,Menck HR . A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995. Cancer 1998;83:2638-2648
CrossRef | Web of Science | Medline4
Cooper DS ,Doherty GM ,Haugen BR , et al. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2006;16:109-142
CrossRef | Web of Science | Medline5
Durante C ,Haddy N ,Baudin E , et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab 2006;91:2892-2899
CrossRef | Web of Science | Medline6
Bunone G ,Vigneri P ,Mariani L , et al. Expression of angiogenesis stimulators and inhibitors in human thyroid tumors and correlation with clinical pathological features. Am J Pathol 1999;155:1967-1976
CrossRef | Web of Science | Medline7
Klein M ,Picard E ,Vignaud JM , et al. Vascular endothelial growth factor gene and protein: strong expression in thyroiditis and thyroid carcinoma. J Endocrinol 1999;161:41-49
CrossRef | Web of Science | Medline8
Kilicarslan AB ,Ogus M ,Arici C ,Pestereli HE ,Cakir M ,Karpuzoglu G . Clinical importance of vascular endothelial growth factor (VEGF) for papillary thyroid carcinomas. APMIS 2003;111:439-443
CrossRef | Web of Science | Medline9
Lennard CM ,Patel A ,Wilson J , et al. Intensity of vascular endothelial growth factor expression is associated with increased risk of recurrence and decreased disease-free survival in papillary thyroid cancer. Surgery 2001;129:552-558
CrossRef | Web of Science | Medline10
Vieira JM ,Santos SC ,Espadinha C , et al. Expression of vascular endothelial growth factor (VEGF) and its receptors in thyroid carcinomas of follicular origin: a potential autocrine loop. Eur J Endocrinol 2005;153:701-709
CrossRef | Web of Science | Medline11
Fagin JA . How thyroid tumors start and why it matters: kinase mutants as targets for solid cancer pharmacotherapy. J Endocrinol 2004;183:249-256
CrossRef | Web of Science | Medline12
Polverino A ,Coxon A ,Starnes C , et al. AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and Kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res 2006;66:8715-8721
CrossRef | Web of Science | Medline13
Rosen LS ,Kurzrock R ,Mulay M , et al. Safety, pharmacokinetics, and efficacy of AMG 706, an oral multikinase inhibitor, in patients with advanced solid tumors. J Clin Oncol 2007;25:2369-2376
CrossRef | Web of Science | Medline14
Therasse P ,Arbuck SG ,Eisenhauer EA , et al. New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205-216
CrossRef | Web of Science | Medline15
Haugen BR . Management of the patient with progressive radioiodine non-responsive disease. Semin Surg Oncol 1999;16:34-41
CrossRef | Web of Science | Medline16
Gottlieb JA ,Hill CS Jr . Chemotherapy of thyroid cancer with adriamycin: experience with 30 patients. N Engl J Med 1974;290:193-197
Full Text | Web of Science | Medline17
Droz JP ,Schlumberger M ,Rougier P ,Ghosn M ,Gardet P ,Parmentier C . Chemotherapy in metastatic nonanaplastic thyroid cancer: experience at the Institut Gustave-Roussy. Tumori 1990;76:480-483
Web of Science | Medline18
Ain KB ,Lee C ,Williams KD . Phase II trial of thalidomide for therapy of radioiodine-unresponsive and rapidly progressive thyroid carcinomas. Thyroid 2007;17:663-670
CrossRef | Web of Science | Medline19
Cohen EE, Rosen LS, Vokes EE, et al. Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J Clin Oncol (in press).
20
Kloos R ,Ringel M ,Knopp M , et al. Significant clinical and biologic activity of RAF/VEGF-R kinase inhibitor BAY 43-9006 in patients with metastatic papillary thyroid carcinoma (PTC): updated results of a phase II study. J Clin Oncol 2006;24:Suppl:288s-288s
Web of Science21
Pennell NA ,Daniels GH ,Haddad RI , et al. A phase II study of gefitinib in patients with advanced thyroid cancer. Thyroid 2008;18:317-323
CrossRef | Web of Science | Medline22
Sherman SI . Thyroid carcinoma. Lancet 2003;361:501-511
CrossRef | Web of Science | Medline23
Spencer CA ,LoPresti JS ,Fatemi S ,Nicoloff JT . Detection of residual and recurrent differentiated thyroid carcinoma by serum thyroglobulin measurement. Thyroid 1999;9:435-441
CrossRef | Web of Science | Medline24
Sisson JC ,Giordano TJ ,Jamadar DA , et al. 131-I treatment of micronodular pulmonary metastases from papillary thyroid carcinoma. Cancer 1996;78:2184-2192
CrossRef | Web of Science | Medline25
Jo YS ,Li S ,Song JH , et al. Influence of the BRAF V600E mutation on expression of vascular endothelial growth factor in papillary thyroid cancer. J Clin Endocrinol Metab 2006;91:3667-3670
CrossRef | Web of Science | Medline26
Desai J ,Yassa L ,Marqusee E , et al. Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med 2006;145:660-664
Web of Science | Medline27
de Groot JW ,Zonnenberg BA ,van Ufford-Mannesse PQ , et al. A phase II trial of imatinib therapy for metastatic medullary thyroid carcinoma. J Clin Endocrinol Metab 2007;92:3466-3469
CrossRef | Web of Science | Medline28
Robinson SI ,Hobday TJ ,Sathananthan A ,Morris JC III ,McWilliams RR . Can sorafenib cause hypothyroidism? J Chemother 2007;19:352-353
Web of Science | Medline29
Gupta-Abramson V, Troxel AB, Nellore A, et al. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol (in press).
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F.C. Uecker, S. Laban, R. Knecht. (2012) Stellenwert neuer Behandlungsansätze mit Targettherapeutika bei malignen Schilddrüsenerkrankungen. HNO 60:5, 398-403
CrossRef2
Katarina L Kojic, Stefan L Kojic, Sam M Wiseman. (2012) Differentiated thyroid cancers: a comprehensive review of novel targeted therapies. Expert Review of Anticancer Therapy 12:3, 345-357
CrossRef3
Furio Pacini, Maria Grazia Castagna. (2012) Approach to and Treatment of Differentiated Thyroid Carcinoma. Medical Clinics of North America 96:2, 369-383
CrossRef4
S. Walsh, R. Prichard, A.D.K. Hill. (2012) Emerging therapies for thyroid carcinoma. The Surgeon 10:1, 53-58
CrossRef5
J. Capdevila, L. Iglesias, I. Halperin, A. Segura, J. Martinez-Trufero, M. A. Vaz, J. Corral, G. Obiols, E. Grande, J. J. Grau, J. Tabernero. (2012) Sorafenib in metastatic thyroid cancer. Endocrine Related Cancer
CrossRef6
Christian Lerch, Bernd Richter. (2012) Pharmacotherapy Options for Advanced Thyroid Cancer. Drugs 72:1, 67-85
CrossRef7
M. Schlumberger, S. I. Sherman. (2012) ENDOCRINE TUMOURS: Approach to the patient with advanced differentiated thyroid cancer. European Journal of Endocrinology 166:1, 5-11
CrossRef8
E. Kapiteijn, T. C. Schneider, H. Morreau, H. Gelderblom, J. W. R. Nortier, J. W. A. Smit. (2012) New treatment modalities in advanced thyroid cancer. Annals of Oncology 23:1, 10-18
CrossRef9
Naifa Lamki Busaidy, Maria E. Cabanillas. (2012) Differentiated Thyroid Cancer: Management of Patients with Radioiodine Nonresponsive Disease. Journal of Thyroid Research 2012, 1-12
CrossRef10
Martin Schlumberger, Cécile Chougnet, Éric Baudin, Sophie Leboulleux. (2011) Cancers réfractaires de la thyroïde. La Presse Médicale 40:12, 1189-1198
CrossRef11
Jin Chul Paeng, Keon Wook Kang, Do Joon Park, So Won Oh, June-Key Chung. (2011) Alternative Medical Treatment for Radioiodine-Refractory Thyroid Cancers. Nuclear Medicine and Molecular Imaging 45:4, 241-247
CrossRef12
Rebecca L. Brown. (2011) Tyrosine kinase inhibitor-induced hypothyroidism: incidence, etiology, and management. Targeted Oncology 6:4, 217-226
CrossRef13
Eric J. Sherman, Su Hsien Lim, Alan L. Ho, Ronald A. Ghossein, Matthew G. Fury, Ashok R. Shaha, Michael Rivera, Oscar Lin, Suzanne Wolden, Nancy Y. Lee, David G. Pfister. (2011) Concurrent doxorubicin and radiotherapy for anaplastic thyroid cancer: A critical re-evaluation including uniform pathologic review. Radiotherapy and Oncology 101:3, 425-430
CrossRef14
O.-P. R. Hamnvik, P. R. Larsen, E. Marqusee. (2011) Thyroid Dysfunction from Antineoplastic Agents. JNCI Journal of the National Cancer Institute 103:21, 1572-1587
CrossRef15
Juan Carlos Galofré, José Manuel Gómez-Sáez, Cristina Álvarez Escola, Elías Álvarez García, Emma Anda Apiñaniz, Amparo Calleja, Sergio Donnay, Anna Lucas-Martin, Edelmiro Menéndez Torre, Elena Navarro González, Vicente Pereg, Begoña Pérez Corral, Javier Santamaría Sandi, Garcilaso Riesco Eizaguirre, Carles Zafón Llopis. (2011) Use of new molecules in the treatment of advanced thyroid cancer. Endocrinología y Nutrición (English Edition) 58:8, 381-386
CrossRef16
J. C. Galofre, J. M. Gomez-Saez, C. A. Escola, E. Anda, A. Calleja, S. Donnay, A. Lucas-Martin, E. Menendez-Torre, V. Pereg, B. Perez-Corral, J. Santamaria, G. Riesco-Eizaguirre, C. Zafon, . (2011) Treatment of thyroid cancer with the new oral agents. Annals of Oncology 22:10, 2343-2343
CrossRef17
Pamela Jo Harris, Keith C Bible. (2011) Emerging therapeutics for advanced thyroid malignancies: rationale and targeted approaches. Expert Opinion on Investigational Drugs 20:10, 1357-1375
CrossRef18
Juan Carlos Galofré, José Manuel Gómez-Sáez, Cristina Álvarez Escola, Elías Álvarez García, Emma Anda Apiñaniz, Amparo Calleja, Sergio Donnay, Anna Lucas-Martin, Edelmiro Menéndez Torre, Elena Navarro González, Vicente Pereg, Begoña Pérez Corral, Javier Santamaría Sandi, Garcilaso Riesco Eizaguirre, Carles Zafón Llopis. (2011) Uso de nuevas moléculas en el tratamiento del cáncer avanzado de tiroides. Endocrinología y Nutrición 58:8, 381-386
CrossRef19
Jean-Philippe Spano, Y. Vano, S. Vignot, T. La Motte Rouge, L. Hassani, R. Mouawad, F. Menegaux, D. Khayat, L. Leenhardt. (2011) GEMOX regimen in the treatment of metastatic differentiated refractory thyroid carcinoma. Medical Oncology
CrossRef20
C. Durante, G. Tallini, E. Puxeddu, M. Sponziello, S. Moretti, C. Ligorio, A. Cavaliere, K. J. Rhoden, A. Verrienti, M. Maranghi, L. Giacomelli, D. Russo, S. Filetti. (2011) BRAFV600E mutation and expression of proangiogenic molecular markers in papillary thyroid carcinomas. European Journal of Endocrinology 165:3, 455-463
CrossRef21
G. R. Blumenschein Jr, F. Kabbinavar, H. Menon, T. S. K. Mok, J. Stephenson, J. T. Beck, K. Lakshmaiah, K. Reckamp, Y.- J. Hei, K. Kracht, Y.- N. Sun, R. Sikorski, L. Schwartzberg, . (2011) A phase II, multicenter, open-label randomized study of motesanib or bevacizumab in combination with paclitaxel and carboplatin for advanced nonsquamous non-small-cell lung cancer. Annals of Oncology 22:9, 2057-2067
CrossRef22
Matti L. Gild, Martyn Bullock, Bruce G. Robinson, Roderick Clifton-Bligh. (2011) Multikinase inhibitors: a new option for the treatment of thyroid cancer. Nature Reviews Endocrinology 7:10, 617-624
CrossRef23
Javier Martínez Trufero, Jaume Capdevilla, Juan Jesús Cruz, Dolores Isla. (2011) SEOM clinical guidelines for the treatment of thyroid cancer. Clinical and Translational Oncology 13:8, 574-579
CrossRef24
Christelle de la Fouchardiere, Jean-Pierre Droz. (2011) Targeted therapies and thyroid cancer. Anti-Cancer Drugs 22:7, 688-699
CrossRef25
M. Ahmed, Y. Barbachano, A. Riddell, J. Hickey, K. L. Newbold, A. Viros, K. J. Harrington, R. Marais, C. M. Nutting. (2011) Analysis of the efficacy and toxicity of sorafenib in thyroid cancer: a phase II study in a UK based population. European Journal of Endocrinology 165:2, 315-322
CrossRef26
Robert S. Benjamin, Patrick Schöffski, Jörg Thomas Hartmann, Allan Oosterom, Binh Nguyen Bui, Justus Duyster, Scott Schuetze, Jean-Yves Blay, Peter Reichardt, Lee S. Rosen, Keith Skubitz, Sheryl McCoy, Yu-Nien Sun, Daniel E. Stepan, Laurence Baker. (2011) Efficacy and safety of motesanib, an oral inhibitor of VEGF, PDGF, and Kit receptors, in patients with imatinib-resistant gastrointestinal stromal tumors. Cancer Chemotherapy and Pharmacology 68:1, 69-77
CrossRef27
H. Prazeres, J. P. Couto, F. Rodrigues, J. Vinagre, J. Torres, V. Trovisco, T. C. Martins, M. Sobrinho-Simoes, P. Soares. (2011) In vitro transforming potential, intracellular signaling properties, and sensitivity to a kinase inhibitor (sorafenib) of RET proto-oncogene variants Glu511Lys, Ser649Leu, and Arg886Trp. Endocrine Related Cancer 18:4, 401-412
CrossRef28
Kanwal Pratap Singh Raghav, George R Blumenschein. (2011) Motesanib and advanced NSCLC: experiences and expectations. Expert Opinion on Investigational Drugs 20:6, 859-869
CrossRef29
C. Nozières, C. Damatte-Fauchery, F. Borson-Chazot. (2011) Thyroid effects and anticancer treatment. Annales d'Endocrinologie 72:3, 198-202
CrossRef30
Steven Sherman. 2011. Biologically Targeted Therapies for Thyroid Cancers. , 329-349.
CrossRef31
György Kéri, László Őrfi, Gábor Németh. 2011. Kinase Inhibitors in Signal Transduction Therapy. , 115-144.
CrossRef32
Yassine Lalami, Ahmad Awada. (2011) Recurrent thyroid cancer: a molecular-based therapeutic breakthrough. Current Opinion in Oncology 23:3, 235-240
CrossRef33
Lucia Brilli, Furio Pacini. (2011) Targeted therapy in refractory thyroid cancer: current achievements and limitations. Future Oncology 7:5, 657-668
CrossRef34
Steven I Sherman. (2011) Targeted therapies for thyroid tumors. Modern Pathology 24, S44-S52
CrossRef35
M. Schlumberger. (2011) Prise en charge des cancers réfractaires de la thyroïde. Annales d'Endocrinologie 72:2, 149-157
CrossRef36
Li Zhang, Su Li, Yang Zhang, Jing Zhan, Ben-Yan Zou, Robert Smith, Paul D. Martin, Yinrui Jiang, Hai Liao, Zhongzhen Guan. (2011) Pharmacokinetics and Tolerability of Vandetanib in Chinese Patients With Solid, Malignant Tumors: An Open-Label, Phase I, Rising Multiple-Dose Study. Clinical Therapeutics 33:3, 315-327
CrossRef37
Hendrieke C Hoftijzer, Ellen Kapiteijn, Tatiana Schneider, Guido C Hovens, Hans Morreau, Hans Gelderblom, Johannes WA Smit. (2011) Tyrosine kinase inhibitors in differentiated thyroid carcinoma: a review of the clinical evidence. Clinical Investigation 1:2, 241-253
CrossRef38
Andrew G. Gianoukakis, Silvana M. Giannelli, Wael A. Salameh, Laron W. McPhaul. (2011) Well differentiated follicular thyroid neoplasia: Impact of molecular and technological advances on detection, monitoring and treatment. Molecular and Cellular Endocrinology 332:1-2, 9-20
CrossRef39
Efisio Puxeddu, Serena Romagnoli, Massimo Eugenio Dottorini. (2011) Targeted therapies for advanced thyroid cancer. Current Opinion in Oncology 23:1, 13-21
CrossRef40
Shannon R. Bales, Inder J. Chopra. (2011) Targeted Treatment of Differentiated and Medullary Thyroid Cancer. Journal of Thyroid Research 2011, 1-11
CrossRef41
Hugo Prazeres, Joana Torres, Fernando Rodrigues, Joana P. Couto, João Vinagre, Manuel Sobrinho-Simões, Paula Soares. (2011) How to Treat a Signal? Current Basis for RET-Genotype-Oriented Choice of Kinase Inhibitors for the Treatment of Medullary Thyroid Cancer. Journal of Thyroid Research 2011, 1-10
CrossRef42
Howard Burris, Joe Stephenson, Gregory A. Otterson, Mark Stein, Jesse McGreivy, Yu-Nien Sun, Megan Ingram, Yining Ye, Lee S. Schwartzberg. (2011) Safety and Pharmacokinetics of Motesanib in Combination with Panitumumab and Gemcitabine-Cisplatin in Patients with Advanced Cancer. Journal of Oncology 2011, 1-11
CrossRef43
Dusan Kotasek, Niall Tebbutt, Jayesh Desai, Stephen Welch, Lillian L Siu, Sheryl McCoy, Yu-Nien Sun, Jessica Johnson, Adeboye H Adewoye, Timothy Price. (2011) Safety and pharmacokinetics of motesanib in combination with gemcitabine and erlotinib for the treatment of solid tumors: a phase 1b study. BMC Cancer 11:1, 313
CrossRef44
Cesar A. Perez, Edgardo S. Santos, Belisario A. Arango, Luis E. Raez, Ezra E. W. Cohen, David W. Eisele. (2011) Novel molecular targeted therapies for refractory thyroid cancer. Head & Neckn/a-n/a
CrossRef45
M. Schott. (2011) Phase II Clinical Trial of Sorafenib in Metastatic Medullary Thyroid Cancer. Yearbook of Endocrinology 2011, 123-124
CrossRef46
Martin-Jean Schlumberger, Sebastiano Filetti, Ian D. Hay. 2011. Nontoxic Diffuse and Nodular Goiter and Thyroid Neoplasia. , 440-475.
CrossRef47
Dingxie Liu, Joanna Xing, Barry Trink, Mingzhao Xing. (2010) BRAF mutation-selective inhibition of thyroid cancer cells by the novel MEK inhibitor RDEA119 and genetic-potentiated synergism with the mTOR inhibitor temsirolimus. International Journal of Cancer 127:12, 2965-2973
CrossRef48
William R. Burns, Martha A. Zeiger. (2010) Differentiated Thyroid Cancer. Seminars in Oncology 37:6, 557-566
CrossRef49
Jian-Feng Lu, Laurent Claret, Liviawati Sutjandra, Mita Kuchimanchi, Rebeca Melara, René Bruno, Yu-Nien Sun. (2010) Population pharmacokinetic/pharmacodynamic modeling for the time course of tumor shrinkage by motesanib in thyroid cancer patients. Cancer Chemotherapy and Pharmacology 66:6, 1151-1158
CrossRef50
Theo D. Kim, Michaela Schwarz, Hendrik Nogai, Peggy Grille, Jörg Westermann, Ursula Plöckinger, Doreen Braun, Ulrich Schweizer, Renate Arnold, Bernd Dörken, Philipp le Coutre. (2010) Thyroid Dysfunction Caused by Second-Generation Tyrosine Kinase Inhibitors in Philadelphia Chromosome-Positive Chronic Myeloid Leukemia. Thyroid 20:11, 1209-1214
CrossRef51
Laurent Claret, Jian-Feng Lu, Yu-Nien Sun, René Bruno. (2010) Development of a modeling framework to simulate efficacy endpoints for motesanib in patients with thyroid cancer. Cancer Chemotherapy and Pharmacology 66:6, 1141-1149
CrossRef52
Keith C Bible, Vera J Suman, Julian R Molina, Robert C Smallridge, William J Maples, Michael E Menefee, Joseph Rubin, Kostandinos Sideras, John C Morris, Bryan McIver, Jill K Burton, Kevin P Webster, Carolyn Bieber, Anne M Traynor, Patrick J Flynn, Boon Cher Goh, Hui Tang, Susan Percy Ivy, Charles Erlichman. (2010) Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study. The Lancet Oncology 11:10, 962-972
CrossRef53
Martin Schlumberger. (2010) Kinase inhibitors for refractory thyroid cancers. The Lancet Oncology 11:10, 912-913
CrossRef54
Sissy M. Jhiang, Manisha H. Shah. (2010) Prospects for Small Interfering RNA Therapeutics in Thyroid Cancer. Thyroid 20:10, 1049-1050
CrossRef55
Herbert Chen, Rebecca S. Sippel, M. Sue O'Dorisio, Aaron I. Vinik, Ricardo V. Lloyd, Karel Pacak. (2010) The North American Neuroendocrine Tumor Society Consensus Guideline for the Diagnosis and Management of Neuroendocrine Tumors. Pancreas 39:6, 775-783
CrossRef56
C. Chougnet, M. Brassard, S. Leboulleux, E. Baudin, M. Schlumberger. (2010) Molecular Targeted Therapies for Patients with Refractory Thyroid Cancer. Clinical Oncology 22:6, 448-455
CrossRef57
Daniel M. Bernad, Paul W. Sperduto, Luis Souhami, Ashley W. Jensen, David Roberge. (2010) Stereotactic radiosurgery in the management of brain metastases from primary thyroid cancers. Journal of Neuro-Oncology 98:2, 249-252
CrossRef58
M. L. Maitland, G. L. Bakris, H. R. Black, H. X. Chen, J. B. Durand, W. J. Elliott, S. P. Ivy, C. V. Leier, J. Lindenfeld, G. Liu, S. C. Remick, R. Steingart, W. H. W. Tang, . (2010) Initial Assessment, Surveillance, and Management of Blood Pressure in Patients Receiving Vascular Endothelial Growth Factor Signaling Pathway Inhibitors. JNCI Journal of the National Cancer Institute 102:9, 596-604
CrossRef59
Motoyasu Saji, Matthew D. Ringel. (2010) The PI3K-Akt-mTOR pathway in initiation and progression of thyroid tumors. Molecular and Cellular Endocrinology 321:1, 20-28
CrossRef60
F. Pacini, M. G. Castagna, L. Brilli, G. Pentheroudakis, . (2010) Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 21:Supplement 5, v214-v219
CrossRef61
Kristien Boelaert. (2010) Thyroid gland: Revised guidelines for the management of thyroid cancer. Nature Reviews Endocrinology 6:4, 185-186
CrossRef62
Maria Graziella Catalano, Roberta Poli, Mariateresa Pugliese, Nicoletta Fortunati, Giuseppe Boccuzzi. (2010) Emerging molecular therapies of advanced thyroid cancer. Molecular Aspects of Medicine 31:2, 215-226
CrossRef63
Lisa Licitra, Laura D. Locati, Angela Greco, Roberta Granata, P. Bossi. (2010) Multikinase inhibitors in thyroid cancer. European Journal of Cancer 46:6, 1012-1018
CrossRef64
Aihua Tan, Ning Xia, Feng Gao, Zengnan Mo, Yunfei Cao, Ning Xia. 2010. Angiogenesis-inhibitors for metastatic thyroid cancer. .
CrossRef65
Marcus Middendorp, Frank Grünwald. (2010) Update on Recent Developments in the Therapy of Differentiated Thyroid Cancer. Seminars in Nuclear Medicine 40:2, 145-152
CrossRef66
Jerome M. Hershman, Llanyee Liwanpo. (2010) How Does Sunitinib Cause Hypothyroidism?. Thyroid 20:3, 243-244
CrossRef67
Claudia Papewalis, Margret Ehlers, Matthias Schott. (2010) Advances in Cellular Therapy for the Treatment of Thyroid Cancer. Journal of Oncology 2010, 1-11
CrossRef68
David Tai, Donald Poon. (2010) Molecular and Other Novel Advances in Treatment of Metastatic Epithelial and Medullary Thyroid Cancers. Journal of Oncology 2010, 1-7
CrossRef69
Alessandro Antonelli, Clodoveo Ferri, Silvia Martina Ferrari, Marco Sebastiani, Michele Colaci, Ilaria Ruffilli, Poupak Fallahi. (2010) New Targeted Molecular Therapies for Dedifferentiated Thyroid Cancer. Journal of Oncology 2010, 1-6
CrossRef70
Eun Sook Kim. (2010) Targeted Therapies in Thyroid Cancer. Endocrinology and Metabolism 25:2, 94
CrossRef71
Jae Young Choi, Ja Seong Bae, Young Ae Kim, Eun Deok Chang, Hang Joo Cho, Ki Hwan Kim, Chang Hyeok Ahn, Woo Chan Park, Jeong Soo Kim. (2010) Clinical Significance of MMP-2, MMP-9 and HIF-1α Expression in Thyroid Micropapillary Cancer. Journal of the Korean Surgical Society 78:3, 157
CrossRef72
Nicholas Mitsiades, James A. Fagin. 2010. Molecular Genetics of Thyroid CancerPathogenetic Significance and Clinical Applications. , 117-138.
CrossRef73
Patrick S. Swift, Steven Larson, Orlo H. Clark, Daniel Ruan. 2010. Cancer of the Thyroid. , 726-736.
CrossRef74
M. Schott. (2010) Phase II Study of Safety and Efficacy of Motesanib in Patients With Progressive or Symptomatic, Advanced of Metastatic Medullary Thyroid Cancer. Yearbook of Endocrinology 2010, 176-178
CrossRef75
Steven I. Sherman. (2009) Tyrosine kinase inhibitors and the thyroid. Best Practice & Research Clinical Endocrinology & Metabolism 23:6, 713-722
CrossRef76
Caroline S. Kim, Xuguang Zhu. (2009) Lessons from Mouse Models of Thyroid Cancer. Thyroid 19:12, 1317-1331
CrossRef77
Martin Schlumberger, Steven I. Sherman. (2009) Clinical Trials for Progressive Differentiated Thyroid Cancer: Patient Selection, Study Design, and Recent Advances. Thyroid 19:12, 1393-1400
CrossRef78
Jaume Capdevila, Jose Perez-Garcia, Gabriel Obiols, Josep Tabernero. (2009) Targeted therapies in thyroid cancer. Targeted Oncology 4:4, 275-285
CrossRef79
David S. Cooper, Gerard M. Doherty, Bryan R. Haugen, Richard T. Kloos, Stephanie L. Lee, Susan J. Mandel, Ernest L. Mazzaferri, Bryan McIver, Furio Pacini, Martin Schlumberger, Steven I. Sherman, David L. Steward, R. Michael Tuttle. (2009) Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 19:11, 1167-1214
CrossRef80
Elizabeth L. Strevel, Lillian L. Siu. (2009) Cardiovascular toxicity of molecularly targeted agents. European Journal of Cancer 45, 318-331
CrossRef81
Steven I. Sherman. (2009) Molecularly Targeted Therapies for Thyroid Cancers. Endocrine Practice 15:6, 605-611
CrossRef82
Lei Ye, Libero Santarpia, Robert F. Gagel. (2009) Targeted Therapy for Endocrine Cancer: The Medullary Thyroid Carcinoma Paradigm. Endocrine Practice 15:6, 597-604
CrossRef83
Mingzhao Xing. (2009) Genetic-Targeted Therapy of Thyroid Cancer: A Real Promise. Thyroid 19:8, 805-809
CrossRef84
L. Santarpia, L. Ye, R. F. Gagel. (2009) Beyond RET: potential therapeutic approaches for advanced and metastatic medullary thyroid carcinoma. Journal of Internal Medicine 266:1, 99-113
CrossRef85
Anita K. Ying, Winston Huh, Sarah Bottomley, Douglas B. Evans, Steven G. Waguespack. (2009) Thyroid Cancer in Young Adults. Seminars in Oncology 36:3, 258-274
CrossRef86
John C. Morris. (2009) How do you approach the problem of TSH elevation in a patient on high-dose thyroid hormone replacement?. Clinical Endocrinology 70:5, 671-673
CrossRef87
Jens Soltau, Joachim Drevs. (2009) Mode of action and clinical impact of VEGF signaling inhibitors. Expert Review of Anticancer Therapy 9:5, 649-662
CrossRef88
Ming Hui Chen. (2009) Cardiac dysfunction induced by novel targeted anticancer therapy: An emerging issue. Current Cardiology Reports 11:3, 167-174
CrossRef89
Carmelo Nucera, Melanie Goldfarb, Richard Hodin, Sareh Parangi. (2009) Role of B-RafV600E in differentiated thyroid cancer and preclinical validation of compounds against B-RafV600E. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1795:2, 152-161
CrossRef90
Scott N. Pinchot, Muthusamy Kunnimalaiyaan, Rebecca S. Sippel, Herbert Chen. (2009) Medullary Thyroid Carcinoma: Targeted Therapies and Future Directions. Journal of Oncology 2009, 1-7
CrossRef91
M. Schott. (2009) Phase II Trial of Sorafenib in Advanced Thyroid Cancer. Yearbook of Medicine 2009, 571-574
CrossRef92
(2008) Motesanib Diphosphate in Progressive Differentiated Thyroid Cancer. New England Journal of Medicine 359:25, 2727-2727
Full Text93
Ranee Mehra, Roger B. Cohen. (2008) New Agents in the Treatment for Malignancies of the Salivary and Thyroid Glands. Hematology/Oncology Clinics of North America 22:6, 1279-1295
CrossRef94
James A. Fagin, Nicholas Mitsiades. (2008) Molecular pathology of thyroid cancer: diagnostic and clinical implications. Best Practice & Research Clinical Endocrinology & Metabolism 22:6, 955-969
CrossRef95
Maria Domenica Castellone, Francesca Carlomagno, Giuliana Salvatore, Massimo Santoro. (2008) Receptor tyrosine kinase inhibitors in thyroid cancer. Best Practice & Research Clinical Endocrinology & Metabolism 22:6, 1023-1038
CrossRef96
Giuliana Salvatore, Francesca Carlomagno, Massimo Santoro. (2008) Pros and Cons of Cellular Studies in Developing New Drugs for Thyroid Cancers. Thyroid 18:8, 819-822
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