المؤلفون: Elisei, Rossella, Grande, Enrique, Kreissl, Michael C, Leboulleux, Sophie, Puri, Tarun, Fasnacht, Nicolas, Capdevila, Jaume

المساهمون: Elisei, Rossella, Grande, Enrique, Kreissl, Michael C, Leboulleux, Sophie, Puri, Tarun, Fasnacht, Nicola, Capdevila, Jaume

مصطلحات موضوعية: RET, medullary thyroid cancer, papillary thyroid cancer, receptor-tyrosine kinase, thyroid cancer, tyrosine kinase inhibitor

الوصف: The incidence of thyroid cancer is increasing worldwide with the disease burden in Europe second only to that in Asia. In the last several decades, molecular pathways central to the pathogenesis of thyroid cancer have revealed a spectrum of targetable kinases/kinase receptors and oncogenic drivers characteristic of each histologic subtype, such as differentiated thyroid cancer, including papillary, follicular, and medullary thyroid cancer. Oncogenic alterations identified include B-Raf proto-oncogene (BRAF) fusions and mutations, neurotrophic tyrosine receptor kinase (NTRK) gene fusions, and rearranged during transfection (RET) receptor tyrosine kinase fusion and mutations. Multikinase inhibitors (MKIs) targeting RET in addition to multiple other kinases, such as sorafenib, lenvatinib and cabozantinib, have shown favourable activity in advanced radioiodine-refractory differentiated thyroid cancer or RET-altered medullary thyroid cancer; however, the clinical utility of MKI RET inhibition is limited by off-target toxicity resulting in high rates of dose reduction and drug discontinuation. Newer and selective RET inhibitors, selpercatinib and pralsetinib, have demonstrated potent efficacy and favourable toxicity profiles in clinical trials in the treatment of RET-driven advanced thyroid cancer and are now a therapeutic option in some clinical settings. Importantly, the optimal benefits of available specific targeted treatments for advanced RET-driven thyroid cancer require genetic testing. Prior to the initiation of systemic therapy, and in treatment-naive patients, RET inhibitors may be offered as first-line therapy if a RET alteration is found, supported by a multidisciplinary team approach.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/37207147; info:eu-repo/semantics/altIdentifier/wos/WOS:000987574600001; volume:13; numberofpages:15; journal:FRONTIERS IN ONCOLOGY; https://hdl.handle.net/11568/1207867Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85159874687; https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1141314/fullTest

الإتاحة: https://doi.org/10.3389/fonc.2023.1141314Test
https://hdl.handle.net/11568/1207867Test

المؤلفون: Capdevila, Jaume¹ (AUTHOR) jcapdevila@vhio.net, Krajewska, Jolanta² (AUTHOR), Hernando, Jorge³ (AUTHOR), Robinson, Bruce⁴ (AUTHOR), Sherman, Steven I.⁵ (AUTHOR), Jarzab, Barbara² (AUTHOR), Lin, Chia-Chi⁶ (AUTHOR), Vaisman, Fernanda⁷ (AUTHOR), Hoff, Ana O.⁸ (AUTHOR), Hitre, Erika⁹ (AUTHOR), Bowles, Daniel W.¹⁰ (AUTHOR), Williamson, Denise¹¹ (AUTHOR), Levytskyy, Roman¹² (AUTHOR), Oliver, Jennifer¹³ (AUTHOR), Keam, Bhumsuk¹⁴ (AUTHOR), Brose, Marcia S.¹⁵ (AUTHOR)

المصدر: Thyroid. Mar2024, Vol. 34 Issue 3, p347-359. 13p.

مصطلحات موضوعية: *THYROID cancer, *VASCULAR endothelial growth factors, *PROGRESSION-free survival, *PROTEIN-tyrosine kinase inhibitors, *SUBGROUP analysis (Experimental design), *PLACEBOS

مستخلص: Background: Lenvatinib and sorafenib are standard of care first-line treatments for advanced, radioiodine-refractory (RAIR) differentiated thyroid cancer (DTC). However, most patients eventually become treatment-resistant and require additional therapies. The phase 3 COSMIC-311 study investigated cabozantinib in patients with RAIR DTC who progressed on lenvatinib, sorafenib, or both and showed that cabozantinib provided substantial clinical benefit. Presented in this study is an analysis of COSMIC-311 based on prior therapy and histology. Methods: Patients were randomized 2:1 (stratification: prior lenvatinib [yes/no]; age [≤65, >65 years]) to oral cabozantinib (60 mg tablet/day) or matched placebo. Eligible patients received 1–2 prior vascular endothelial growth factor receptor-targeting tyrosine kinase inhibitors for DTC (lenvatinib or sorafenib required), had a confirmed DTC diagnosis, and were refractory to or ineligible for radioiodine therapy. For this analysis, progression-free survival (PFS) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 by a blinded independent radiology committee were evaluated by prior therapy (lenvatinib only, sorafenib only, both) and histology (papillary, follicular, oncocytic, poorly differentiated). Results: Two hundred fifty-eight patients were randomized (170 cabozantinib/88 placebo) who previously received sorafenib only (n = 96), lenvatinib only (n = 102), or both (n = 60). The median follow-up was 10.1 months. The median PFS (months) with cabozantinib/placebo was 16.6/3.2 (sorafenib only: hazard ratio [HR] 0.13 [95% confidence interval, CI, 0.06–0.26]), 5.8/1.9 (lenvatinib only: HR 0.28 [95% CI 0.16–0.48]), and 7.6/1.9 (both: HR 0.27 [95% CI 0.13–0.54]). The ORR with cabozantinib/placebo was 21%/0% (sorafenib only), 4%/0% (lenvatinib only), and 8%/0% (both). Disease histology consisted of 150 papillary and 113 follicular, including 43 oncocytic and 36 poorly differentiated. The median PFS (months) with cabozantinib/placebo was 9.2/1.9 (papillary: HR 0.27 [95% CI 0.17–0.43]), 11.2/2.5 (follicular: HR 0.18 [95% CI 0.10–0.31]), 11.2/2.5 (oncocytic: HR 0.06 [95% CI 0.02–0.21]), and 7.4/1.8 (poorly differentiated: HR 0.18 [95% CI 0.08–0.43]). The ORR with cabozantinib/placebo was 15%/0% (papillary), 8%/0% (follicular), 11%/0% (oncocytic), and 9%/0% (poorly differentiated). Safety outcomes evaluated were consistent with those previously observed for the overall population. Conclusions: Results indicate that cabozantinib benefits patients with RAIR DTC, regardless of prior lenvatinib or sorafenib treatments or histology. Clinical Trial Registration Number: NCT03690388. [ABSTRACT FROM AUTHOR]

المؤلفون: Oh, Do‐Youn, Algazi, Alain, Capdevila, Jaume, Longo, Federico, Miller, Wilson, Chun Bing, Jerry Tan, Bonilla, Carlos Eduardo, Chung, Hyun Cheol, Guren, Tormod K., Lin, Chia‐Chi, Motola‐Kuba, Daniel, Shah, Manisha, Hadoux, Julien, Yao, Lili, Jin, Fan, Norwood, Kevin, Lebellec, Loïc

المصدر: Cancer (0008543X); Apr2023, Vol. 129 Issue 8, p1195-1204, 10p

مصطلحات موضوعية: THYROID cancer, CANCER patients, IMMUNE checkpoint inhibitors, PROGRESSION-free survival, PEMBROLIZUMAB, ADVERSE health care events

مستخلص: Background: The authors report results from the thyroid carcinoma cohort of the multicohort phase 2 KEYNOTE‐158 study (NCT02628067), which evaluated pembrolizumab monotherapy in patients with previously treated cancers. Methods: Eligible patients had histologically and/or cytologically confirmed papillary or follicular thyroid carcinoma, failure of or intolerance to prior therapy, and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Patients received pembrolizumab (200 mg) every 3 weeks for up to 35 cycles. The primary end point was objective response rate (ORR) per RECIST v1.1 by independent central review. Results: A total of 103 patients were enrolled and received pembrolizumab. Median duration from first dose to data cutoff (October 5, 2020) was 49.4 (range, 43.9–54.9) months. ORR was 6.8% (95% confidence interval [CI], 2.8%–13.5%), and median duration of response was 18.4 (range, 4.2‒47.2+) months. ORR was 8.7% (95% CI, 2.4%‒20.8%) among patients with programmed cell death ligand 1 (PD‐L1) combined positive score (CPS) ≥1 (n = 46) and 5.7% (95% CI, 1.2%‒15.7%) among patients with PD‐L1 CPS <1 (n = 53). Median overall survival and progression‐free survival were 34.5 (95% CI, 21.2 to not reached) and 4.2 (95% CI, 3.9‒6.2) months, respectively. Treatment‐related adverse events occurred in 69.9% of patients (grade 3‒5, 14.6%). Conclusions: Pembrolizumab demonstrated manageable toxicity and durable antitumor activity in a small subset of patients with advanced thyroid cancer. These results provide evidence of modest antitumor activity in this setting regardless of tumor PD‐L1 expression. Future studies evaluating immune checkpoint inhibitors in patients with differentiated thyroid cancer should focus on biomarker‐driven patient selection or combination of immune checkpoint inhibitors with other agents, in order to achieve higher response rates than observed in this study. Among 103 patients with previously treated papillary or follicular thyroid cancer who received pembrolizumab monotherapy, seven patients (6.8%) had an objective response. Responses occurred regardless of tumor programmed cell death ligand 1 status and were durable. [ABSTRACT FROM AUTHOR]

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المؤلفون: Taylor, Matthew H., Takahashi, Shunji, Capdevila, Jaume, Tahara, Makoto, Leboulleux, Sophie, Kiyota, Naomi, Dutcus, Corina E., Xie, Ran, Robinson, Bruce, Sherman, Steven, Habra, Mouhammed Amir, Elisei, Rossella, Wirth, Lori J.

المصدر: Thyroid; Aug2021, Vol. 31 Issue 8, p1226-1234, 9p

مصطلحات موضوعية: NEUTROPHIL lymphocyte ratio, THYROID cancer, OVERALL survival, PROGNOSIS, PROGRESSION-free survival

مستخلص: Background: Radioiodine-refractory differentiated thyroid cancer (RR-DTC) has a low 10-year patient-survival rate and is challenging to treat. Lenvatinib is a multikinase inhibitor approved for the treatment of RR-DTC. This study aims to assess Eastern Cooperative Oncology Group performance status (ECOG PS) and neutrophil-to-lymphocyte ratio (NLR) as prognostic markers for patients with RR-DTC treated with lenvatinib. Methods: In this retrospective analysis of the Study of (E7080) LEnvatinib in Differentiated Cancer of the Thyroid (SELECT), patients randomly assigned to receive lenvatinib were classified according to baseline ECOG PS (0 or 1) or baseline NLR (≤3 or >3). The effects of baseline ECOG PS and NLR on progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were evaluated. In addition, the effects of baseline ECOG PS on the change in diameter of target lesions and correlations between baseline NLR and the sums of the diameters of target lesions were calculated. Results: Among patients who received lenvatinib, patients with a baseline ECOG PS of 0 had statistically improved PFS (hazard ratio [HR] 0.52; 95% confidence interval [CI 0.35–0.77]; p = 0.001), OS (HR 0.42 [CI 0.26–0.69]; p = 0.0004), and ORR (odds ratio [OR] 3.51 [CI 2.02–6.10]; p < 0.0001) compared with patients with a baseline ECOG PS of 1. Patients who received lenvatinib with a baseline NLR ≤3 also had improved PFS (HR 0.43 [CI 0.29–0.65]; p < 0.0001) and OS (HR 0.48 [CI 0.29–0.78]; p = 0.0029) versus patients with a baseline NLR >3. Moreover, patients with a baseline NLR ≤3 had a trend toward increased ORR (OR 1.57 [CI 0.94–2.64]; p = 0.08) compared with patients with a baseline NLR >3. Treatment-emergent adverse events were generally similar among patients who received lenvatinib, irrespective of patients' ECOG PS at baseline. Conclusion: Lower ECOG PS and NLR may provide prognostic value for improved efficacy in patients with RR-DTC. ClinicalTrials.gov no. NCT01321554. [ABSTRACT FROM AUTHOR]

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المؤلفون: Capdevila, Jaume, Galofré, J. C., Grande, Enrique, Zafón Llopis, C., Ramón y Cajal Asensio, T., Navarro González, Elena, Jiménez-Fonseca, Paula, Santamaría Sandi, J., Gómez Sáez, J. M., Riesco-Eizaguirre, Garcilaso

مصطلحات موضوعية: Differentiated thyroid cancer, Lenvatinib Radioactive iodine-refractory thyroid cancer, Review, Sorafenib, Targeted therapy, Thyroid cancer

الوصف: Thyroid cancer is the single most prevalent endocrine malignancy; differentiated thyroid cancer (DTC) accounts for more than 90 % of all malignancies and its incidence has been rising steadily. For more patients, surgical treatment, radioactive iodine (RAI) ablation, and thyroid-stimulating hormone (TSH) suppressive therapy achieve an overall survival (OS) rate of 97.7 % at 5 years. Nevertheless, locoregional recurrence occurs in up to 20 % and distant metastases in approximately 10 % at 10 years. Two-thirds of these patients will never be cured with radioactive iodine therapy and will become RAI-refractory, with a 3-year OS rate of less than 50 %. Over the last decade, substantial progress has been made in the management of RAI-refractory DTC. Given the controversy in some areas, the Spanish Task Force for Thyroid Cancer on behalf of Spanish Society of Endocrinology Thyroid Cancer Working Group (GTSEEN) and the Spanish Rare Cancer Working Group (GETHI) have created a national joint task force to reach a consensus addressing the most challenging aspects of management in these patients. In this way, multidisciplinary management should be mandatory and nuclear medicine targeted therapy, novel molecular targeted agents, and combinations are currently changing the natural history of RAI-refractory DTC.

العلاقة: http://dx.doi.org/10.1007/s12094-016-1554-5Test; Sí; e-issn: 1699-3055; Clinical and Translational Oncology 19(3): 279-287 (2017); http://hdl.handle.net/10261/198638Test

الإتاحة: https://doi.org/10.1007/s12094-016-1554-5Test
http://hdl.handle.net/10261/198638Test

المؤلفون: Cortés-Mateus, KarEN S., Holub, Katarzyna, Racca, Fabricio, Grau, Juan José, Capdevila, Jaume

المصدر: Oncology Letters; Sep2018, Vol. 16 Issue 3, p4085-4089, 5p, 5 Black and White Photographs, 1 Chart

مصطلحات موضوعية: THYROID cancer treatment, CANCER radiotherapy, PALLIATIVE treatment, DOXORUBICIN, SORAFENIB, THERAPEUTICS

مستخلص: Administration of external beam radiotherapy (EBRT) for a bulky recurrence or primary bulky tumor of differentiated thyroid carcinoma (DTC) is rare. No previous experience is available on the feasibility of administering EBRT simultaneously with systemic treatment with doxorubicin or sorafenib, or both. The present case study reported the results from two different institutions on 5 consecutive patients. Side effects and tolerance to radiotherapy plus systemic treatment with doxorubicin (20 mg/m² intravenously weekly for 6/8 consecutive weeks) or sorafenib (400 mg/12 h orally for 8 weeks) or both, were analyzed in patients with DTC. The local response to radiotherapy and patient outcome was also analyzed. A total of 4 males and 1 female, aged 37‑62 years with cervical bulky mass DTC were included. The pathological tumor types were papillary (2 patients), follicular (2 patients) and medullar thyroid carcinoma (1 patient). The radiated cervical mass was local recurrence in 3 cases and primary tumor in the other two. The total dose of radiotherapy ranged between 50 and 64.8 Gy. Three patients received sorafenib, 1 patient received doxorubicin and 1 patient received both treatments. The total planned dose of radiotherapy was administered to all patients. Grade 2 anemia and erythrodysesthesia was the most frequent toxicity. Only the patient who received doxorubicin plus sorafenib had grade 3 toxicity consisting of lymphopenia, folliculitis and mucositis. All but 1 patient had a good local response to radiotherapy. The administration of EBRT concurrently with sorafenib and doxorubicin to patients with DTC with a bulky cervical mass is feasible. [ABSTRACT FROM AUTHOR]

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المؤلفون: Gupta, Anubha, Jarzab, Barbara, Capdevila, Jaume, Shumaker, Robert, Hussein, Ziad

المصدر: British Journal of Clinical Pharmacology; Jun2016, Vol. 81 Issue 6, p1124-1133, 10p

مصطلحات موضوعية: IODINE isotopes, THYROID cancer, BIOAVAILABILITY, AMINOTRANSFERASES, BILIRUBIN

مستخلص: Aims Lenvatinib was recently approved for the treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). Here, we characterized the pharmacokinetic (PK) profile of lenvatinib and identified intrinsic and extrinsic factors that explain interindividual PK variability in humans. Methods This population PK analysis used pooled data from 15 clinical studies, including eight phase 1 studies in healthy subjects, four phase 1 studies in patients with solid tumours, two phase 2 studies in patients with thyroid cancer and one phase 3 study in patients with RR-DTC. Results The final pooled dataset included data from 779 subjects receiving 3.2-32 mg oral lenvatinib, mainly once daily as tablets or capsules. Lenvatinib PK was best described by a three-compartment model with linear elimination. Lenvatinib absorption was best described by simultaneous first- and zero-order absorption. The population mean value for lenvatinib apparent clearance (CL/F) was 6.56 l h⁻¹ [percent coefficient of variation (%CV) 25.5], and was independent of dose and time. The relative bioavailability of lenvatinib in capsule form was 90% vs. tablets (%CV 30.2). The final PK model included significant but marginal effects of body weight (2.8% of CL/F variation), liver-function markers [alkaline phosphatase (−11.7%) and albumin (−6.3%)] and concomitant cytochrome P450 3A4 inducers (+30%) and inhibitors (−7.8%) on lenvatinib CL/F. Lenvatinib PK was unaffected by pH-elevating agents, dose, age, sex, race, alanine aminotransferase, aspartate aminotransferase or bilirubin levels, or renal function. Conclusions The significant effects of several covariates on lenvatinib PK variability were small in magnitude, and therefore were not considered clinically relevant, or to warrant any dose adjustment. [ABSTRACT FROM AUTHOR]

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المؤلفون: Capdevila, Jaume, Awada, Ahmad, Führer-Sakel, Dagmar, Leboulleux, Sophie, Pauwels, Patrick

المصدر: Cancer Treatment Reviews; May2022, Vol. 106, pN.PAG-N.PAG, 1p

مستخلص: Most malignant thyroid tumours are initially treated with surgery or a combination of surgery and radioactive iodine (RAI) therapy. However, in patients with metastatic disease, many tumours become refractory to RAI, and these patients require alternative treatments, such as locoregional therapies and/or systemic treatment with multikinase inhibitors. Improvements in our understanding of the genetic alterations that occur in thyroid cancer have led to the discovery of several targeted therapies with clinical efficacy. These alterations include NTRK (neurotrophic tyrosine receptor kinase) gene fusions, with the tropomyosin receptor kinase inhibitors larotrectinib and entrectinib both approved by the European Medicines Agency and in other markets worldwide. Inhibitors of aberrant proteins resulting from alterations in RET (rearranged during transfection) and BRAF (B-Raf proto-oncogene) have also shown promising efficacy, and so far have received approval by the US Food and Drug Administration. Selpercatinib, a RET kinase inhibitor, was approved for use in Europe in early 2021. With the discovery of multiple actionable targets, it is imperative that effective testing strategies for these genetic alterations are integrated into the diagnostic armamentarium to ensure that patients who could potentially benefit from targeted treatments are identified. In this review, we offer our recommendations on the optimal testing strategies for detecting genetic alterations in thyroid cancer that have the potential to be targeted by molecular therapy. We also discuss the future of treatments for thyroid cancers, including the use of immune checkpoint inhibitors, and new generations of targeted treatments that are being developed to counter acquired tumour resistance. [ABSTRACT FROM AUTHOR]

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المؤلفون: Stjepanovic, Neda, Capdevila, Jaume

المصدر: Biologics: Targets & Therapy; 2014, Vol. 8, p129-139, 11p

مصطلحات موضوعية: KINASE inhibitors, THYROID cancer treatment, NEOPLASTIC cell transformation, PLACEBOS, CLINICAL trials, THERAPEUTICS

مستخلص: Thyroid cancers are the most frequent neoplasms of the endocrine system and in the initial stages their prognosis is excellent. However, few therapeutic options are available for advanced or metastatic disease. In the last decade, a better understanding of the molecular events involved in the tumorigenesis of thyroid cancers has led to development of new targeted agents for the management of advanced and refractory disease. Multikinase inhibitors that are able to block pathways involved in the proliferation, invasion, and neoangiogenesis of thyroid cancer have been the most widely studied. After an international effort to identify and recruit sufficient patients, four placebo-controlled studies of multikinase inhibitors have been completed. These trials have led to the approval of the first agents with activity in advanced medullary thyroid cancers, which will probably change the landscape of treatment for iodine-refractory differentiated thyroid cancer in the near future. The purpose of this paper is to review the development of targeted agents for thyroid malignancy, with a special focus on lenvatinib, a multikinase inhibitor. [ABSTRACT FROM AUTHOR]

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المؤلفون: Capdevila, Jaume¹ jacapdevila@vhebron.net, Iglesias, Lara², Halperin, Irene³, Segura, Ángel⁴, Martínez-Trufero, Javier⁵, Vaz, Maria Ángeles⁶, Corral, Jesús⁷, Obiols, Gabriel⁸, Grande, Enrique⁶, Grau, Juan Jose⁹, Tabernero, Josep¹

المصدر: Endocrine-Related Cancer. Apr2012, Vol. 19 Issue 2, p209-216. 8p.

مصطلحات موضوعية: *THYROID cancer, *PROTEIN-tyrosine kinase inhibitors, *RETROSPECTIVE studies, *THYROID cancer treatment, *ANTINEOPLASTIC agents, *REGRESSION quantiles, *PROGNOSIS, *THERAPEUTICS

مستخلص: Although thyroid cancer usually has an excellent prognosis, few therapeutic options are available in the refractory setting. Based on the recent results of phase II studies with tyrosine kinase inhibitors, we designed a retrospective analysis of patients with metastatic thyroid cancer treated with sorafenib in seven Spanish referral centers. Consecutive patients with progressive metastatic thyroid cancer (papillary, follicular, medullary, and anaplastic) not suitable for curative surgery, radioactive-iodine therapy, or radiotherapy were treated with sorafenib 400?mg twice a day. The primary end point was objective response rate (RR). Secondary end points included toxicity, median progression-free survival (mPFS), median overall survival (mOS), and correlation between tumor marker levels (thyroglobulin, calcitonin, and carcinoembryonic antigen) and efficacy. Between June 2006 and January 2010, 34 patients were included in the study. Sixteen patients presented differentiated thyroid carcinomas (DTC) of which seven (21%) were papillary, nine (26%) follicular, 15 (44%) medullary (MTC), and three (9%) were anaplastic (ATC). Eleven (32%) patients achieved partial response and 14 (41%) had stable disease beyond 6 months. Regarding histological subtype, RRs were 47% (seven of 15) for MTC, 19% (three of 16) for DTC, and 33% (one of three) for ATC. With a median follow-up of 11.5 months, mPFS were 13.5, 10.5, and 4.4 months for DTC, MTC, and ATC respectively. Tumor markers were evaluated in 22 patients, and a statistically significant association was observed between RR and decrease in tumor marker levels >50% (P=0.033). In this retrospective trial, sorafenib showed antitumor efficacy in all histological subtypes of thyroid cancer, warranting further development in this setting. [ABSTRACT FROM AUTHOR]