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Tyrosine Kinase Inhibitor Treatments in Patients with Metastatic Thyroid Carcinomas: a Retrospective Study of the TUTHYREF Network

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Tyrosine Kinase Inhibitor Treatments in Patients with Metastatic Thyroid Carcinomas: a Retrospective Study of the TUTHYREF Network M-H Massicotte and others TKI treatment in metastatic 170:4 575–582 Clinical Study thyroid carcinoma Tyrosine kinase inhibitor treatments in patients with metastatic thyroid carcinomas: a retrospective study of the TUTHYREF network Marie-He´ le` ne Massicotte1,2, Maryse Brassard3,Me´ de´ ric Claude-Desroches4, Isabelle Borget5, Franc¸oise Bonichon6, Anne-Laure Giraudet7, Christine Do Cao8, Ce´ cile N Chougnet1, Sophie Leboulleux1, Eric Baudin1, Martin Schlumberger1 and Christelle de la Fouchardie` re9 1Department of Nuclear Medicine and Endocrine Oncology, Institut Gustave Roussy, Universite´ Paris-Sud, 114 Rue Edouard Vaillant, 94805 Villejuif, France, 2Endocrinology Service, Department of Medicine, Centre Hospitalier Universitaire de Sherbrooke, 3001 12e Avenue Nord, Sherbrooke, Que´ bec, Canada J1H 5N3, 3Endocrinology Service, Department of Medicine, Centre Hospitalier Universitaire de Que´ bec, Universite´ Laval, 1401 18e Rue, Que´ bec City, Que´ bec, Canada G1J 1Z4, 4Department of Radiology, Institut Universitaire de Cardiologie et de Pneumologie de Que´ bec, 2725 Chemin Sainte-Foy, Que´ bec City, Que´ bec, Canada G1V 4G5, 5Department of Biostatistic and Epidemiology, Institut Gustave Roussy, Universite´ Paris-Sud, 114 Rue Edouard Vaillant, 94805 Villejuif, France, Correspondence 6Department of Nuclear Medicine, Institut Bergonie´ , 229 Cours de l’Argonne, 33000 Bordeaux, France, should be addressed 7Department of Nuclear Medicine, Institut Curie, Hoˆ pital Rene´ Huguenin, 35 Rue Dailly, 92210 Saint-Cloud, France, to M-H Massicotte 8Department of Endocrinology, Hoˆ pital Huriez, Centre Hospitalier Re´ gional Universitaire de Lille, 2 Avenue Oscar Email Lambret, 59037 Lille, France and 9Consortium Cancer Thyroı¨dien, Hospices Civils de Lyon-Centre Anti-Cance´ reux marie-helene.massicotte@ Le´ on-Be´ rard, 28 Rue Laennec, 69008 Lyon, France usherbrooke.ca Abstract Objective: Tyrosine kinase inhibitors (TKIs) are used to treat patients with advanced thyroid cancers. We retrospectively investigated the efficacy of TKIs administered outside of clinical trials in metastatic sites or locally advanced thyroid cancer patients from five French oncology centers. Design and methods: There were 62 patients (37 men, mean age: 61 years) treated with sorafenib (62%), sunitinib (22%), European Journal of Endocrinology and vandetanib (16%) outside of clinical trials; 22 had papillary, five had follicular, five had Hu¨ rthle cell, 13 had poorly differentiated, and 17 had medullary thyroid carcinoma (MTC). Thirty-three, 25, and four patients were treated with one, two, and three lines of TKIs respectively. Primary endpoints were objective tumor response rate and progression-free survival (PFS). Sequential treatments and tumor response according to metastatic sites were secondary endpoints. Results: Among the 39 sorafenib and 12 sunitinib treatments in differentiated thyroid carcinoma (DTC) patients, partial response (PR) rate was 15 and 8% respectively. In the 11 MTC patients treated with vandetanib, 36% had PR. Median PFS was similar in second-line compared with first-line sorafenib or sunitinib therapy (6.7 vs 7.0 months) in DTC patients, but there was no PR with second- and third-line treatments. Bone and pleural lesions were the most refractory sites to treatment. Conclusions: This is the largest retrospective study evaluating TKI therapies outside of clinical trials. DTC patients treated with second-line therapy had stable disease as best response, but had a similar median PFS compared with the first-line treatment. European Journal of Endocrinology (2014) 170, 575–582 Introduction Approximately 5–10% of patients with differentiated disease (1). Medullary thyroid carcinomas (MTCs) account thyroid cancer (DTC) eventually develop metastatic for 5–8% of all thyroid cancers, and distant metastases that disease, of whom two-thirds present with iodine refractory are present at diagnosis in 7–23% of patients represent the www.eje-online.org Ñ 2014 European Society of Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/EJE-13-0825 Printed in Great Britain Downloaded from Bioscientifica.com at 10/02/2021 06:17:56PM via free access Clinical Study M-H Massicotte and others TKI treatment in metastatic 170:4 576 thyroid carcinoma main cause of cancer-related death (2). These patients evaluated tumor response rate according to metastatic often suffer from a progressive course despite local sites and sequential treatments in advanced thyroid treatment modalities such as radiofrequency ablation cancer patients from five referral centers of the French or external beam radiation therapy, and cytotoxic TUTHYREF network. chemotherapies have shown disappointing results. In recent years, several trials have demonstrated the efficacy of tyrosine kinase inhibitors (TKIs) in the treatment Subjects and methods of metastatic or locally advanced thyroid carcinomas (3). In phase II clinical trials, a partial response (PR) rate of Patients about 20% was seen in DTC patients treated with sorafenib All patients with metastatic or locally advanced DTC or (4, 5) or with sunitinib (6, 7). In a phase III trial, sorafenib advanced MTC who were treated with a TKI outside a significantly improved the median progression-free clinical trial in one of the five TUTHYREF participating survival (PFS) from 5.8 months in the placebo group to centers were retrospectively reviewed: these adult patients 10.8 months (hazard ratio (HR)Z0.587, P!0.0001) (8). had at least one measurable lesion and had a baseline and at Vandetanib also produced a significant prolongation of PFS least one follow-up imaging study during TKI treatment in in DTC patients (HRZ0.63, PZ0.008) (9). Sorafenib was order to assess morphological tumor response. All patients approved for the treatment of refractory advanced provided informed consent and the study was approved by DTC by the US Food and Drug Administration (FDA) in research ethics boards of the participating centers. November 2013, but to date no TKI is approved by the European Medicine Agency (EMA) for DTC treatment. Clinical benefit was also seen in MTC patients treated Study endpoints with sorafenib and sunitinib in phase II studies (6, 7, 10), The primary endpoints were tumor response rate and PFS and a phase III study showed that vandetanib prolonged in patients treated with TKIs administered outside of median PFS from 19.3 months to more than 30.5 months clinical trials. Secondary endpoints were tumor response (HRZ0.46, P!0.001) with a PR rate of 45% (11). This rate and PFS with sequential TKI treatments (as second- study led to approval of vandetanib for the treatment of and third-line therapies), and tumor response rate advanced MTC by the FDA in April 2011 and by the EMA according to organ-specific metastatic sites. Only treat- in February 2012. In a phase III trial, cabozantinib ments given outside of clinical trials were analyzed for this improved PFS from 4 to 11 months and PR was observed European Journal of Endocrinology study, but TKI treatments administered in the frame of in 28% of cases (12). Subsequently, the FDA approved clinical trials were considered while evaluating sequential cabozantinib for the treatment of advanced MTC in TKI treatments, counting as first-line treatment. Dose- November 2012. limiting toxicities (DLTs), defined as requiring dose In the absence of labeled drug, inclusion in a clinical reduction or treatment withdrawal, were colligated and trial should always be privileged for patients with graded according to the US National Cancer Institute refractory and progressive thyroid carcinoma. Unfortu- Common Terminology Criteria for Adverse Events V4.0. nately, in clinical practice, a substantial proportion of patients cannot be included in any trial for various reasons, Morphological assessment such as the unavailability of a protocol or the presence of exclusion criteria, and this led to the off-label use of TKIs in Computed tomography (CT) scans were used to determine referral French centers, part of the Tumeurs Re´fractaires de tumor responses during treatment with TKI, according to la Thyroı¨de (TUTHYREF) network. the Response Evaluation Criteria in Solid Tumors (RECIST) Targeted therapies are increasingly prescribed in V1.1 (13). Target lesions (TLs) were defined as soft tissue patients with advanced or metastatic thyroid carcinoma, metastatic lesions that could be measured in at least one and only little is known about their efficacy according to dimension, with the longest diameter of at least 1 cm for organ-specific metastatic sites and in sequential treat- most sites and 1.5 cm for lymph nodes. The soft tissue ment, as second- and third-line TKI therapy. This is indeed component of a bone lesion with a longest diameter of a major issue, because all TKIs used in these patients more than 1 cm could be considered as a TL and previously belong to the same family of anti-angiogenic drugs. We irradiated bone metastases were not considered as TLs. hereby report the efficacy of sorafenib, sunitinib, and Other lesions that were less than these dimensions or vandetanib administered outside of clinical trials and we that were not measurable were considered as non-TLs. www.eje-online.org Downloaded from Bioscientifica.com at 10/02/2021 06:17:56PM via free access Clinical Study M-H Massicotte and others TKI treatment in metastatic 170:4 577 thyroid carcinoma All CT scans were reviewed by an independent radiologist the end of this article and Supplementary Table 1), but (M Claude-Desroches) who was not aware of the outcome only treatments given outside of clinical trials were of any treatment. Tumor response was defined as analyzed for this study, totalizing 69 TKI treatments. progressive disease (PD) if there was R20% increase in Baseline clinical characteristics of patients and treatments the sum of the diameters of TLs or appearance of new administered are detailed in Tables 1 and 2. metastatic lesions, as stable disease (SD) if there was a According to RECIST, 51 (82%) patients had a PD over change between C19 and K29% and PR was defined by a 12 months before treatment initiation, six (10%) had PD R decrease of 30% in the sum of the diameters of TLs.
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