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Early Prediction of Lenvatinib Treatment Efficacy by Using 18F-FDG PET/CT in Patients with Unresectable Or Advanced Thyroid Carc

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Early Prediction of Lenvatinib Treatment Efficacy by Using 18F-FDG PET/CT in Patients with Unresectable Or Advanced Thyroid Carc Open access Protocol BMJ Open: first published as 10.1136/bmjopen-2017-021001 on 30 August 2018. Downloaded from Early prediction of lenvatinib treatment efficacy by using18 F-FDG PET/CT in patients with unresectable or advanced thyroid carcinoma that is refractory to radioiodine treatment: a protocol for a non-randomized single-arm multicenter observational study Satoshi Takeuchi,1 Tohru Shiga,2 Kenji Hirata,2 Jun Taguchi,1 Keiichi Magota,3 Shin Ariga,1 Tomohiro Gouda,1 Yoshihito Ohhara,1 Rio Homma,1 Yasushi Shimizu,1 Ichiro Kinoshita,1 Yasushi Tsuji,4 Akihiro Homma,5 Hiroaki Iijima,6 Nagara Tamaki,2 Hirotoshi Dosaka-Akita1 To cite: Takeuchi S, Shiga T, ABSTRACT Strengths and limitations of this study Hirata K, et al. Early prediction Introduction Lenvatinib, an oral molecular targeted drug, of lenvatinib treatment efficacy is used to treat patients with unresectable or advanced by using 18F-FDG PET/CT in ► The aim of this study is to determine whether thyroid carcinoma that is refractory to radioiodine 18 patients with unresectable F-fluorodeoxyglucose (FDG) positron emission or advanced thyroid treatment. Effective methods for evaluating molecular tomography (PET)/CT 1 week after commencing carcinoma that is refractory targeted drugs are a critical unmet need owing to their lenvatinib can predict the treatment outcome pro- to radioiodine treatment: a expensive costs and unique adverse events. The aim of spectively. A study of this kind has not been previ- 18 protocol for a non-randomized this study is to determine whether F-fluorodeoxyglucose ously attempted. single-arm multicenter http://bmjopen.bmj.com/ (FDG) positron emission tomography (PET)/CT at 1 week ► If FDG PET/CT at an early time-point after treatment observational study. BMJ Open after commencing lenvatinib can predict treatment initiation can predict outcomes, this can be useful 2018;8:e021001. doi:10.1136/ outcomes. bmjopen-2017-021001 for avoiding adverse effects and high treatment Design and methods This study is planned as a non- costs in advance. ► Prepublication history for randomised single-arm multicentre study; patients ► Patient recruitment may be difficult because differ- this paper is available online. with pathologically confirmed differentiated thyroid entiated thyroid carcinoma is a rare malignancy, es- To view these files, please visit carcinoma (DTC) with lesions that are refractory to pecially as patients are required to be refractory to the journal online (http:// dx. doi. radioiodine treatment are eligible. The main exclusion radioiodine treatment. org/ 10. 1136/ bmjopen- 2017- criteria are medullary or anaplastic carcinoma, prior ► FDG PET/CT must be performed using the same de- 021001). on September 27, 2021 by guest. Protected copyright. treatment with chemotherapy, poor general condition vice despite the multicentre nature of the study. Received 6 December 2017 and thromboembolism-requiring treatment. Patients to ► FDG PET/CT and contrast-enhanced CT cannot be Revised 16 June 2018 be included in the study will be treated with lenvatinib performed simultaneously because of radiation ex- Accepted 3 August 2018 and undergo FDG-PET/CT examination twice: before and posure and Japanese national health insurance sys- 1 week after the initiation of treatment. Contrast-enhanced tem restrictions. CT, the gold standard for evaluation, will be performed at least 4 weeks after the initiation of treatment. The primary objective is to evaluate the ability of the lesion maximum the publication of the data in a peer-reviewed journal. The study will be implemented and reported in line with the © Author(s) (or their standard uptake value for FDG PET/CT performed 1 week SPIRIT statement. employer(s)) 2018. Re-use after the initiation of treatment to predict outcomes permitted under CC BY-NC. No compared with the response evaluation obtained via Trial registration number UMIN000022592. commercial re-use. See rights contrast-enhanced CT performed at least 4 weeks after the and permissions. Published by initiation of treatment. BMJ. Ethics and dissemination This study is conducted in INTRODUCTIon For numbered affiliations see accordance with the Declaration of Helsinki and has The incidence of thyroid carcinoma has been 1 end of article. received ethical approval from the institutional review increasing steadily in most countries. Approx- Correspondence to board of the Hokkaido University Hospital (approval imately 298 000 people were estimated to Dr Satoshi Takeuchi; number: 015-402). The results of this study will be have been newly diagnosed with thyroid carci- stakeuch@ med. hokudai. ac. jp disseminated through a presentation at a conference and noma worldwide in 2012.2 There are several Takeuchi S, et al. BMJ Open 2018;8:e021001. doi:10.1136/bmjopen-2017-021001 1 Open access BMJ Open: first published as 10.1136/bmjopen-2017-021001 on 30 August 2018. Downloaded from histological types of thyroid carcinoma: differentiated The exclusion criteria are as follows: medullary or (including papillary, follicular and Hürthle cell), medullary anaplastic carcinoma, prior treatments (including and anaplastic.3 Among these, differentiated thyroid carci- molecular targeted agents and/or conventional chemo- noma (DTC) consisting of papillary and follicular carci- therapy), other synchronous malignancies other than noma accounts for 80%–90% of all thyroid carcinomas. early stage lesions curable via endoscopy, fasting blood DTC accounted for social costs totalling approximately glucose ≥150 mg/dL; ECOG PS 3–4; thromboembolism $1.6 billion in the USA in 2013.4 requiring treatment, pregnant or nursing women, and Surgical resection of the entire tumour is the main- any other reasons as judged by the investigators. stay initial treatment, and it is also important to remove the residual thyroid gland. After surgery, radiotherapy Study design followed by thyroid-stimulating hormone (TSH) This will be a non-randomised multicentre study. The suppression therapy are normally administered; the 5 study protocol has been approved by all relevant institu- recurrence rate in patients with DTC is 7%–23%. Radio- tional review boards; all recruited patients are required to active iodine therapy is usually applied immediately after provide written informed consent. This trial is registered the surgery or after the detection of metastatic disease. in the University Hospital Medical Information Network Chemotherapy is performed for patients with DTC (UMIN) Clinical Trials Registry (number 000022592), refractory to radioiodine treatment. Although tradi- and is being conducted in accordance with the Declara- tional cytotoxic agents have limited efficacy, advances tion of Helsinki. Patient recruitment commenced on 1 in molecular genetics have rendered DTC treatable by 6 June 2016 and will continue through 31 March 2019. The targeting various oncogenic pathways. As such, two data are estimated to be available no earlier than April oral molecular targeted drugs, sorafenib and lenva- 7 2020 considering the median PFS of patients receiving tinib, have emerged in recent years ; however, there are lenvatinib. several pitfalls when using molecular targeted drugs, Eligible patients will undergo FDG PET/CT, including high costs, unique adverse events and the lack contrast-enhanced CT, blood tests for free tri-iodothy- of methods to predict their efficacy. Although there are ronine (fT3), free thyroxine (fT4), TSH, thyroglobulin no trials comparing these two drugs directly, lenvatinib (TG) and other baseline values within 28 days prior to shows a better response rate (RR) and progression-free the initiation of treatment. Next, eligible patients will survival (PFS), and therefore appears to be used more receive treatment with oral lenvatinib 24 mg once daily. frequently in clinical practice. One week after treatment initiation, patients will undergo Nuclear imaging, including 18F-fluorodeoxyglucose FDG PET/CT and repeat blood testing. Contrast-en- (FDG) positron emission tomography (PET)/CT, can be hanced CT will be performed at least 4 weeks after the suitable for earlier evaluation of tumour response than initiation of treatment as the gold standard for evalua- http://bmjopen.bmj.com/ conventional CT because PET/CT visualises pathophysi- tion. Treatment response will further be confirmed by ological function while CT alone determines tumour size. additional CT performed at least 8 weeks thereafter. FDG reflects glucose metabolism, which is controlled by Patients will be observed until disease progression or the phosphatidylinositol-3-kinase/Akt (also known as death (see figure 1). the protein kinase B) pathway. As lenvatinib inhibits this pathway upstream,8 its therapeutic effects can be detected as a decrease of FDG uptake on PET/CT. Refractoriness to radioiodine treatment The aim of this study is to determine whether FDG In this study, a patient is considered refractory to radioio- PET/CT performed 1 week after the initiation of lenva- dine treatment if any of the following apply: on September 27, 2021 by guest. Protected copyright. tinib can predict the treatment outcomes in patients with ► At least one measurable lesion without iodine uptake unresectable or advanced DTC that is refractory to radio- is visible on any radioiodine scan. iodine treatment. ► At least one measurable lesion has progressed after radioiodine therapy despite radioiodine avidity at the time of treatment. METHODS AND ANALYSIS ► Progression persists despite a cumulative activity of Patients radioiodine that is >400 mCi
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