Download PDF
CC BY-NC-ND 4.0 · Horm Metab Res 2021; 53(03): 149-160
DOI: 10.1055/a-1380-4154
Review

Questions and Controversies in the Clinical Application of Tyrosine Kinase Inhibitors to Treat Patients with Radioiodine-Refractory Differentiated Thyroid Carcinoma: Expert Perspectives

Frederik A. Verburg
1   Department of Nuclear Medicine, University Hospital Marburg, Marburg, Germany
2   Erasmus Medical Center, Department of Radiology and Nuclear Medicine, Rotterdam, The Netherlands
,
Holger Amthauer
3   Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Nuclear Medicine, Berlin, Germany
,
Ina Binse†   †
4   Department of Nuclear Medicine, University Clinic Essen, Essen, Germany
,
Ingo Brink
5   Department of Medical Diagnostics and Therapy, Ernst von Bergmann Hospital Potsdam, Potsdam, Germany
,
Andreas Buck
6   Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany
,
Andreas Darr
7   Department of Nuclear Medicine, University Hospital Jena, Jena, Germany
,
Christine Dierks
8   Department of Medical Oncology, University Hospital Freiburg, Freiburg, Germany
,
Christine Koch
9   Department of Gastroenterology, Hepatology, and Endocrinology, University Clinic Frankfurt, Frankfurt Am Main, Germany
,
Ute König
10   Department of Gastroenterology and Endocrinology, University of Göttingen, Göttingen, Germany
,
Michael C. Kreissl
11   Division of Nuclear Medicine, Department of Radiology and Nuclear Medicine, Otto von Guericke University Magdeburg, Magdeburg, Germany
,
Markus Luster
1   Department of Nuclear Medicine, University Hospital Marburg, Marburg, Germany
,
Christoph Reuter
12   Department of Palliative Care, Hannover Medical School, Hannover, Germany
,
Klemens Scheidhauer
13   Interdisclipinary Endocrine Center, Technical University of Munich, Munich, Germany
,
Holger Sven Willenberg 
14   Division of Endocrinology and Metabolism, Medical University of Rostock, Rostock, Germany
,
Andreas Zielke
15   Department of Endocrine Surgery, Diakonie Klinikum Stuttgart, Stuttgart, Germany
,
Matthias Schott
16   Division of Endocrinology, University Hospital Düsseldorf, Düsseldorf, Germany
› Author Affiliations Funding Eisai GmbH, Frankfurt, Germany.
› Further Information
Also available at
   Permissions and Reprints

Abstract

Notwithstanding regulatory approval of lenvatinib and sorafenib to treat radioiodine-refractory differentiated thyroid carcinoma (RAI-R DTC), important questions and controversies persist regarding this use of these tyrosine kinase inhibitors (TKIs). RAI-R DTC experts from German tertiary referral centers convened to identify and explore such issues; this paper summarizes their discussions. One challenge is determining when to start TKI therapy. Decision-making should be shared between patients and multidisciplinary caregivers, and should consider tumor size/burden, growth rate, and site(s), the key drivers of RAI-R DTC morbidity and mortality, along with current and projected tumor-related symptomatology, co-morbidities, and performance status. Another question involves choice of first-line TKIs. Currently, lenvatinib is generally preferred, due to greater increase in progression-free survival versus placebo treatment and higher response rate in its pivotal trial versus that of sorafenib; additionally, in those studies, lenvatinib but not sorafenib showed overall survival benefit in subgroup analysis. Whether recommended maximum or lower TKI starting doses better balance anti-tumor effects versus tolerability is also unresolved. Exploratory analyses of lenvatinib pivotal study data suggest dose-response effects, possibly favoring higher dosing; however, results are awaited of a prospective comparison of lenvatinib starting regimens. Some controversy surrounds determination of net therapeutic benefit, the key criterion for continuing TKI therapy: if tolerability is acceptable, overall disease control may justify further treatment despite limited but manageable progression. Future research should assess potential guideposts for starting TKIs; fine-tune dosing strategies and further characterize antitumor efficacy; and evaluate interventions to prevent and/or treat TKI toxicity, particularly palmar-plantar erythrodysesthesia and fatigue.

Key words

multi-kinase inhibitors - treatment initiation and discontinuation - dosing - second-line therapy - lenvatinib - sorafenib

† In memoriam. This paper is dedicated to the memory of our colleague, Dr. Ina Binse, who passed away during the development of the manuscript.


Supplementary Material



Publication History

Received: 26 April 2020

Accepted after revision: 26 January 2021

Article published online:
02 March 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Luster M, Aktolun C, Amendoeira I. et al. European perspective on 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: proceedings of an interactive international Symposium. Thyroid 2019; 29: 7-26
    CrossrefPubMedGoogle Scholar
  • 2 Van Nostrand D. Radioiodine refractory differentiated thyroid cancer: time to update the classifications. Thyroid 2018; 28: 1083-1093
    CrossrefPubMedGoogle Scholar
  • 3 Haugen BR, Alexander EK, Bible KC. et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 2016; 26:: 1-133
    CrossrefPubMedGoogle Scholar
  • 4 Gild ML, Topliss DJ, Learoyd D. et al. Clinical guidance for radioiodine refractory differentiated thyroid cancer. Clin Endocrinol 2018; 88: 529-537
    CrossrefPubMedGoogle Scholar
  • 5 Berdelou A, Lamartina L, Klain M. et al. Treatment of refractory thyroid cancer. Endocr Relat Cancer 2018; 25: R209-R223
    CrossrefPubMedGoogle Scholar
  • 6 Gosain R, Alexander JS, Gill A. et al. Radioactive iodine-refractory differentiated thyroid cancer in the elderly. Curr Oncol Rep 2018; 20: 82
    CrossrefPubMedGoogle Scholar
  • 7 Brose MS, Nutting CM, Jarzab B. et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet 2014; 384: 319-328
    CrossrefPubMedGoogle Scholar
  • 8 Schlumberger M, Tahara M, Wirth LJ. et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. New Engl J Med 2015; 372: 621-630
    CrossrefPubMedGoogle Scholar
  • 9 Brose MS, Worden FP, Newbold KL. et al. Effect of age on the efficacy and safety of lenvatinib in radioiodine-refractory differentiated thyroid cancer in the Phase III SELECT Trial. J Clin Oncol 2017; 35: 2692-2699
    CrossrefPubMedGoogle Scholar
  • 10 Eisai Inc.. Lenvima (lenvatinib) Summary of Product Characteristics
    PubMed
  • 11 Bayer Healthcare. Nexavar (sorafenib) Summary of Product Characteristics
    PubMed
  • 12 Haddad RI, Schlumberger M, Wirth LJ. et al. Incidence and timing of common adverse events in lenvatinib-treated patients from the SELECT trial and their association with survival outcomes. Endocrine 2017; 56: 121-128
    CrossrefPubMedGoogle Scholar
  • 13 Yu ST, Ge JN, Luo JY. et al. Treatment-related adverse effects with TKIs in patients with advanced or radioiodine refractory differentiated thyroid carcinoma: A systematic review and meta-analysis. Cancer Manag Res 2019; 11: 1525-1532
    CrossrefPubMedGoogle Scholar
  • 14 Giani C, Valerio L, Bongiovanni A. et al. Safety and quality of life data from an Italian expanded access program of lenvatinib for treatment of thyroid cancer. Thyroid. 2020; DOI: 10.1089/thy.2020.0276.
    CrossrefPubMedGoogle Scholar
  • 15 Tuttle RM, Brose MS, Grande E. et al. Novel concepts for initiating multitargeted kinase inhibitors in radioactive iodine refractory differentiated thyroid cancer. Best Pract Res Clin Endocrinol Metab 2017; 31: 295-305
    CrossrefPubMedGoogle Scholar
  • 16 Masaki C, Sugino K, Saito N. et al. Efficacy and limitations of lenvatinib therapy for radioiodine-refractory differentiated thyroid cancer: real-world experiences. Thyroid 2020; 30: 214-221
    CrossrefPubMedGoogle Scholar
  • 17 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma (NCCN Evidence Blocks. Version 2.2020 – 7 August 2020)
    PubMed
  • 18 Kreissl MC, Janssen MJR, Nagarajah J.. Current treatment strategies in metastasized differentiated. thyroid cancer. J Nucl Med 2019; 60: 9-15
    PubMedGoogle Scholar
  • 19 Eisenhauer EA, Therasse P, Bogaerts J. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-247
    CrossrefPubMedGoogle Scholar
  • 20 Jaber T, Waguespack SG, Cabanillas ME. et al. Targeted therapy in advanced. thyroid cancer to resensitize tumors to radioactive iodine. J Clin Endocrinol Metab 2018; 103: 3698-3705
    PubMedGoogle Scholar
  • 21 Manohar PM, Beesley LJ, Bellile EL. et al. Prognostic value of FDG-PET/CT metabolic parameters in metastatic radioiodine-refractory differentiated thyroid cancer. Clin Nucl Med 2018; 43: 641-647
    CrossrefPubMedGoogle Scholar
  • 22 Oken MM, Creech RH, Tormey DC. et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group Am J Clin Oncol 1982; 5: 649-655
    CrossrefPubMed
  • 23 Berdelou A, Borget I, Godbert Y. et al. Lenvatinib for the treatment of radioiodine-refractory. thyroid cancer in real-life practice. Thyroid 2018; 28: 72-78
    PubMedGoogle Scholar
  • 24 Locati LD, Piovesan A, Durante C. et al. Real-world efficacy and safety of lenvatinib: data from a compassionate use in the treatment of radioactive iodine-refractory differentiated thyroid cancer patients in Italy. Eur J Cancer 2019; 118: 35-40
    CrossrefPubMedGoogle Scholar
  • 25 Jerkovich F, Califano I, Bueno F. et al. Real-life use of lenvatinib in patients with differentiated thyroid cancer: experience from Argentina. Endocrine 2020; 69: 142-148
    CrossrefPubMedGoogle Scholar
  • 26 Kish JK, Chatterjee D, Wan Y. et al. Lenvatinib and subsequent therapy for radioactive iodine-refractory differentiated thyroid cancer: A real-world study of clinical effectiveness in the United States. Adv Ther 2020; 37: 2841-2852
    CrossrefPubMedGoogle Scholar
  • 27 De Leo S, Di Stefano M, Persani L. et al. Lenvatinib as first-line treatment for advanced thyroid cancer: long progression-free survival. Endocrine 2020; DOI: 10.1007/s12020-020-02477-0.
    CrossrefPubMedGoogle Scholar
  • 28 Okamoto K, Ikemori-Kawada M, Jestel A. et al. Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization. ACS Med Chem Lett 2015; 6: 89-94
    CrossrefPubMedGoogle Scholar
  • 29 Tsoli M, Alexandraki KI, Spei ME. et al. Anti-tumor activity and safety of multikinase inhibitors in advanced and/or metastatic thyroid cancer: a systematic review and network meta-analysis of randomized controlled trials. Horm Metab Res 2020; 52: 25-31
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Schlumberger M, Tahara M, Wirth LJ. Lenvatinib in radioiodine-refractory thyroid cancer. New Engl J Med 2015; 372: 1868
    CrossrefPubMedGoogle Scholar
  • 31 Robinson B, Schlumberger M, Wirth LJ. et al. Characterization of tumor size changes over time from the phase 3 study of lenvatinib in thyroid cancer. J Clin Endocrinol Metab 2016; 101: 4103-4109
    CrossrefPubMedGoogle Scholar
  • 32 Tahara M, Brose MS, Wirth LJ. et al. Impact of dose interruption on the efficacy of lenvatinib in a phase 3 study in patients with radioiodine-refractory differentiated thyroid cancer. Eur J Cancer 2019; 106: 61-68
    CrossrefPubMedGoogle Scholar
  • 33 Giani C, Valerio L, Pieruzzi L et al. Hypertension, nausea, anorexia, and weight loss were significantly associated with better progression-free survival in patients with radioiodine-refractory differentiated thyroid carcinoma treated with lenvatinib. European Society of Medical Oncology, 19–23 October 2018, Munich, Germany
    PubMed
  • 34 Wirth LJ, Tahara M, Robinson B. et al. Treatment-emergent hypertension and efficacy in the phase 3 Study of (E7080) lenvatinib in differentiated cancer of the thyroid (SELECT). Cancer 2018; 124: 2365-2372
    CrossrefPubMedGoogle Scholar
  • 35 Resteghini C, Cavalieri S, Galbiati D. et al. Management of tyrosine kinase inhibitors (TKI) side effects in differentiated and medullary thyroid cancer patients. Best Pract Res Clin Endocrinol Metab 2017; 31: 349-361
    CrossrefPubMedGoogle Scholar
  • 36 Resteghini C, Locati LD, Bossi P. et al. Do not throw the baby out with the bathwater: SELECT a personalized, de-escalated lenvatinib schedule allows response in locally advanced DTC while controlling major drug-related bleeding. Ann Oncol 2017; 28: 2321-2322
    CrossrefPubMedGoogle Scholar
  • 37 Dadu R, Waguespack SG, Sherman SI. et al. Efficacy and tolerability of different starting doses of sorafenib in patients with differentiated thyroid cancer. Oncologist 2014; 19: 477-482
    CrossrefPubMedGoogle Scholar
  • 38 Chen L, Shen Y, Luo Q. et al. Response to sorafenib at a low dose in patients with radioiodine-refractory pulmonary metastases from papillary thyroid carcinoma. Thyroid 2011; 21: 119-124
    CrossrefPubMedGoogle Scholar
  • 39 Lin CY, Chang JS, Huang SM. et al. Experience of sorafenib treatment in differentiated thyroid cancer from Taiwan. J Formos Med Assoc 2020; 120: 189-195. DOI: 10.1016/j.jfma.2020.04.021 .
    CrossrefPubMedGoogle Scholar
  • 40 Ogawa-Morita T, Sano Y, Okano T. et al. Validation of a liquid chromatography-tandem mass spectrometric assay for quantitative analysis of lenvatinib in human plasma. Int J Anal Chem 2017; 2017: 2341876
    CrossrefPubMedGoogle Scholar
  • 41 Watanabe Y, Doki K, Sekine I. et al. High-performance liquid chromatography for therapeutic drug monitoring of serum lenvatinib. Ther Drug Monit 2020; 42: 554-558
    CrossrefPubMedGoogle Scholar
  • 42 Nagahama M, Ozeki T, Suzuki A. et al. Association of lenvatinib trough plasma concentrations with lenvatinib-induced toxicities in Japanese patients with thyroid cancer. Med Oncol 2019; 36: 39
    CrossrefPubMedGoogle Scholar
  • 43 Tamai T, Hayato S, Hojo S. et al. Dose finding of lenvatinib in subjects with advanced hepatocellular carcinoma based on population pharmacokinetic and exposure-response analyses. J Clin Pharmacol 2017; 57: 1138-1147
    CrossrefPubMedGoogle Scholar
  • 44 Bellesoeur A, Carton E, Mir O. et al. Critical role of sorafenib exposure over time for its antitumor activity in thyroid cancer. Invest New Drugs 2014; 32: 569-572
    CrossrefPubMedGoogle Scholar
  • 45 Jerkovich F, Garcia Falcone MG, Pitoia F.. The experience of an Endocrinology Division on the use of tyrosine multikinase inhibitor therapy in patients with radioiodine-resistant differentiated thyroid cancer. Endocrine 2019; 64: 632-638
    CrossrefPubMedGoogle Scholar
  • 46 Tori M, Shimo T. Long-term efficacy of lenvatinib for recurrent papillary thyroid carcinoma after multimodal treatment and management of complications: A case report. BMC Cancer 2018; 18: 698
    CrossrefPubMedGoogle Scholar
  • 47 Dadu R, Devine C, Hernandez M. et al. Role of salvage targeted therapy in differentiated thyroid cancer patients who failed first-line sorafenib. J Clin Endocrinol Metab 2014; 99: 2086-2094
    CrossrefPubMedGoogle Scholar
  • 48 Takinami M, Yokota T. Rechallenge with lenvatinib after refractoriness to initial lenvatinib followed by sorafenib in a patient with metastatic papillary thyroid carcinoma. Case Rep Oncol 2020; 13: 522-527
    CrossrefPubMedGoogle Scholar
  • 49 Huillard O, Jouinot A, Tlemsani C. et al. Body composition in patients with radioactive iodine-refractory, advanced differentiated thyroid cancer treated with sorafenib or placebo: A retrospective analysis of the Phase III DECISION Trial. Thyroid 2019; 29: 1820-1827
    CrossrefPubMedGoogle Scholar
  • 50 Capdevila J, Newbold K, Licitra L. et al. Optimisation of treatment with lenvatinib in radioactive iodine-refractory differentiated thyroid cancer. Cancer Treat Rev 2018; 69: 164-176
    CrossrefPubMedGoogle Scholar
  • 51 Cabanillas ME, Takahashi S. Managing the adverse events associated with lenvatinib therapy in radioiodine-refractory differentiated thyroid cancer. Sem Oncol 2019; 46: 57-64
    CrossrefPubMedGoogle Scholar
  • 52 Kiess AP, Agrawal N, Brierley JD. et al. External-beam radiotherapy for differentiated thyroid cancer locoregional control: A statement of the American Head and Neck Society. Head Neck 2016; 38: 493-498
    CrossrefPubMedGoogle Scholar
  • 53 Kiyota N, Schlumberger M, Muro K. et al. Subgroup analysis of Japanese patients in a phase 3 study of lenvatinib in radioiodine-refractory differentiated thyroid cancer. Cancer Sci 2015; 106: 1714-1721
    CrossrefPubMedGoogle Scholar
  • 54 Carhill AA, Cabanillas ME, Jimenez C. et al. The noninvestigational use of tyrosine kinase inhibitors in thyroid cancer: establishing a standard for patient safety and monitoring. J Clin Endocrinol Metab 2013; 98: 31-42
    CrossrefPubMedGoogle Scholar
  • 55 Suzuki S, Horinouchi A, Uozumi S. et al. Impact of outpatient pharmacy interventions on management of thyroid patients receiving lenvatinib. SAGE Open Med 2020; 8: 2050312120930906
    CrossrefPubMedGoogle Scholar
  • 56 Agrawal VR, Jodon G, Mushtaq R. et al. Update on multikinase inhibitor therapy for differentiated thyroid cancer. Drugs Today (Barc) 2018; 54: 535-545
    CrossrefPubMedGoogle Scholar
  • 57 Escudier B, Worden F, Kudo M. Sorafenib: Key lessons from over 10 years of experience. Expert Rev Anticancer Ther 2019; 19: 177-189
    CrossrefPubMedGoogle Scholar
  • 58 Di Desidero T, Orlandi P, Gentile D. et al. Pharmacological effects of vinorelbine in combination with lenvatinib in anaplastic thyroid cancer. Pharmacol Res 2020; 158: 104920
    CrossrefPubMedGoogle Scholar
  • 59 Garcia-Rodriguez S, Pinillos GM, Chaves-Conde M. Lenvatininb as treatment for naive patients with aggressive thyroid cancer bone metastases and bad performance status. Case Rep Oncol Med 2020; 2020: 8679149
    PubMedGoogle Scholar
  • 60 Dadu R, Shah K, Busaidy NL. et al. Efficacy and tolerability of vemurafenib in patients with BRAF(V600E) -positive papillary thyroid cancer: M.D. Anderson Cancer Center off-label experience. J Clin Endocrinol Metab 2015; 100: E77-81
    CrossrefPubMedGoogle Scholar
  • 61 Iva J, Filip G, Martin B. et al. The significance of BRAFV600E mutation in thyroid cancer in terms of novel targeted therapies - overview of current knowledge and studies. Klin Onkol 2019; 31: 339-344
    PubMedGoogle Scholar
  • 62 Iyer PC, Dadu R, Gule-Monroe M. et al. Salvage pembrolizumab added to kinase inhibitor therapy for the treatment of anaplastic thyroid carcinoma. J Immunother Cancer 2018; 6: 68
    CrossrefPubMedGoogle Scholar
  • 63 Kim SY, Kim SM, Chang HJ. et al. SoLAT (Sorafenib Lenvatinib alternating treatment): A new treatment protocol with alternating sorafenib and lenvatinib for refractory thyroid cancer. BMC Cancer 2018; 18: 956
    CrossrefPubMedGoogle Scholar
  • 64 Hong DS, DuBois SG, Kummar S. et al. Larotrectinib in patients with TRK fusion-positive solid tumours: A pooled analysis of three phase 1/2 clinical trials. Lancet Oncol 2020; 21: 531-540
    CrossrefPubMedGoogle Scholar
  • 65 Chu YH, Dias-Santagata D, Farahani AA. et al. Clinicopathologic and molecular characterization of NTRK-rearranged thyroid carcinoma (NRTC). Mod Pathol 2020; 33: 2189-2197
    PubMedGoogle Scholar
  • 66 Wirth LJ, Sherman E, Robinson B. et al. Efficacy of selpercatinib in RET-altered thyroid cancers. New Engl J Med 2020; 383: 825-835
    CrossrefPubMedGoogle Scholar
  • 67 Brose MS, Nutting CM, Sherman SI. et al. Rationale and design of DECISION: a double-blind, randomized, placebo-controlled phase III trial evaluating the efficacy and safety of sorafenib in patients with locally advanced or metastatic radioactive iodine (RAI)-refractory, differentiated thyroid cancer. BMC Cancer 2011; 11: 349
    CrossrefPubMedGoogle Scholar
  • 68 Dittus KL, Gramling RE, Ades PA.. Exercise interventions for individuals with advanced cancer: a systematic review. Prev Med 2017; 104: 124-132
    CrossrefPubMedGoogle Scholar
  • 69 Masaki C, Sugino K, Kobayashi S. et al. Urinalysis by combination of the dipstick test and urine protein-creatinine ratio (UPCR) assessment can prevent unnecessary lenvatinib interruption in patients with thyroid cancer. Int J Clin Oncol 2020; 25: 1278-1284
    CrossrefPubMedGoogle Scholar