Skip to main content

Advertisement

SpringerLink
Log in

Late toxicities burden in patients with radioiodine-refractory differentiated thyroid cancer treated with lenvatinib

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Purpose

Radioactive-iodine (RAI)-resistant differentiated thyroid cancer (DTC) patients benefit from multi-kinase inhibitors (MKIs), such as lenvatinib. Incidence of treatment-related (TR) late toxicities has been not yet described.

Methods

From January 2015 to June 2019 we retrospectively reviewed clinical records of patients with RAI-resistant DTC treated with lenvatinib at Istituto Nazionale dei Tumori (Milan, Italy). New side effect of any grade, appeared after 12 months of lenvatinib, was defined as late adverse event (AE). Descriptive analyses were performed. Survival curves were estimated with Kaplan–Meier method and compared with log-rank test.

Results

Thirty-seven patients were included, 65% had ≥65 years and 68% were female. Thirty patients received lenvatinib for >12 months. Lenvatinib was started at ≤20 mg/daily in 59% of patients, 64% were ≥65 years. The frequency of late AEs was 80% and cardiovascular toxicity was the most common (57%). There was no difference in the incidence of late AEs between younger/older population (77% and 82%, respectively). Median lenvatinib treatment duration (TD) was 39.96 months (95% CI 21.64-NR): 39.96 months for patients <65 years (95% CI: 13.25-NR) and 37.53 months for those ≥65 years, respectively (95% CI: 15.85-NR). Median overall survival (OS) was 39.96 months (95% CI: 21.84-NR), no statistically differences in OS was observed between younger (<65 years) and older patients (≥65 years) (HR 1.013; 95% CI 0.963–1.065; p = 0.62).

Conclusion

Late toxicity burden of lenvatinib is not negligible. Cardiovascular toxicity remains the principal side effect even after a prolonged lenvatinib exposition.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

Electronic dataset.

References

  1. N. Howlader, A. M. Noone, M. Krapcho, et al. SEER Cancer Statistics Review, 1975–2013. (National Cancer Institute, Bethesda, 2016) http://seer.cancer.gov/csr/1975_2013

  2. M. Schlumberger, M. Tahara, L.J. Wirth et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N. Engl. J. Med. 372(7), 621–630 (2015)

    Article  CAS  Google Scholar 

  3. M.S. Brose, C.M. Nutting, B. Jarzab et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomized, double-blind, phase 3 trial. Lancet 384(9940), 319–328 (2014)

    Article  CAS  Google Scholar 

  4. R.I. Haddad, M. Schlumberger, L.J. Wirth et al. Incidence and timing of common adverse events in Lenvatinib-treated patients from the SELECT trial and their association with survival outcomes. Endocrine 56(1), 121–128 (2017)

    Article  CAS  Google Scholar 

  5. A. Berdelou, I. Borget, Y. Godbert, et al. Lenvatinib for the Treatment of Radioiodine-Refractory Thyroid Cancer in Real-Life Practice. Thyroid; https://doi.org/10.1089/thy.2017.0205 (2017)

  6. A. Nervo, M. Gallo, M.T. Samà et al. Lenvatinib in Advanced Radioiodine-refractory Thyroid Cancer: a Snapshot of Real-life Clinical Practice. Anticancer Res. 38(3), 1643–1649 (2018)

    PubMed  CAS  Google Scholar 

  7. L.D. Locati, A. Piovesan, C. Durante 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 118, 35–40 (2019)

    Article  CAS  Google Scholar 

  8. F. Jerkovich, I. Califano, F. Bueno et al. Real-life use of lenvatinib in patients with differentiated thyroid cancer: experience from Argentina. Endocrine 69(1), 142–148 (2020)

    Article  CAS  Google Scholar 

  9. E.V. Borodavina, P. Isaev, A. Shurinov, V. Krylov, Efficacy and tolerability of lenvatinib in patients with radioiodine-refractory differentiated thyroid Cancer: results a multicentre observational study Russian Federation. Head Neck Tumours 10, 65–72 (2020)

    Article  Google Scholar 

  10. AAVV, AIOM guidelines on thyroid cancer, https://www.aiom.it (2017)

  11. B.R. Haugen, E.K. Alexander, K.C. Bible 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 26(1), 1–133 (2016)

    Article  Google Scholar 

  12. S. Filetti, C. Durante, D. Hartl et al. ESMO Guidelines Committee. Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 30(12), 1856–1883 (2019)

    Article  CAS  Google Scholar 

  13. M.E. Cabanillas, D.G. McFadden, C. Durante, Thyroid Cancer Lancet 388(10061), 2783–2795 (2016)

    PubMed  CAS  Google Scholar 

  14. L.J. Wirth, M. Tahara, B. Robinson et al. Treatment-emergent hypertension and efficacy in the phase 3 Study of (E7080) lenvatinib in differentiated cancer of the thyroid (SELECT). Cancer 124(11), 2365–2372 (2018)

    Article  CAS  Google Scholar 

  15. J.F. Piccirillo, Importance of comorbidity in head and neck cancer. Laryngoscope 110(4), 593–602 (2000)

    Article  CAS  Google Scholar 

  16. M. Schlumberger, M. Brose, R. Elisei et al. Definition and management of radioactive iodine-refractory differentiated thyroid cancer. Lancet Diabetes Endocrinol. 2(5), 356–358 (2014)

    Article  Google Scholar 

  17. M. Tahara, M.S. Brose, L.J. Wirth 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 106, 61–68 (2019)

    Article  CAS  Google Scholar 

  18. L. Paschke, T. Lincke, K. Mühlberg, T.H. Lindner, R. Paschke, Myocardial Infarction after Long-Term Treatment with a Tyrosine Kinase Inhibitor (TKI) with Anti-VEGF Receptor Activity. Case Rep. Endocrinol. 2019, 7927450 (2019)

    PubMed  PubMed Central  CAS  Google Scholar 

  19. A. Ravaud, C. de la Fouchardière, P. Caron et al. A multicenter phase II study of sunitinib in patients with locally advanced or metastatic differentiated, anaplastic or medullary thyroid carcinomas: mature data from the THYSU study. Eur. J. Cancer 76, 110–117 (2017)

    Article  CAS  Google Scholar 

  20. G. Curigliano, D. Lenihan, M. Fradley et al. ESMO Guidelines Committee. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann. Oncol. 31(2), 171–190 (2020)

    Article  CAS  Google Scholar 

  21. S. Cavalieri, L. Cosmai, A. Genderini et al. Lenvatinib-induced renal failure: two first-time case reports and review of literature. Expert Opin. Drug Metab. Toxicol. 14(4), 379–385 (2018)

    Article  CAS  Google Scholar 

  22. C. Resteghini, S. Cavalieri, D. Galbiati et al. Management of tyrosine kinase inhibitors (TKI) side effects in differentiated and medullary thyroid cancer patients. Best. Pr. Res. Clin. Endocrinol. Metab. 31(3), 349–361 (2017)

    Article  CAS  Google Scholar 

  23. M. Sanda, H. Tamai, H. Deguchi et al. Acalculous cholecystitis in a patient with hepatocellular carcinoma on sorafenib. ISRN Gastroenterol. 2011, 201529 (2011)

    PubMed  Google Scholar 

  24. Y. Aihara, H. Yoshiji, M. Yamazaki et al. A case of severe acalculous cholecystitis associated with sorafenib treatment for advanced hepatocellular carcinoma. World J. Gastrointest. Oncol. 4(5), 115–118 (2012)

    Article  Google Scholar 

  25. J. Song, S.B. Kim, K.H. Kim, T.N. Kim, K.H. Lee, A case report of motesanib-induced biliary sludge formation causing obstructive cholangitis with acute pancreatitis treated by endoscopic sphincterotomy. Med. (Baltim.) 95(37), e4645 (2016)

    Article  CAS  Google Scholar 

  26. K. Ishigaki, T. Hamada, Y. Nakai et al. Lenvatinib-induced acute acalculous cholecystitis in a patient with hepatocellular carcinoma. Clin. J. Gastroenterol. 13(4), 568–571 (2020)

    Article  Google Scholar 

  27. A. Nervo, A. Ragni, M. Gallo et al. Symptomatic Biliary Disorders During Lenvatinib Treatment for Thyroid Cancer: an Underestimated Problem. Thyroid 30(2), 229–236 (2020)

    Article  CAS  Google Scholar 

  28. C. Colombo, S. De Leo, M. Di Stefano, G. Vannucchi, L. Persani, L. Fugazzola, Primary Adrenal Insufficiency During Lenvatinib or Vandetanib and Improvement of Fatigue After Cortisone Acetate Therapy. J. Clin. Endocrinol. Metab. 104(3), 779–784 (2019)

    Article  Google Scholar 

  29. J.D. Cox, J. Stetz, T.F. Pajak, Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J. Radiat. Oncol. Biol. Phys. 31(5), 1341–1346 (1995)

    Article  CAS  Google Scholar 

  30. J.A. Langendijk, P. Doornaert, Verdonck-de Leeuw IM, Leemans CR, Aaronson NK, Slotman BJ. Impact of late treatment-related toxicity on quality of life among patients with head and neck cancer treated with radiotherapy. J. Clin. Oncol. 26(22), 3770–3776 (2008)

    Article  Google Scholar 

  31. G. Thanarajasingam, P.J. Atherton, P.J. Novotny, C.L. Loprinzi, J.A. Sloan, A. Grothey, Longitudinal adverse event assessment in oncology clinical trials: the Toxicity over Time (ToxT) analysis of Alliance trials NCCTG N9741 and 979254. Lancet Oncol. 17(5), 663e70 (2016)

    Article  CAS  Google Scholar 

  32. A. Hochhaus, S.G. O’Brien, F. Guilhot et al. Six-year follow-up of patients receiving imatinib for the first line treatment of chronic myeloid leukemia. Leukemia 23, 1054–1061 (2009)

    Article  CAS  Google Scholar 

  33. C. Giani, L. Valerio, A. Bongiovanni et al. Safety and Quality-of-Life Data from an Italian Expanded Access Program of Lenvatinib for Treatment of Thyroid Cancer. Thyroid 31(2), 224–232 (2021)

    Article  CAS  Google Scholar 

  34. T.H. Brümmendorf, J.E. Cortes, C.A. de Souza et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronicmyeloid leukaemia: results from the 24-month follow-up of the BELA trial. Br. J. Haematol. 168, 69–81 (2014)

    Article  CAS  Google Scholar 

  35. E. Jabbour, H.M. Kantarjian, G. Saglio et al. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year followup from a randomized phase 3 trial (DASISION). Blood 123, 494–500 (2014)

    Article  CAS  Google Scholar 

  36. R.A. Larson, A. Hochhaus, T.P. Hughes et al. Nilotinib vs. imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia 26, 2197–2203 (2012)

    Article  CAS  Google Scholar 

  37. M.S. Marcolino, E. Boersma, N.C.D. Clementino et al. Imatinib treatment duration is related to decreased estimated glomerular filtration rate in chronic myeloid leukemia patients. Ann. Oncol. 22, 2073–2079 (2011)

    Article  CAS  Google Scholar 

  38. M.S. Brose, F.P. Worden, K.L. Newbold, M. Guo, A. Hurria, 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. 35(23), 2692–2699 (2017)

    Article  CAS  Google Scholar 

Download references

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Author information

Authors and Affiliations

  1. Head and Neck Cancer Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    F. Platini, S. Cavalieri, S. Alfieri, C. Bergamini, C. Resteghini, A. Bottiglieri, E. Colombo, L. Mazzeo, L. Licitra & L. D. Locati

  2. Medical Oncology Department, University of Milan, Milan, Italy

    L. Licitra

  3. Pathology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    B. Paolini

  4. Struttura di Terapia Medico Nucleare ed Endocrinologia U.O. Medicina Nucleare, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    E. Seregni

Authors
  1. F. Platini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Cavalieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Alfieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. Bergamini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C. Resteghini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. Bottiglieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E. Colombo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. L. Mazzeo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L. Licitra
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. B. Paolini
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. E. Seregni
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. L. D. Locati
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors revised the paper; F.P., S.C. and L.D.L. wrote the first paper draft.

Corresponding author

Correspondence to L. D. Locati.

Ethics declarations

Conflict of interest

L.D.L. reports grant and other financial relationship with Eisai, Ipsen, Merck Serono, MSD, BMS, Lilly. No competing interests could be perceived as prejudicing the impartiality of the research reported.

Ethical approval

Approved with the code INT 135/20.

Informed consent

All the patients signed up a written informed consent.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Platini, F., Cavalieri, S., Alfieri, S. et al. Late toxicities burden in patients with radioiodine-refractory differentiated thyroid cancer treated with lenvatinib. Endocrine 73, 641–647 (2021). https://doi.org/10.1007/s12020-021-02702-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-021-02702-4

Keywords

Search

Navigation