Improved survival in patients with thyroid function test abnormalities secondary to immune-checkpoint inhibitors

Abstract

Immune-checkpoint inhibitors (ICI) are monoclonal antibodies which target molecules to enhance antitumor response. Several adverse events have been described and the major ICI-related endocrinopathies are thyroid dysfunction and hypophysitis. Its occurrence has been associated with improved outcomes, but it is still to be proven. We performed a retrospective study of patients treated with ICI between 2014 and 2019 at an oncologic center to characterize thyroid function test abnormalities (TFTA) and to evaluate clinical outcomes. We excluded patients without regular monitoring of thyroid function, with previous thyroid or pituitary disease, previous head/neck radiotherapy and who performed only one ICI cycle. We included 161 of 205 patients treated with pembrolizumab, nivolumab or ipilimumab for several neoplasms, with a median duration of 18.9 weeks (9.1–42.6) of ICI treatment and 49.4 weeks (26.5–75.8) of follow-up. New-onset TFTA was diagnosed in 18% of patients (n = 29), in median at 10.6 weeks (6.1–31.1) of ICI therapy. On the whole, 8.7% had primary hypothyroidism, 4.3% central hypothyroidism, 2.5% biphasic thyroiditis and 2.5% thyrotoxicosis. Patients who experienced primary or central thyroid dysfunction had a significantly improved overall response rate (58.6% vs 34.2%, p = 0.015) and overall survival (3.27 vs 1.76 years, p = 0.030), compared to the control group. The risk of mortality was two times higher for control group (adjusted HR = 2.43, 95% CI 1.13–5.23, p = 0.023). This study recognizes that primary and central thyroid dysfunction can be a predictive clinical biomarker of a better response to ICI across several neoplasms.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

Data availability

Data are protected in accordance with indications of Local Ethical Committee.

Abbreviations

Abs:

Antibodies

BB:

Beta-blocker

CI:

Confidence interval

CTCAE:

Common terminology criteria for adverse events

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

DIRE:

Delayed immune-related events

18FDG-PET/CT:

18Fluorodeoxyglucose positron emission tomography/computed tomography

fT3:

Free triiodothyronine

fT4:

Free thyroxine

HR:

Hazard ratio

ICI:

Immune checkpoint inhibitors

IQR:

Interquartile range

irAEs:

Immune-related adverse events

MSI-H:

Microsatellite instability-high

NSCLC:

Non-small-cell lung cancer

PD-L1:

Programmed cell death ligand 1

PD-1:

Programmed cell death protein 1

TFTA:

Thyroid function tests abnormalities

Tg:

Thyroglobulin

TPO:

Thyroid peroxidase

TRAbs:

Thyrotropin receptor antibodies

TSH:

Thyroid-stimulating hormone

vs:

Versus

References

  1. 1.

    Chalan P, Di Dalmazi G, Pani F, De Remigis A, Corsello A, Caturegli P (2018) Thyroid dysfunctions secondary to cancer immunotherapy. J Endocrinol Invest 41:625–638. https://doi.org/10.1007/s40618-017-0778-8

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264. https://doi.org/10.1038/nrc3239

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Page DB, Postow MA, Callahan MK, Allison JP, Wolchok JD (2014) Immune modulation in cancer with antibodies. Annu Rev Med 65:185–202. https://doi.org/10.1146/annurev-med-092012-112807

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Hargadon KM, Johnson CE, Williams CJ (2018) Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors. Int Immunopharmacol 62:29–39. https://doi.org/10.1016/j.intimp.2018.06.001(S1567-5769(18)30252-2 [pii])

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Ferrari SM, Fallahi P, Galetta F, Citi E, Benvenga S, Antonelli A (2018) Thyroid disorders induced by checkpoint inhibitors. Rev Endocr Metab Disord 19:325–333. https://doi.org/10.1007/s11154-018-9463-2

    Article  PubMed  Google Scholar 

  6. 6.

    Osorio JC, Ni A, Chaft JE et al (2017) Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. Ann Oncol 28:583–589. https://doi.org/10.1093/annonc/mdw640

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Presotto EM, Rastrelli G, Desideri I et al (2019) Endocrine toxicity in cancer patients treated with nivolumab or pembrolizumab: results of a large multicentre study. J Endocrinol Invest. https://doi.org/10.1007/s40618-019-01112-8

    Article  PubMed  Google Scholar 

  8. 8.

    Sibaud V, Meyer N, Lamant L, Vigarios E, Mazieres J, Delord JP (2016) Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. Curr Opin Oncol 28:254–263. https://doi.org/10.1097/CCO.0000000000000290

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Abdel-Wahab N, Shah M, Suarez-Almazor ME (2016) Adverse events associated with immune checkpoint blockade in patients with cancer: a systematic review of case reports. PLoS ONE 11:e0160221. https://doi.org/10.1371/journal.pone.0160221

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Lacouture ME, Wolchok JD, Yosipovitch G, Kahler KC, Busam KJ, Hauschild A (2014) Ipilimumab in patients with cancer and the management of dermatologic adverse events. J Am Acad Dermatol 71:161–169. https://doi.org/10.1016/j.jaad.2014.02.035(S0190-9622(14)01152-9[pii])

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Weber JS, Gibney G, Sullivan RJ et al (2016) Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Lancet Oncol 17:943–955. https://doi.org/10.1016/S1470-2045(16)30126-7(S1470-2045(16)30126-7[pii])

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Bajwa R, Cheema A, Khan T et al (2019) Adverse effects of immune checkpoint inhibitors (programmed death-1 inhibitors and cytotoxic T-lymphocyte-associated protein-4 inhibitors): results of a retrospective study. J Clin Med Res 11:225–236. https://doi.org/10.14740/jocmr3750

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Kassi E, Angelousi A, Asonitis N et al (2019) Endocrine-related adverse events associated with immune-checkpoint inhibitors in patients with melanoma. Cancer Med. https://doi.org/10.1002/cam4.2533

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Scott ES, Long GV, Guminski A, Clifton-Bligh RJ, Menzies AM, Tsang VH (2018) The spectrum, incidence, kinetics and management of endocrinopathies with immune checkpoint inhibitors for metastatic melanoma. Eur J Endocrinol 178:173–180. https://doi.org/10.1530/EJE-17-0810

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Peiro I, Palmero R, Iglesias P et al (2019) Thyroid dysfunction induced by nivolumab: searching for disease patterns and outcomes. Endocrine 64:605–613. https://doi.org/10.1007/s12020-019-01871-7

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Illouz F, Drui D, Caron P, Do Cao C (2018) Expert opinion on thyroid complications in immunotherapy. Ann Endocrinol (Paris) 79:555–561. https://doi.org/10.1016/j.ando.2018.07.007(S0003-4266(18)31185-5[pii])

    Article  Google Scholar 

  17. 17.

    Campredon P, Mouly C, Lusque A, Bigay-Game L, Bousquet E, Mazieres J, Caron P (2019) Incidence of thyroid dysfunctions during treatment with nivolumab for non-small cell lung cancer: retrospective study of 105 patients. Presse Med 48:e199–e207. https://doi.org/10.1016/j.lpm.2018.10.019(S0755-4982(19)30088-0[pii])

    Article  PubMed  Google Scholar 

  18. 18.

    Patel NS, Oury A, Daniels GA, Bazhenova L, Patel SP (2018) Incidence of thyroid function test abnormalities in patients receiving immune-checkpoint inhibitors for cancer treatment. Oncologist 23:1236–1241. https://doi.org/10.1634/theoncologist.2017-0375

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Al Mushref M, Guido PA, Collichio FA, Moore DT, Clemmons DR (2019) Thyroid dysfunction, recovery, and prognosis in melanoma patients treated with immune checkpoint inhibitors: a retrospective review. Endocr Pract. https://doi.org/10.4158/EP-2019-0244

    Article  PubMed  Google Scholar 

  20. 20.

    Morganstein DL, Lai Z, Spain L, Diem S, Levine D, Mace C, Gore M, Larkin J (2017) Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 and programmed death receptor protein-1 inhibitors in the treatment of melanoma. Clin Endocrinol (Oxf) 86:614–620. https://doi.org/10.1111/cen.13297

    CAS  Article  Google Scholar 

  21. 21.

    Guaraldi F, La Selva R, Sama MT, D'Angelo V, Gori D, Fava P, Fierro MT, Savoia P, Arvat E (2018) Characterization and implications of thyroid dysfunction induced by immune checkpoint inhibitors in real-life clinical practice: a long-term prospective study from a referral institution. J Endocrinol Invest 41:549–556. https://doi.org/10.1007/s40618-017-0772-1

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Faje AT, Sullivan R, Lawrence D, Tritos NA, Fadden R, Klibanski A, Nachtigall L (2014) Ipilimumab-induced hypophysitis: a detailed longitudinal analysis in a large cohort of patients with metastatic melanoma. J Clin Endocrinol Metab 99:4078–4085. https://doi.org/10.1210/jc.2014-2306

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Albarel F, Gaudy C, Castinetti F, Carre T, Morange I, Conte-Devolx B, Grob JJ, Brue T (2015) Long-term follow-up of ipilimumab-induced hypophysitis, a common adverse event of the anti-CTLA-4 antibody in melanoma. Eur J Endocrinol 172:195–204. https://doi.org/10.1530/EJE-14-0845

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Weber J, Mandala M, Del Vecchio M et al (2017) Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 377:1824–1835. https://doi.org/10.1056/NEJMoa1709030

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Iglesias P (2018) Cancer immunotherapy-induced endocrinopathies: clinical behavior and therapeutic approach. Eur J Intern Med 47:6–13. https://doi.org/10.1016/j.ejim.2017.08.019(S0953-6205(17)30321-7[pii])

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Hryniewicki AT, Wang C, Shatsky RA, Coyne CJ (2018) Management of immune checkpoint inhibitor toxicities: a review and clinical guideline for emergency physicians. J Emerg Med 55:489–502. https://doi.org/10.1016/j.jemermed.2018.07.005(S0736-4679(18)30660-7[pii])

    Article  PubMed  Google Scholar 

  27. 27.

    Das S, Johnson DB (2019) Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J Immunother Cancer 7:306. https://doi.org/10.1186/s40425-019-0805-8

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Barquin-Garcia A, Molina-Cerrillo J, Garrido P, Garcia-Palos D, Carrato A, Alonso-Gordoa T (2019) New oncologic emergencies: What is there to know about inmunotherapy and its potential side effects? Eur J Intern Med 66:1–8. https://doi.org/10.1016/j.ejim.2019.05.020(S0953-6205(19)30178-5[pii])

    Article  PubMed  Google Scholar 

  29. 29.

    Tan MH, Iyengar R, Mizokami-Stout K, Yentz S, MacEachern MP, Shen LY, Redman B, Gianchandani R (2019) Spectrum of immune checkpoint inhibitors-induced endocrinopathies in cancer patients: a scoping review of case reports. Clin Diabetes Endocrinol 5:1. https://doi.org/10.1186/s40842-018-0073-4

    Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Chang LS, Barroso-Sousa R, Tolaney SM, Hodi FS, Kaiser UB, Min L (2019) Endocrine toxicity of cancer immunotherapy targeting immune checkpoints. Endocr Rev 40:17–65. https://doi.org/10.1210/er.2018-00006

    Article  PubMed  Google Scholar 

  31. 31.

    Barroso-Sousa R, Ott PA, Hodi FS, Kaiser UB, Tolaney SM, Min L (2018) Endocrine dysfunction induced by immune checkpoint inhibitors: practical recommendations for diagnosis and clinical management. Cancer 124:1111–1121. https://doi.org/10.1002/cncr.31200

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Girotra M, Hansen A, Farooki A et al (2018) The current understanding of the endocrine effects from immune checkpoint inhibitors and recommendations for management. JNCI Cancer Spectr 2:pky021. https://doi.org/10.1093/jncics/pky021

    Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Gomes-Lima C, Kwagyan J, King F, Fernandez S, Burman K, Veytsman I (2019) A comprehensive meta-analysis of endocrine immune-related adverse events of immune checkpoint inhibitors and outcomes in head and neck cancer and lung cancer. J Clin Oncol 37:e14096. https://doi.org/10.1200/JCO.2019.37.15_suppl.e14096

    Article  Google Scholar 

  34. 34.

    Kim HI, Kim M, Lee SH et al (2017) Development of thyroid dysfunction is associated with clinical response to PD-1 blockade treatment in patients with advanced non-small cell lung cancer. Oncoimmunology 7:e1375642. https://doi.org/10.1080/2162402X.2017.1375642.1375642[pii]

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Velu V, Titanji K, Zhu B et al (2009) Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 458:206–210. https://doi.org/10.1038/nature07662

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Kotwal A, Gustafson MP, Bornschlegl S, Kottschade L, Delivanis DA, Dietz AB, Gandhi M, Ryder M (2020) Immune checkpoint inhibitor-induced thyroiditis is associated with increased intrathyroidal T lymphocyte subpopulations. Thyroid. https://doi.org/10.1089/thy.2020.0075

    Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Varricchi G, Loffredo S, Marone G, Modestino L, Fallahi P, Ferrari SM, de Paulis A, Antonelli A, Galdiero MR (2019) The immune landscape of thyroid cancer in the context of immune checkpoint inhibition. Int J Mol Sci 20:3934. https://doi.org/10.3390/ijms20163934

    CAS  Article  PubMed Central  Google Scholar 

  38. 38.

    Downey SG, Klapper JA, Smith FO et al (2007) Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res 13:6681–6688. https://doi.org/10.1158/1078-0432.CCR-07-0187

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Bronstein Y, Ng CS, Hwu P, Hwu WJ (2011) Radiologic manifestations of immune-related adverse events in patients with metastatic melanoma undergoing anti-CTLA-4 antibody therapy. AJR Am J Roentgenol 197:W992–W1000. https://doi.org/10.2214/AJR.10.6198

    Article  PubMed  Google Scholar 

  40. 40.

    Sarnaik AA, Yu B, Yu D et al (2011) Extended dose ipilimumab with a peptide vaccine: immune correlates associated with clinical benefit in patients with resected high-risk stage IIIc/IV melanoma. Clin Cancer Res 17:896–906. https://doi.org/10.1158/1078-0432.CCR-10-2463

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Weber J, Thompson JA, Hamid O et al (2009) A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res 15:5591–5598. https://doi.org/10.1158/1078-0432.CCR-09-1024

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Schadendorf D, Wolchok JD, Hodi FS et al (2017) Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials. J Clin Oncol 35:3807–3814. https://doi.org/10.1200/JCO.2017.73.2289

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank Darlene Rodrigues (Gerontology and Geriatrics PhD student and Radiation Oncology Resident of Department of Radiotherapy, Centro Hospitalar e Universitário de São João, E.P.E., Porto, Portugal) for support in survival data analysis (orcid number 0000-0001-8170-3952).

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. No writing assistance was utilized in the production of this manuscript.

Author information

Affiliations

Authors

Contributions

JLF, ILS, CC and BM were involved in the study concept and design; JLF, CC, SC, MV and ILS were involved in data acquisition. JLF and BM were involved in the analysis and interpretation of the data. JLF drafted the manuscript. APM, BM and CC were involved in critical revision of an early draft of the manuscript. All authors have reviewed the manuscript and approved its final version.

Corresponding author

Correspondence to Joana Lima Ferreira.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest, namely relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Ethical approval

This research study was conducted retrospectively from data obtained for clinical purposes. This study was approved by the Local Ethical Committee of the Instituto Português de Oncologia do Porto (CES.180/020) and has been performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Informed consent

Informed consent was not obtained from each patient, because this retrospective analysis of existing data did not require any interaction with patients and did not intervene in their treatment.

Code availability

Not applicable.

Additional information

Publisher's Note

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

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 29 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lima Ferreira, J., Costa, C., Marques, B. et al. Improved survival in patients with thyroid function test abnormalities secondary to immune-checkpoint inhibitors. Cancer Immunol Immunother 70, 299–309 (2021). https://doi.org/10.1007/s00262-020-02664-y

Download citation

Keywords

  • Thyroid
  • Hypophysitis
  • Immunotherapy
  • Anti-PD-1
  • Anti-CTLA-4
  • Survival