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Zhao P, Li J, Yu L, Ma W, Zhao T. Clinical manifestations and risk factors of immune-related thyroid adverse events in patients treated with PD-1 inhibitors: a case-control study. Front Immunol 2025; 16:1581057. [PMID: 40356893 PMCID: PMC12066586 DOI: 10.3389/fimmu.2025.1581057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Accepted: 04/04/2025] [Indexed: 05/15/2025] Open
Abstract
Background Immune checkpoint inhibitors (ICPIs) have emerged as a powerful strategy to cancer treatment. However, while demonstrating antitumor efficacy, they can also induce a range of immune-related adverse events (irAEs). Immune-related thyroid dysfunction is one of the most common irAEs. This study aims to investigate the clinical characteristics and identify potential risk factors associated with PD-1 inhibitor-induced immune-related thyroid dysfunction in real-world. Methods A retrospective analysis was conducted on the clinical data of cancer patients treated with PD-1 inhibitors at Weifang People's Hospital from January 2021 to December 2024. The incidence, clinical subtypes, onset time, and prognostic outcomes of thyroid dysfunction were analyzed. Univariate and multivariate logistic regression analyses were performed to identify risk factors. Results 119 patients of PD-1 inhibitor-associated thyroid dysfunction were identified. The overall incidence of thyroid dysfunction was 2.97%, with hypothyroidism occurring in 1.20%, hyperthyroidism in 1.77%, and thyroiditis in 0.50% of patients. Tislelizumab exhibited the highest incidence at 3.48%, followed by camrelizumab at 3.10%, sintilimab at 2.24%, and toripalimab at 1.75%. The median time from the initiation of immunotherapy to the onset of thyroid dysfunction was 67 days, with hypothyroidism and hyperthyroidism developing at median times of 64.5 and 69 days, respectively. 77.31% of cases occurred within the first four months of immunotherapy. Female gender, lower baseline FT3 levels, history of targeted therapy, and baseline TgAb positivity were identified as independent risk factors for PD-1 inhibitor-associated thyroid dysfunction. Furthermore, higher baseline TSH levels, younger age, and treatment with tislelizumab or camrelizumab were associated with an increased risk of immune-related hypothyroidism, whereas lower baseline TSH levels were linked to a higher risk of immune-related hyperthyroidism. Conclusions Close clinical and hormonal monitoring is recommended for patients with high-risk factors before and throughout the course of immunotherapy, particularly during the initial 2 to 4 months of PD-1 inhibitor treatment.
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Affiliation(s)
- Pengfei Zhao
- Department of Clinical Pharmacy, Weifang People’s Hospital, Shandong Second Medical University, Weifang, Shandong, China
| | - Jia Li
- Department of Adverse Drug Reaction Monitoring, Weifang Market Regulation Development Service Center, Weifang, Shandong, China
| | - Lihong Yu
- Department of Clinical Pharmacy, Weifang People’s Hospital, Shandong Second Medical University, Weifang, Shandong, China
| | - Wenming Ma
- Department of Clinical Pharmacy, Weifang People’s Hospital, Shandong Second Medical University, Weifang, Shandong, China
| | - Ting Zhao
- Department of Clinical Pharmacy, Weifang People’s Hospital, Shandong Second Medical University, Weifang, Shandong, China
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Li L, Ding X, Zhang X, Kong S, Chen M. Clinical Significance of Thyroid Autoantibodies in Differential Diagnosis and Predicting the Course of Programmed Cell Death Protein-1 Inhibitor-Induced Thyroid Dysfunction. Endocr Pract 2024; 30:1166-1170. [PMID: 39216687 DOI: 10.1016/j.eprac.2024.08.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 08/15/2024] [Accepted: 08/23/2024] [Indexed: 09/04/2024]
Abstract
OBJECTIVE Thyroid immune-related thyrotoxicosis is one of the most common adverse effects in patients treated with programmed cell death protein-1 (PD-1) inhibitors. We investigated the significance of levels of serum anti-thyroglobulin antibodies (TgAbs), anti-thyroid peroxidase antibodies (TPOAbs), and thyroid-stimulating hormone receptor antibodies (TRAbs) in the identification of anti-PD-1-induced thyroid thyrotoxicosis. METHODS We divided 161 patients with thyroid dysfunction who received PD-1 inhibitors at our hospital between January 2022 and June 2024 into 3 groups: primary hypothyroidism group, primary hyperthyroidism group, and destructive thyroiditis group. The characteristics of the 3 groups were determined, and the positivity rates of serum TgAbs, TPOAbs, and TRAbs were assessed. An additional 42 patients diagnosed with Hashimoto's thyroiditis were selected as the control group for PD-1 inhibition-induced destructive thyroiditis. Age, sex, and time of transition from thyrotoxicosis to hypothyroidism in the 2 groups were compared. RESULTS In the primary hypothyroidism group, only 1 case was TPOAbs-positive (1/1%). In the destructive thyroiditis group, the positivity rate for TPOAbs or TgAbs was 92.9%, and TPOAbs and TgAbs were negative in the primary hyperthyroidism group. TRAbs were undetectable in all 3 groups. There were statistically significant differences in age, sex, and time from thyrotoxicosis to hypothyroidism in the PD-1 induced destructive thyroiditis and Hashimoto's thyroiditis groups. CONCLUSIONS In patients with thyrotoxicosis caused by PD-1 inhibitors, serum TgAb, and TPOAb levels can be used to distinguish between primary hyperthyroidism and destructive thyroiditis. This study provides insights into novel treatment targets and effective management strategies for PD-1-induced thyrotoxicosis.
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Affiliation(s)
- Li Li
- Department of Clinical Laboratory, Taixing City People's Hospital, Taixing, China
| | - Xiaoxia Ding
- Department of Clinical Laboratory, Taixing City People's Hospital, Taixing, China
| | - Xihui Zhang
- Department of Clinical Laboratory, Taixing City People's Hospital, Taixing, China
| | - Shuangming Kong
- Anaesthesiology Department, Taixing City People's Hospital, Taixing, China.
| | - Ming Chen
- Department of Clinical Laboratory, Taixing City People's Hospital, Taixing, China.
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Li Y, Zhao J, Wang Y, Xu Y, Li R, Zhao Y, Dong X, Yao X, Li Y. Common endocrine system adverse events associated with immune checkpoint inhibitors. CANCER PATHOGENESIS AND THERAPY 2024; 2:164-172. [PMID: 39027145 PMCID: PMC11252504 DOI: 10.1016/j.cpt.2023.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 11/23/2023] [Accepted: 11/28/2023] [Indexed: 07/20/2024]
Abstract
Immune checkpoint inhibitors (ICIs), a novel anti-tumor therapeutic modality, are monoclonal antibodies targeting certain immune checkpoints (ICs) that reactivate T cells to achieve anti-tumor immunity by targeting, binding, and blocking ICs. Targeted inhibitory antibodies against the ICs cytotoxic T-lymphocyte antigen and programmed death receptor-1 have demonstrated efficacy and durable anti-tumor activity in patients with cancer. ICs may prevent autoimmune reactions. However, ICIs may disrupt ICs properties and trigger autoimmune-related adverse reactions involving various organ systems including the cardiovascular, pulmonary, gastrointestinal, renal, musculoskeletal, dermal, and endocrine systems. Approximately 10% of patients with damage to target organs such as the thyroid, pituitary, pancreas, and adrenal glands develop endocrine system immune-related adverse events (irAEs) such as thyroid dysfunction, pituitary gland inflammation, diabetes mellitus, and primary adrenal insufficiency. However, the symptoms of immunotherapy-associated endocrine system irAEs may be nonspecific and similar to those of other treatment-related adverse reactions, and failure to recognize them early may lead to death. Timely detection and treatment of immunotherapy-associated endocrine irAEs is essential to improve the efficacy of immunotherapy, prognosis, and the quality of life of patients. This study aimed to review the mechanisms by which ICIs cause endocrine irAEs providing guidance for the development of appropriate management protocols. Here, we discuss (1) the biological mechanisms of ICs in tumorigenesis and progression, focusing on cytotoxic T-lymphocyte antigen and programmed cell death-1/programmed cell death-ligand 1; and (2) the epidemiology, clinical symptoms, diagnosis, and treatment of four immunotherapy-related endocrine complications.
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Affiliation(s)
- Ying Li
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China
| | - Junfeng Zhao
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China
| | - Yue Wang
- National Institutes for Food and Drug Control, Beijing 102629, China
| | - Yali Xu
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250000, China
| | - Ruyue Li
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Affiliated Hospital of Weifang Medical University, School of Clinical Medicine, Weifang Medical University, Weifang, Shandong 261000, China
| | - Ying Zhao
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China
| | - Xue Dong
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China
| | - Xiujing Yao
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Affiliated Hospital of Weifang Medical University, School of Clinical Medicine, Weifang Medical University, Weifang, Shandong 261000, China
| | - Yintao Li
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China
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Shi H, He Y, Dan S, Yang L, Wang J, Chen L, Chen Z. Endocrine system-related adverse events associated with PD-1/PD-L1 inhibitors: data mining from the FDA adverse event reporting system. Front Med (Lausanne) 2024; 11:1366691. [PMID: 38711784 PMCID: PMC11073539 DOI: 10.3389/fmed.2024.1366691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Accepted: 02/07/2024] [Indexed: 05/08/2024] Open
Abstract
Background Various immune checkpoint inhibitors, such as programmed cell death protein-1 (PD-1) and its ligand (PD-L1), have been approved for use, but they have side effects on the endocrine glands. Methods Adverse event reports related to PD-1/PD-L1 inhibitors from the FDA Adverse Event Reporting System (FAERS) from the first quarter of 2019 to the first quarter of 2023 were extracted, and the reported Odds ratio methods (ROR method) and comprehensive standard methods (MHRA methods) were used for data mining and analysis. Results A total of 5,322 reports (accounts for 6.68% of the total reports)of AEs in endocrine system were collected, including 1852 of pabolizumab (34.80%), 2,326 of navuliumab (43.71%), 54 of cimipriliumab (1.01%), 800 of atilizumab (15.03%), 222 of duvariumab (4.17%) and 68 of averumab (1.28%). Endocrine system-related AEs were mainly present in men (excluding those treated with pembrolizumab) aged ≥65 years. The ratio of AEs components in the endocrine system for the six drugs was approximately 3-8%. The main endocrine glands involved in AEs were the thyroid (pembrolizumab), pituitary and adrenal (nivolumab), adrenal (cemiplimab, atezolizumab, and avelumab), and thyroid (durvalumab). Most patients experienced AEs between 30 and 365 (mean, 117) days,the median time was 61d. AEs resulted in prolonged hospitalization in >40% and death in >10% of cases after administration of pembrolizumab, nivolumab, or durvalumab. Conclusion Men aged ≥65 years should be concerned about endocrine-related AEs. There was a lengthy interval between the use of PD-1/PD-L1 inhibitors and endocrine system-related AEs, but the outcome was serious. Special attention should be given to endocrine system-related AEs when using pembrolizumab, nivolumab, or durvalumab.
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Affiliation(s)
- Hongxia Shi
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Yunhua He
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Siyuan Dan
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Lin Yang
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Jing Wang
- Department of Pharmacy, Sichuan Mianyang 404 Hospital, Mianyang, China
| | - Li Chen
- Department of Pharmacy/Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, China
- Department of Pharmacology, Faculty of Medicine, University of the Basque Country UPV/EHU, Leioa, Spain
| | - Zelian Chen
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
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Basek A, Jakubiak GK, Cieślar G, Stanek A. Life-Threatening Endocrinological Immune-Related Adverse Events of Immune Checkpoint Inhibitor Therapy. Cancers (Basel) 2023; 15:5786. [PMID: 38136332 PMCID: PMC10742092 DOI: 10.3390/cancers15245786] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 11/29/2023] [Accepted: 12/06/2023] [Indexed: 12/24/2023] Open
Abstract
Malignant neoplasms are currently one of the leading causes of morbidity and mortality worldwide, posing a major public health challenge. However, recent advances in research in cancer biology and immunity have led to the development of immunotherapy, which is now used on an everyday basis in cancer treatment in addition to surgical treatment, classical cytostatics, and radiotherapy. The efficacy of immunotherapy has promoted the great popularity of this treatment among patients, as well as significant research interest. The increasing number of patients being treated with immunotherapy not only reassures physicians of the efficacy of this technique but also shows the wide spectrum of side effects of this therapy, which has not been considered before. Immune-related adverse events may affect many systems and organs, such as digestive, cardiovascular, respiratory, skin, or endocrine organs. Most complications have a mild or moderate course, but there are life-threatening manifestations that are essential to be aware of because if they are not properly diagnosed and treated on time, they can have fatal consequences. The purpose of this paper was to present the results of a literature review on the current state of knowledge on life-threatening endocrine side effects (such as adrenal crisis, thyroid storm, myxoedema crisis, diabetic ketoacidosis, and severe hypocalcaemia) of immune checkpoint inhibitors to provide information on symptoms, diagnostics, and management strategies.
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Affiliation(s)
- Aleksandra Basek
- Student Research Group, Department and Clinic of Internal Medicine, Angiology, and Physical Medicine, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Batorego 15 St., 41-902 Bytom, Poland;
| | - Grzegorz K. Jakubiak
- Department and Clinic of Internal Medicine, Angiology, and Physical Medicine, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Batorego 15 St., 41-902 Bytom, Poland; (G.C.); (A.S.)
| | - Grzegorz Cieślar
- Department and Clinic of Internal Medicine, Angiology, and Physical Medicine, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Batorego 15 St., 41-902 Bytom, Poland; (G.C.); (A.S.)
| | - Agata Stanek
- Department and Clinic of Internal Medicine, Angiology, and Physical Medicine, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Batorego 15 St., 41-902 Bytom, Poland; (G.C.); (A.S.)
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Liguori L, Luciano A, Polcaro G, Ottaiano A, Cascella M, Perri F, Pepe S, Sabbatino F. Prior Anti-Angiogenic TKI-Based Treatment as Potential Predisposing Factor to Nivolumab-Mediated Recurrent Thyroid Disorder Adverse Events in mRCC Patients: A Case Series. Biomedicines 2023; 11:2974. [PMID: 38001973 PMCID: PMC10669217 DOI: 10.3390/biomedicines11112974] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 10/26/2023] [Accepted: 11/02/2023] [Indexed: 11/26/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) or its ligand 1 (PD-L1) have revolutionized the management of many types of solid tumors, including metastatic renal cell carcinoma (mRCC). Both sequential and combinatorial therapeutic strategies utilizing anti-PD-1 monoclonal antibodies (mAbs) and anti-angiogenic tyrosine kinase inhibitors (TKIs) have demonstrated to improve the survival of patients with mRCC as compared to standard therapies. On the other hand, both ICIs and TKIs are well known to potentially cause thyroid disorder adverse events (TDAEs). However, in the context of sequential therapeutic strategy, it is not clear whether prior anti-angiogenic TKI may increase the risk and/or the severity of ICI-related TDAEs. In this work, by describing and analyzing a case series of mRCC patients treated sequentially with prior TKIs and then with ICIs, we investigated the role of prior anti-angiogenic TKI-based treatment as a potential predisposing factor to anti-PD-1-mediated recurrent TDAEs, as well as its potential impact on the clinical characteristics of nivolumab-mediated recurrent TDAEs. Fifty mRCC patients were included in the analysis. TKI-mediated TDAEs were reported in ten out of fifty patients. TKI-mediated TDAEs were characterized by hypothyroidism in all ten patients. Specifically, 40%, 40% and 20% of patients presented grade 1, 2 and 3 hypothyroidisms, respectively. Following tumor progression and during anti-PD-1 nivolumab treatment, five out of ten patients developed anti-PD-1 nivolumab-mediated recurrent TDAEs. Anti-PD-1 nivolumab-mediated recurrent TDAEs were characterized by an early transient phase of thyrotoxicosis and a late phase of hypothyroidism in all five patients. The TDAEs were grade 1 and 2 in four and one patients, respectively. Prior anti-angiogenic TKI did not modify the clinical characteristics of nivolumab-mediated recurrent TDAEs. However, all five patients required an increased dosage of levothyroxine replacement therapy. In conclusion, our work suggests that prior anti-angiogenic TKI-based treatment significantly increases the risk of ICI-mediated recurrent TDAEs in patients with mRCC without modifying their clinical characteristics. The most relevant effect for these patients is the need to increase the dosage of lifelong levothyroxine replacement therapy.
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Affiliation(s)
- Luigi Liguori
- Oncology Unit, Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80131 Naples, Italy; (L.L.); (A.L.)
- Oncology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy; (G.P.); (S.P.)
| | - Angelo Luciano
- Oncology Unit, Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80131 Naples, Italy; (L.L.); (A.L.)
- Oncology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy; (G.P.); (S.P.)
| | - Giovanna Polcaro
- Oncology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy; (G.P.); (S.P.)
| | - Alessandro Ottaiano
- SSD Innovative Therapies for Abdominal Metastases, Abdominal Oncology, INT IRCCS Foundation “G. Pascale”, 80131 Naples, Italy;
| | - Marco Cascella
- Unit of Anesthesiology, Intensive Care Medicine, and Pain, Department of Medicine, Surgery and Dentistry Medicine, University of Salerno, 84081 Baronissi, Italy;
| | - Francesco Perri
- Medical and Experimental Head and Neck Oncology Unit, INT IRCCS Foundation “G. Pascale”, 80131 Naples, Italy;
| | - Stefano Pepe
- Oncology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy; (G.P.); (S.P.)
| | - Francesco Sabbatino
- Oncology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy; (G.P.); (S.P.)
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Profili NI, Castelli R, Gidaro A, Merella A, Manetti R, Palmieri G, Maioli M, Delitala AP. Endocrine Side Effects in Patients Treated with Immune Checkpoint Inhibitors: A Narrative Review. J Clin Med 2023; 12:5161. [PMID: 37568563 PMCID: PMC10419837 DOI: 10.3390/jcm12155161] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/19/2023] [Accepted: 08/03/2023] [Indexed: 08/13/2023] Open
Abstract
Checkpoint inhibitors are monoclonal antibodies that elicit an anti-tumor response by stimulating immune system. Their use has improved the treatment of different types of cancer such as melanoma, breast carcinoma, lung, stomach, colon, liver, renal cell carcinoma, and Hodgkin's lymphoma, but several adverse events have been reported. Although the etiology of these effects is not completely understood, an uncontrolled activation of the immune system has been postulated. Indeed, some studies showed a cross reactivity of T cells, which acted against tumor antigens as well as antigens in the tissues of patients who developed immune-related adverse events. Despite the known possibility of developing immune-related adverse events, early diagnosis, monitoring during therapy, and treatment are fundamental for the best supportive care and administration of immune checkpoint inhibitors. The aim of this review is to guide the clinician in early diagnosis, management, and treatment of the endocrinological adverse effects in the major endocrine glands (thyroid, pituitary, adrenal, endocrine pancreas, and parathyroid).
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Affiliation(s)
- Nicia I. Profili
- Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy
| | - Roberto Castelli
- Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy
| | - Antonio Gidaro
- Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Luigi Sacco Hospital, 20157 Milan, Italy
| | - Alessandro Merella
- Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy
| | - Roberto Manetti
- Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy
| | - Giuseppe Palmieri
- Department of Biochemical Science, University of Sassari, 07100 Sassari, Italy
| | - Margherita Maioli
- Department of Biochemical Science, University of Sassari, 07100 Sassari, Italy
| | - Alessandro P. Delitala
- Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy
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Roberto M, Panebianco M, Aschelter AM, Buccilli D, Cantisani C, Caponnetto S, Cortesi E, d’Amuri S, Fofi C, Ierinò D, Maestrini V, Marchetti P, Marignani M, Stigliano A, Vivona L, Santini D, Tomao S. The value of the multidisciplinary team in metastatic renal cell carcinoma: Paving the way for precision medicine in toxicities management. Front Oncol 2023; 12:1026978. [PMID: 36713496 PMCID: PMC9879059 DOI: 10.3389/fonc.2022.1026978] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 10/07/2022] [Indexed: 01/14/2023] Open
Abstract
The new landscape of treatments for metastatic clear cell renal carcinoma (mRCC) is constantly expanding, but it is associated with the emergence of novel toxicities, adding to up to those observed in the tyrosine-kinase inhibitor (TKI) era. Indeed, the introduction of immune checkpoint inhibitors (ICIs) alone or in combination has been associated with the development of immune-related adverse events (irAEs) involving multiple-organ systems which, even if rarely, had led to fatal outcomes. Moreover, due to the relatively recent addition of ICIs to the previously available treatments, the potential additive adverse effects of these combinations are still unknown. A prompt recognition and management of these toxicities currently represents a fundamental issue in oncology, since it correlates with the outcome of cancer patients. Even if clinical guidelines provide indications for the management of irAEs, no specific protocol to evaluate the individual risk of developing an adverse event during therapy is currently available. A multidisciplinary approach addressing appropriate interventions aimed at reducing the risk of any insidious, severe, and/or dose-limiting toxicity might represent the most efficacious strategy to timely prevent and manage severe irAEs, allowing indirectly to improve both patients' cancer-specific survival and quality of life. In this review, we reported a five-case series of toxicity events that occurred at our center during treatment for mRCC followed by the remarks of physicians from different specialties, pinpointing the relevant role of an integrated and extended multidisciplinary team in a modern model of mRCC patient management.
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Affiliation(s)
- Michela Roberto
- Department of Radiological, Oncological and Anatomo-Pathological Sciences, Medical Oncology Unit A, Policlinico Umberto I Hospital, Sapienza University of Rome, Rome, Italy
| | - Martina Panebianco
- Department of Clinical and Molecular Medicine, Oncology Unit, Sant’ Andrea University Hospital, Sapienza University of Rome, Rome, Italy,*Correspondence: Martina Panebianco,
| | - Anna Maria Aschelter
- Department of Clinical and Molecular Medicine, Oncology Unit, Sant’ Andrea University Hospital, Sapienza University of Rome, Rome, Italy
| | - Dorelsa Buccilli
- Department of Radiological, Oncological and Anatomo-Pathological Sciences, Medical Oncology Unit A, Policlinico Umberto I Hospital, Sapienza University of Rome, Rome, Italy
| | - Carmen Cantisani
- Department of Dermatology, Complex Operative Unit (UOC) of Dermatology, Policlinico Umberto I Hospital, Sapienza University of Rome, Rome, Italy
| | - Salvatore Caponnetto
- Department of Radiological, Oncological and Anatomo-Pathological Sciences, Medical Oncology Unit B, Policlinico Umberto I Hospital, Sapienza University of Rome, Rome, Italy
| | - Enrico Cortesi
- Department of Radiological, Oncological and Anatomo-Pathological Sciences, Medical Oncology Unit B, Policlinico Umberto I Hospital, Sapienza University of Rome, Rome, Italy
| | - Sara d’Amuri
- Department of Clinical and Molecular Medicine, Oncology Unit, Sant’ Andrea University Hospital, Sapienza University of Rome, Rome, Italy
| | - Claudia Fofi
- Department of Clinical and Molecular Medicine, Nephrology and Dialysis Unit, Sant’ Andrea Hospital, Sapienza University of Rome, Rome, Italy
| | - Debora Ierinò
- Department of Clinical and Molecular Medicine, Oncology Unit, Sant’ Andrea University Hospital, Sapienza University of Rome, Rome, Italy
| | - Viviana Maestrini
- Department of Clinical, Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Paolo Marchetti
- Scientific Direction, Istituto Dermopatico dell’Immacolata (IDI-IRCCS), Rome, Italy
| | - Massimo Marignani
- Head Liver Disease Section, Digestive and Liver Diseases Department, Sant’ Andrea Hospital, Sapienza University of Rome, Rome, Italy
| | - Antonio Stigliano
- Department of Clinical and Molecular Medicine, Endocrinology Unit, Sant ‘Andrea University Hospital, Sapienza University of Rome, Rome, Italy
| | - Luca Vivona
- Department of Radiological, Oncological and Anatomo-Pathological Sciences, Medical Oncology Unit A, Policlinico Umberto I Hospital, Sapienza University of Rome, Rome, Italy
| | - Daniele Santini
- Complex Operative Unit (UOC) Oncologia Medica, Sapienza University, Polo Pontino, Latina, Italy
| | - Silverio Tomao
- Department of Radiological, Oncological and Anatomo-Pathological Sciences, Medical Oncology Unit A, Policlinico Umberto I Hospital, Sapienza University of Rome, Rome, Italy
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Lee HJ, Manavalan A, Stefan-Lifshitz M, Schechter C, Maity A, Tomer Y. Permanent hypothyroidism following immune checkpoint inhibitors induced thyroiditis may be associated with improved survival: results of an exploratory study. Front Endocrinol (Lausanne) 2023; 14:1169173. [PMID: 37168978 PMCID: PMC10165534 DOI: 10.3389/fendo.2023.1169173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Accepted: 04/03/2023] [Indexed: 05/13/2023] Open
Abstract
Background Immune-related endocrinopathies are common after immune checkpoint inhibitor (ICI) therapy, among which destructive thyroiditis is the most prevalent. Improved survival outcomes have been associated with immune-related adverse events. We aimed to compare the clinical course and biochemical parameters of two subtypes of ICI-related destructive thyroiditis: a transient thyrotoxicosis that reverts to either euthyroidism (TT; transient thyroiditis) versus progression to permanent hypothyroidism (PH), and to identify prognostic markers in cancer patients receiving ICI therapy who developed DT. Methods This retrospective observational study included 124 patients who developed a transient thyrotoxicosis due to a destructive thyroiditis after ICI therapy from January 1, 2016 to April 30, 2021 at the Montefiore Medical Center. Patients were categorized as either TT or PH based on spontaneous renormalization of the TSH or the permanent need for thyroid hormone replacement, respectively. Thyroid hormone and antibody levels, serum inflammatory markers, eosinophils, and metabolic uptake of the thyroid on PET imaging, each corresponding closest to a suppressed TSH, were characterized. Survival from TT and PH were also analyzed. Results Of the 124 patients, 53 developed PH and 71 developed TT. The PH group developed thyrotoxicosis at a median of 42 days from the first ICI dose while the TT group took significantly longer at 56 days. Thyroidal PET uptake was increased in 18.9% of the PH group versus 6.0% of the TT group (P=0.04). Three different survival models consistently demonstrated a trend towards increased survival in the PH group, compared to the TT group. Conclusion Our results suggest that PH developing after ICI-induced destructive thyroiditis may be associated with a more robust inflammatory and antitumor response to ICI therapy. The results suggests that PH may be a potential clinical predictor of improved survival.
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Affiliation(s)
- Hanna J. Lee
- Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States
- *Correspondence: Hanna J. Lee,
| | - Anjali Manavalan
- Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Mihaela Stefan-Lifshitz
- Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Clyde Schechter
- Department of Family and Social Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, United States
| | - Aloke Maity
- Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, United States
| | - Yaron Tomer
- Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States
- Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, United States
- Fleischer Institute of Diabetes and Metabolism, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, United States
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10
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Abdelnour SA, Metwally MGE, Bahgat LB, Naiel MAE. Pumpkin seed oil-supplemented diets promoted the growth productivity, antioxidative capacity, and immune response in heat-stressed growing rabbits. Trop Anim Health Prod 2023; 55:55. [PMID: 36715777 PMCID: PMC9886635 DOI: 10.1007/s11250-023-03460-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 01/04/2023] [Indexed: 01/31/2023]
Abstract
Heat stress is the most major environmental element contributing to rabbit health problems and reduced production. It is proposed that essential oils be applied to alleviate heat stress-induced oxidative damage in rabbits. The purpose of this feeding trial was to determine the protective impact of pumpkin seed essential oil (PSO)-supplemented diets in reducing the threat of unambient temperature on growing rabbits. Five groups of 5-week-old rabbits were allocated randomly into separated galvanized wire battery. The first group was raised under normal conditions (18 ± 2 °C) and fed a control diet (control group; CNT), whereas the other four groups were exposed to high ambient temperature (38 ± 2 °C) and fed a control diet supplemented with 0 (PSO0.0), 0.5 (PSO0.05), 1.0 (PSO1.0), and 2.0 (PSO2.0) mL PSO/kg diet. Results indicated that all supplemented groups and the positive control have higher live body weight compared with the heat stress group (PSO0.0) at 9 weeks of age. Supplementing of PSO resulted in significant improvement in weight gain at 5-9 weeks and 9-13 weeks compared with PSO0.0 group. The highest feed intake was detected in PSO0.05 group compared with that in other groups. Both PSO2.0 and PSO2.0 groups showed the lowest feed conversion ration compared with other groups. Heat-stressed rabbits given a high dose of PSO (1 to 2 mL) had higher hemoglobin concentrations and lower white blood cell counts throughout the experiment than those given a control diet and subjected to heat stress. All hepatic and renal function parameters improved significantly in the rabbits fed a high dose of PSO as compared to the heat-stressed control group, while protein constituents were significantly higher in experimental groups fed 2 mL PSO compared with other groups. Heat-stressed rabbits administered graded amounts of PSO had the lowest plasma glucose, cortisol, thyroid, and corticosterone concentrations and were noticed to be equivalent to the control group fed unsupplemented diet and reared under normal conditions. The immunohistochemistry analysis demonstrated that rabbit groups reared under heat stress and given 2 mL PSO supplemented diets had negative caspase-3 immunoreactivity surrounding portal tract and normal structure. In conclusion, adding pumpkin seed oil up to 2 mL/kg diet for growing rabbits is indorsed to promote growth as well as antioxidant and immunological status under heat stress conditions.
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Affiliation(s)
- Sameh A. Abdelnour
- grid.31451.320000 0001 2158 2757Department of Animal Production, Faculty of Agriculture, Zagazig University, Zagazig, 44519 Egypt
| | - Mohamed G. E. Metwally
- grid.31451.320000 0001 2158 2757Department of Animal Production, Faculty of Agriculture, Zagazig University, Zagazig, 44519 Egypt
| | - Laila B. Bahgat
- grid.31451.320000 0001 2158 2757Department of Animal Production, Faculty of Agriculture, Zagazig University, Zagazig, 44519 Egypt
| | - Mohammed A. E. Naiel
- grid.31451.320000 0001 2158 2757Department of Animal Production, Faculty of Agriculture, Zagazig University, Zagazig, 44519 Egypt
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11
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Spagnolo CC, Giuffrida G, Cannavò S, Franchina T, Silvestris N, Ruggeri RM, Santarpia M. Management of Endocrine and Metabolic Toxicities of Immune-Checkpoint Inhibitors: From Clinical Studies to a Real-Life Scenario. Cancers (Basel) 2022; 15:cancers15010246. [PMID: 36612243 PMCID: PMC9818218 DOI: 10.3390/cancers15010246] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/22/2022] [Accepted: 12/24/2022] [Indexed: 01/03/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of solid tumors. However, although ICIs are better tolerated than conventional chemotherapy, their use is associated with a peculiar toxicity profile, related to the enhancement of the immune response, affecting several organs. Among immune-related adverse events (irAEs), up to 10% involve the endocrine system. Most of them are represented by thyroid disorders (hypothyroidism and hyperthyroidism), mainly correlated to the use of anti-PD-1 and/or anti-PD-L1 agents. Less common endocrine irAEs include hypophysitis, adrenalitis, and metabolic irAEs. A deeper understanding of endocrine toxicities is a critical goal for both oncologists and endocrinologists. A strict collaboration between these specialists is mandatory for early recognition and proper treatment of these patients. In this review we will provide a comprehensive overview of endocrine and metabolic adverse events of ICIs, with particular interest in the pathogenesis, predisposing factors and clinical presentation of these irAEs, and their impact on clinical outcomes of patients. Furthermore, we will summarize the most recent studies and recommendations on the clinical approach to immune-related endocrinopathies with the purpose to optimize the diagnostic algorithm, and to help both oncologists and endocrinologists to improve the therapeutic management of these unique types of irAEs, in a real-life scenario.
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Affiliation(s)
- Calogera Claudia Spagnolo
- Medical Oncology Unit, Department of Human Pathology “G.Barresi”, University of Messina, 98125 Messina, Italy
| | - Giuseppe Giuffrida
- Endocrinology Unit, Department of Human Pathology of Adulthood and Childhood DETEV, University of Messina, 98125 Messina, Italy
| | - Salvatore Cannavò
- Endocrinology Unit, Department of Human Pathology of Adulthood and Childhood DETEV, University of Messina, 98125 Messina, Italy
| | - Tindara Franchina
- Medical Oncology Unit, Department of Human Pathology “G.Barresi”, University of Messina, 98125 Messina, Italy
| | - Nicola Silvestris
- Medical Oncology Unit, Department of Human Pathology “G.Barresi”, University of Messina, 98125 Messina, Italy
| | - Rosaria Maddalena Ruggeri
- Endocrinology Unit, Department of Human Pathology of Adulthood and Childhood DETEV, University of Messina, 98125 Messina, Italy
| | - Mariacarmela Santarpia
- Medical Oncology Unit, Department of Human Pathology “G.Barresi”, University of Messina, 98125 Messina, Italy
- Correspondence:
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12
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Hirao N, Iijima T, Tanuma D, Ohira E, Kurai H, Shinzawa T, Kase M, Sakurai S, Tomaru T, Jojima T, Usui I, Aso Y. Effects of treatment with methimazole on circulating CD4 + and CD8 + T cells positive for programed cell death protein-1 and on subsets of CD4 + T cells in untreated hyperthyroid patients with Graves' disease. Clin Endocrinol (Oxf) 2022; 97:841-848. [PMID: 35692119 DOI: 10.1111/cen.14788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 05/31/2022] [Accepted: 06/08/2022] [Indexed: 11/26/2022]
Abstract
OBJECTIVE We investigated longitudinal changes in circulating CD4+ and CD8+ T cells positive for programed cell death protein-1 (PD-1) and in other subsets of CD4+ T cells in untreated hyperthyroid patients with Graves' disease after treatment with methimazole (MMI). DESIGN AND PATIENTS The study included 18 untreated hyperthyroid patients with Graves' disease and 18 age-matched controls. Before and after 12-week treatment with MMI, we used flow cytometry to measure circulating PD-1+ D4+ and PD-1+ CD8+ T cells and subsets of CD4+ T cells in peripheral blood, as well as serum levels of chemokines related to T-helper type 1 (Th-1) and Th-2 cells. RESULTS At baseline, the percentage of CD4+ and CD8+ T cells expressing PD-1 was significantly higher in patients than in age-matched controls. Serum levels of chemokines related to Th-1 and Th-2 also were higher in patients. Twelve weeks after initiation of MMI, the percentage of CD4+ T cells expressing PD-1 was significantly lower than at baseline, but no such change was seen in CD8+ T cells. Furthermore, the percentage of Th-1 cells among CD4+ T cells and the serum levels of soluble CD26/dipeptidyl peptidase-4, a surface marker of Th-1 cells, also were significantly lower than at baseline. CONCLUSIONS The expression of PD-1 on circulating CD4+ and CD8+ T cells is increased in hyperthyroid patients with active Graves' disease. MMI significantly decreases levels of circulating PD-1+ CD4+ T cells, suggesting that PD-1+ T lymphocytes may be associated with the pathogenesis of Graves' disease.
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Affiliation(s)
- Nanako Hirao
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Toshie Iijima
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Dai Tanuma
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Eriko Ohira
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Hidetaka Kurai
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Toshimitsu Shinzawa
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Masato Kase
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Shintaro Sakurai
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Takuya Tomaru
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Teruo Jojima
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Isao Usui
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Yoshimasa Aso
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Tochigi, Japan
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Chye A, Allen I, Barnet M, Burnett DL. Insights Into the Host Contribution of Endocrine Associated Immune-Related Adverse Events to Immune Checkpoint Inhibition Therapy. Front Oncol 2022; 12:894015. [PMID: 35912205 PMCID: PMC9329613 DOI: 10.3389/fonc.2022.894015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 06/10/2022] [Indexed: 12/12/2022] Open
Abstract
Blockade of immune checkpoints transformed the paradigm of systemic cancer therapy, enabling substitution of a cytotoxic chemotherapy backbone to one of immunostimulation in many settings. Invigorating host immune cells against tumor neo-antigens, however, can induce severe autoimmune toxicity which in many cases requires ongoing management. Many immune-related adverse events (irAEs) are clinically and pathologically indistinguishable from inborn errors of immunity arising from genetic polymorphisms of immune checkpoint genes, suggesting a possible shared driver for both conditions. Many endocrine irAEs, for example, have analogous primary genetic conditions with varied penetrance and severity despite consistent genetic change. This is akin to onset of irAEs in response to immune checkpoint inhibitors (ICIs), which vary in timing, severity and nature despite a consistent drug target. Host contribution to ICI response and irAEs, particularly those of endocrine origin, such as thyroiditis, hypophysitis, adrenalitis and diabetes mellitus, remains poorly defined. Improved understanding of host factors contributing to ICI outcomes is essential for tailoring care to an individual’s unique genetic predisposition to response and toxicity, and are discussed in detail in this review.
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Affiliation(s)
- Adrian Chye
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW, Australia
- Department of Medical Oncology, The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia
| | - India Allen
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW, Australia
| | - Megan Barnet
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW, Australia
- Department of Medical Oncology, The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia
- *Correspondence: Megan Barnet, ; Deborah L. Burnett,
| | - Deborah L. Burnett
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW, Australia
- *Correspondence: Megan Barnet, ; Deborah L. Burnett,
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14
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Deligiorgi MV, Trafalis DT. The continuum of care of anticancer treatment-induced hypothyroidism in patients with solid non thyroid tumors: time for an intimate collaboration between oncologists and endocrinologists. Expert Rev Clin Pharmacol 2022; 15:531-549. [PMID: 35757870 DOI: 10.1080/17512433.2022.2093714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Hypothyroidism is a common adverse event of various anticancer treatment modalities, constituting a notable paradigm of the integration of the endocrine perspective into precision oncology. AREAS COVERED The present narrative review provides a comprehensive and updated overview of anticancer treatment-induced hypothyroidism in patients with solid non-thyroid tumors. A study search was conducted on the following electronic databases: PubMed, Google Scholar, Scopus.com, ClinicalTrials.gov, and European Union Clinical Trials Register from 2011 until August 2021. EXPERT OPINION In patients with solid non-thyroid tumors, hypothyroidism is a common adverse event of radiotherapy, high dose interleukin 2 (HD IL-2), interferon alpha (IFN-α), bexarotene, immune checkpoint inhibitors (ICPi), and tyrosine kinase inhibitors (TKIs), while chemotherapy may induce hypothyroidism more often than initially considered. The path forward for the management of anticancer treatment-induced hypothyroidism in patients with solid non-thyroid tumors is an integrated approach grounded on 5 pillars: prevention, vigilance, diagnosis, treatment and monitoring. Current challenges concerning anticancer treatment-induced hypothyroidism await counteraction, namely awareness of the growing list of related anticancer treatments, identification of predictive factors, counteraction of diagnostic pitfalls, tuning of thyroid hormone replacement, and elucidation of its prognostic significance. Close collaboration of oncologists with endocrinologists will provide optimal patient care.
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Affiliation(s)
- Maria V Deligiorgi
- Department of Pharmacology - Clinical Pharmacology Unit, National and Kapodistrian University of Athens, Faculty of Medicine, Athens, Greece
| | - Dimitrios T Trafalis
- Department of Pharmacology - Clinical Pharmacology Unit, National and Kapodistrian University of Athens, Faculty of Medicine, Athens, Greece
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15
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Rallis KS, Makrakis D, Ziogas IA, Tsoulfas G. Immunotherapy for advanced hepatocellular carcinoma: From clinical trials to real-world data and future advances. World J Clin Oncol 2022; 13:448-472. [PMID: 35949435 PMCID: PMC9244967 DOI: 10.5306/wjco.v13.i6.448] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 04/27/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated mortality worldwide. HCC is an inflammation-associated immunogenic cancer that frequently arises in chronically inflamed livers. Advanced HCC is managed with systemic therapies; the tyrosine kinase inhibitor (TKI) sorafenib has been used in 1st-line setting since 2007. Immunotherapies have emerged as promising treatments across solid tumors including HCC for which immune checkpoint inhibitors (ICIs) are licensed in 1st- and 2nd-line treatment setting. The treatment field of advanced HCC is continuously evolving. Several clinical trials are investigating novel ICI candidates as well as new ICI regimens in combination with other therapeutic modalities including systemic agents, such as other ICIs, TKIs, and anti-angiogenics. Novel immunotherapies including adoptive cell transfer, vaccine-based approaches, and virotherapy are also being brought to the fore. Yet, despite advances, several challenges persist. Lack of real-world data on the use of immunotherapy for advanced HCC in patients outside of clinical trials constitutes a main limitation hindering the breadth of application and generalizability of data to this larger and more diverse patient cohort. Consequently, issues encountered in real-world practice include patient ineligibly for immunotherapy because of contraindications, comorbidities, or poor performance status; lack of response, efficacy, and safety data; and cost-effectiveness. Further real-world data from high-quality large prospective cohort studies of immunotherapy in patients with advanced HCC is mandated to aid evidence-based clinical decision-making. This review provides a critical and comprehensive overview of clinical trials and real-world data of immunotherapy for HCC, with a focus on ICIs, as well as novel immunotherapy strategies underway.
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Affiliation(s)
- Kathrine S Rallis
- Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AD, United Kingdom
- Surgery Working Group, Society of Junior Doctors, Athens 15123, Greece
| | - Dimitrios Makrakis
- Surgery Working Group, Society of Junior Doctors, Athens 15123, Greece
- Division of Oncology, University of Washington School of Medicine, Seattle, WA 98195, United States
| | - Ioannis A Ziogas
- Surgery Working Group, Society of Junior Doctors, Athens 15123, Greece
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States
| | - Georgios Tsoulfas
- Department of Transplantation Surgery, Aristotle University School of Medicine, Thessaloniki 54622, Greece
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16
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Mechanisms underlying immune-related adverse events during checkpoint immunotherapy. Clin Sci (Lond) 2022; 136:771-785. [PMID: 35621125 DOI: 10.1042/cs20210042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 05/01/2022] [Accepted: 05/06/2022] [Indexed: 11/17/2022]
Abstract
Immune checkpoint (IC) proteins are some of the most important factors that tumor cells hijack to escape immune surveillance, and inhibiting ICs to enhance or relieve antitumor immunity has been proven efficient in tumor treatment. Immune checkpoint blockade (ICB) agents such as antibodies blocking programmed death (PD) 1, PD-1 ligand (PD-L) 1, and cytotoxic T lymphocyte-associated antigen (CTLA)-4 have been approved by the U.S. Food and Drug Administration (FDA) to treat several types of cancers. Although ICB agents have shown outstanding clinical success, and their application has continued to expand to additional tumor types in the past decade, immune-related adverse events (irAEs) have been observed in a wide range of patients who receive ICB treatment. Numerous studies have focused on the clinical manifestations and pathology of ICB-related irAEs, but the detailed mechanisms underlying irAEs remain largely unknown. Owing to the wide expression of IC molecules on distinct immune cell subpopulations and the fact that ICB agents generally affect IC-expressing cells, the influences of ICB agents on immune cells in irAEs need to be determined. Here, we discuss the expression and functions of IC proteins on distinct immune cells and the potential mechanism(s) related to ICB-targeted immune cell subsets in irAEs.
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17
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Yuen KCJ, Samson SL, Bancos I, Gosmanov AR, Jasim S, Fecher LA, Weber JS. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGY (AACE) DISEASE STATE CLINICAL REVIEW EVALUATION AND MANAGEMENT OF IMMUNE CHECKPOINT INHIBITOR-MEDIATED ENDOCRINOPATHIES: A PRACTICAL CASE-BASED CLINICAL APPROACH. Endocr Pract 2022; 28:719-731. [PMID: 35477029 DOI: 10.1016/j.eprac.2022.04.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/14/2022] [Accepted: 04/18/2022] [Indexed: 12/17/2022]
Abstract
OBJECTIVE The aim of this case-based clinical review is to provide a practical approach for clinicians regarding the management of patients with immune checkpoint inhibitor (ICI)-mediated endocrinopathies. METHODS A literature search was conducted using PubMed, Embase and Scopus, and appropriate keywords. The discussions and strategies for diagnosis and management of ICI-mediated endocrinopathies are based on evidence available from prospective randomized clinical studies, cohort studies, cross-sectional studies, case-based studies, and expert consensus. RESULTS Immunotherapy with ICIs has transformed the treatment landscape of diverse cancer types, but frequently results in immune-mediated endocrinopathies that can cause acute and persistent morbidity, and rarely, death. The patterns of endocrinopathies differ between inhibitors of the CTLA-4 and PD-1/PD-L1 pathways, but most often involve the thyroid and pituitary glands. Less common but important presentations include insulin-deficient diabetes mellitus, primary adrenal insufficiency, primary hypoparathyroidism, central diabetes insipidus, primary hypogonadism, and pancreatitis with or without subsequent progression to diabetes or exocrine insufficiency. CONCLUSION In recent years, with increasing numbers of cancer patients being treated with ICIs, more clinicians in a variety of specialties are called upon to diagnose and treat ICI-mediated endocrinopathies. Herein, we review case scenarios of various clinical manifestations, and emphasize the need for a high index of clinical suspicion by all clinicians caring for these patients including endocrinologists, oncologists, primary care providers, and emergency department physicians. We also provide diagnostic and therapeutic approaches for ICI-induced endocrinopathies, and we propose that patients on ICI-therapy be evaluated and treated in a multidisciplinary team in collaboration with endocrinologists.
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Affiliation(s)
- Kevin C J Yuen
- Co-Chair of Task Force; Professor of Medicine, Department of Medicine, University of Arizona College of Medicine and Creighton School of Medicine, Phoenix, Arizona.
| | - Susan L Samson
- Co-Chair of Task Force; Senior Associate Consultant, Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic, Jacksonville, Florida
| | - Irina Bancos
- Associate Professor of Medicine; Associate Program Director, Endocrinology Fellowship Program, Division of Endocrinology, Metabolism and Nutrition, Mayo Clinic, Rochester, MN
| | - Aidar R Gosmanov
- Professor of Medicine, Division of Endocrinology, Albany Medical College; Chief, Endocrinology Section, Stratton VAMC, Albany, NY
| | - Sina Jasim
- Associate Professor of Medicine, Washington University in St. Louis, School of Medicine, Division of Endocrinology, Metabolism and Lipid Research, St. Louis, Missouri
| | - Leslie A Fecher
- ASCO Representative, Associate Professor of Medicine and Dermatology, University of Michigan, Rogel Cancer Center, Ann Arbor, Michigan
| | - Jeffrey S Weber
- ASCO Representative, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, New York
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18
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Izawa N, Shiokawa H, Onuki R, Hamaji K, Morikawa K, Saji H, Ohashi H, Kasugai S, Hayakawa N, Ohara T, Sunakawa Y. The clinical utility of comprehensive measurement of autoimmune disease-related antibodies in patients with advanced solid tumors receiving immune checkpoint inhibitors: a retrospective study. ESMO Open 2022; 7:100415. [PMID: 35247869 PMCID: PMC9058890 DOI: 10.1016/j.esmoop.2022.100415] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 12/18/2021] [Accepted: 01/19/2022] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The comprehensive measurement of autoimmune disease-related antibodies (Abs) before immune checkpoint inhibitor (ICI) treatment may be useful for predicting the development of immune-related adverse events (irAEs); however, the clinical utility is not well known. MATERIALS AND METHODS We retrospectively analyzed patients with advanced solid tumors treated with ICI monotherapy or doublet combination therapy between July 2014 and December 2020 at single institute. Anti-nuclear antibody (ANA), anti-thyroglobulin (Tg) Ab, anti-thyroid peroxidase (TPO) Ab, anti-glutamic acid decarboxylase (GAD) Ab, anti-acetylcholine esterase receptor (AchR) Ab, and platelet-associated immunoglobulin G (PA-IgG) Ab were comprehensively measured for the screening before ICI therapy. RESULTS Of 275 registered patients (median age, 70 years; male, 64.4%; Eastern Cooperative Oncology Group performance status of 0 or 1, 88.7%; and prior regimen of 0-1/≥2, 88.7%/11.3%), 128 non-small-cell lung cancer, 35 gastric cancer, 33 head and neck cancer, 24 melanoma, 19 renal cell carcinoma, 13 urothelial carcinoma, 12 esophageal cancer, 5 malignant mesothelioma of pleura, 2 endometrial cancer, and 4 other cancer were included. The number of patients with positive ANA, Tg, TPO, PA-IgG, GAD, and AchR Abs was 52 (24.9%), 38 (14.5%), 11 (10.1%), 6 (3.5%), 5 (2.0%), and 1 (0.5%), respectively. There was no association between the development of any irAEs and Abs positivity, while thyroid dysfunction developed more frequently among patients with than without Tg Ab or TPO Ab (39.5% versus 12.5%, P < 0.01; 45.5% versus 14.3%, P = 0.02). CONCLUSIONS The clinical utility of comprehensive measurement of autoimmune disease-related Abs before introduction of ICI therapy was limited for predicting irAE. However, Tg and TPO Abs were risk factors as regards the development of ICI-induced thyroid dysfunction.
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Affiliation(s)
- N Izawa
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - H Shiokawa
- Department of Pharmacy, St. Marianna University Hospital, Kawasaki, Japan
| | - R Onuki
- Department of Pharmacy, St. Marianna University Hospital, Kawasaki, Japan
| | - K Hamaji
- Department of Pharmacy, St. Marianna University Hospital, Kawasaki, Japan
| | - K Morikawa
- Department of Internal Medicine, Division of Respiratory Medicine, St. Marianna University School of Medicine, Kawasaki, Japan
| | - H Saji
- Department of Chest Surgery, St. Marianna University School of Medicine, Kawasaki, Japan
| | - H Ohashi
- Department of Dermatology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - S Kasugai
- Department of Otorhinolaryngology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - N Hayakawa
- Department of Urology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - T Ohara
- Department of Obstetrics and Gynecology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Y Sunakawa
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.
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Alchalabi H, Albustani S, Fareen N, Udongwo N, Chaughtai S, Holland S. An Unusual Etiology of Hypothyroidism and New-Onset Insulin-Dependent Diabetes: A Rare Side Effect of Nivolumab. Cureus 2022; 14:e24463. [PMID: 35651456 PMCID: PMC9135045 DOI: 10.7759/cureus.24463] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/21/2022] [Indexed: 11/18/2022] Open
Abstract
Nivolumab, a monoclonal antibody targeting programmed cell death 1 receptor, is prescribed for many advanced cancers like malignant melanoma, non-small cell lung cancer, renal cell cancer, etc. With the increase in the use of nivolumab like immunotherapy, the incidences of immune-related side effects are also on the rise. Immune-related endocrinopathies like hypothyroidism and new-onset type 2 diabetes mellitus associated with nivolumab use, although rare, are already documented in the literature. Here we present a case of hypothyroidism and new-onset type 2 diabetes mellitus in a renal cell cancer patient receiving nivolumab for the past six months. The patient was managed successfully with discontinuation of nivolumab, intravenous insulin, and thyroid hormone replacement therapy. These types of endocrinopathies can be fatal; hence, prompt diagnosis and management are required. Thus, not only physicians' awareness of such endocrinopathies among nivolumab-treated patients but also patients' awareness regarding warning signs and symptoms are essential.
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Affiliation(s)
- Halah Alchalabi
- Internal Medicine, Jersey Shore University Medical Center, Neptune Township, USA
| | - Safa Albustani
- Internal Medicine, Jersey Shore University Medical Center, Neptune Township, USA
| | - Nusha Fareen
- Internal Medicine, Jersey Shore University Medical Center, Neptune Township, USA
| | - Ndausung Udongwo
- Internal Medicine, Jersey Shore University Medical Center, Neptune Township, USA
| | - Saira Chaughtai
- Internal Medicine, Jersey Shore University Medical Center, Neptune Township, USA
| | - Soemiwati Holland
- Endocrinology, Diabetes and Metabolism, Jersey Shore University Medical Center, Neptune Township, USA
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Poto R, Troiani T, Criscuolo G, Marone G, Ciardiello F, Tocchetti CG, Varricchi G. Holistic Approach to Immune Checkpoint Inhibitor-Related Adverse Events. Front Immunol 2022; 13:804597. [PMID: 35432346 PMCID: PMC9005797 DOI: 10.3389/fimmu.2022.804597] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 03/07/2022] [Indexed: 12/12/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) block inhibitory molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or its ligand, programmed cell death protein ligand 1 (PD-L1) and enhance antitumor T-cell activity. ICIs provide clinical benefits in a percentage of patients with advanced cancers, but they are usually associated with a remarkable spectrum of immune-related adverse events (irAEs) (e.g., rash, colitis, hepatitis, pneumonitis, endocrine, cardiac and musculoskeletal dysfunctions). Particularly patients on combination therapy (e.g., anti-CTLA-4 plus anti-PD-1/PD-L1) experience some form of irAEs. Different mechanisms have been postulated to explain these adverse events. Host factors such as genotype, gut microbiome and pre-existing autoimmune disorders may affect the risk of adverse events. Fatal ICI-related irAEs are due to myocarditis, colitis or pneumonitis. irAEs usually occur within the first months after ICI initiation but can develop as early as after the first dose to years after ICI initiation. Most irAEs resolve pharmacologically, but some appear to be persistent. Glucocorticoids represent the mainstay of management of irAEs, but other immunosuppressive drugs can be used to mitigate refractory irAEs. In the absence of specific trials, several guidelines, based on data from retrospective studies and expert consensus, have been published to guide the management of ICI-related irAEs.
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Affiliation(s)
- Remo Poto
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Teresa Troiani
- Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Gjada Criscuolo
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
| | | | - Fortunato Ciardiello
- Medical Oncology, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | | | - Gilda Varricchi
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
- World Allergy Organization (WAO) Center of Excellence, Naples, Italy
- Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council, Naples, Italy
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21
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Kristan MM, Toro-Tobon D, Francis N, Desale S, Bikas A, Jonklaas J, Goyal RM. Immunotherapy-Associated Hypothyroidism: Comparison of the Pre-Existing With De-Novo Hypothyroidism. Front Endocrinol (Lausanne) 2022; 13:798253. [PMID: 35360059 PMCID: PMC8962946 DOI: 10.3389/fendo.2022.798253] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 02/10/2022] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Immunotherapy has revolutionized the treatment of solid malignancies, but is associated with endocrine-related adverse events. This study aims to dissect the natural course of immunotherapy-induced hypothyroidism and provide guidance regarding diagnosis and management in patients with and without pre-existing hypothyroidism. METHODS A retrospective analysis was conducted using patients who received immunotherapy between 2010-2019 within a multicenter hospital system. Participants were separated in three groups-those with pre-existing hypothyroidism, those who developed primary hypothyroidism and those with hypophysitis within a year of their first immunotherapy. Serial effects of immunotherapy on thyroid function tests (TFTs) and levothyroxine dosing were evaluated. RESULTS 822 patients were screened, with 85 determined to have pre-existing hypothyroidism, 48 de-novo primary hypothyroidism and 12 de-novo hypophysitis. All groups displayed fluctuations in TFTs around weeks 6-8 of treatment. In the pre-existing hypothyroidism group, the levothyroxine dose was higher at 54 weeks than at baseline with the difference showing a trend towards statistical significance (p=0.06). The observed mean levothyroxine dose was significantly lower than the mean calculated weight-based dose for all groups. This finding was most clinically significant for the de-novo hypophysitis group (mean difference: -58.3 mcg, p<0.0001). The mean 0.9 mcg/kg levothyroxine dose at week 54 for the de-novo hypophysitis group was statistically lower than the other groups (p=0.009). CONCLUSION It is reasonable to screen with TFTs every 4 weeks, and space out TFTs surveillance to every 12 weeks after week 20. Our findings suggest a more conservative approach for levothyroxine dosing in those developing de-novo hypothyroidism, especially hypophysitis, such as initiating at 0.9-1.2 mcg/kg.
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Affiliation(s)
- Megan M. Kristan
- Division of Endocrinology, University of Maryland Medical Center, Baltimore, MD, United States
| | - David Toro-Tobon
- Division of Endocrinology, Mayo Clinic Rochester, Rochester, MN, United States
| | - Nnenia Francis
- Division of Endocrinology, University of Pennsylvania Health System, Philadelphia, PA, United States
| | - Sameer Desale
- Department of Biostatistics and Bioinformatics, Medstar Health Research Institute, Hyattsville, MD, United States
| | - Athanasios Bikas
- Division of Endocrinology, Brigham and Women’s Hospital, Boston, MA, United States
| | - Jacqueline Jonklaas
- Division of Endocrinology, Georgetown University Medical Center, Washington, DC, United States
| | - Rachna M. Goyal
- Division of Endocrinology, Georgetown University Medical Center, Washington, DC, United States
- *Correspondence: Rachna M. Goyal,
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22
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Deligiorgi MV, Sagredou S, Vakkas L, Trafalis DT. The Continuum of Thyroid Disorders Related to Immune Checkpoint Inhibitors: Still Many Pending Queries. Cancers (Basel) 2021; 13:5277. [PMID: 34771441 PMCID: PMC8582503 DOI: 10.3390/cancers13215277] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/11/2021] [Accepted: 10/18/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Until more data are available to shed light on the thyroid disorders related to immune checkpoint inhibitors (ICPi) implemented for the treatment of hematological malignancies, the decision-making is guided by pertinent data derived mostly from solid tumors. METHODS The present review provides a comprehensive and updated overview of the thyroid disorders related to ICPi, namely to inhibitors of cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death (PD) 1 (PD-1), and the ligand of the latter (PD-L1). RESULTS With the increasing recognition of ir thyroid disorders, many outstanding issues have emerged. Ir thyroid disorders are reminiscent of, but not identical to, thyroid autoimmunity. Interclass and intraclass ICPi differences regarding thyroid immunotoxicity await interpretation. The available data concerning the predictive value of thyroid autoantibodies for the development of ir thyroid disorders are inconclusive. Mounting data indicate an association of ir thyroid disorders with ICPi efficacy, but a causative link is still lacking. The path forward is a tailored approach, entailing: (i) the validation of tumor-specific, patient-specific, and ICPi-specific predictive factors; (ii) appropriate patient selection; (iii) the uncoupling of antitumor immunity from immunotoxicity; (iv) a multidisciplinary initiative; and (v) global registry strategies. CONCLUSIONS Untangling and harnessing the interrelationship of immuno-oncology with endocrinology underlying the ir thyroid disorders will yield the optimal patient care.
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Affiliation(s)
- Maria V. Deligiorgi
- Department of Pharmacology—Clinical Pharmacology Unit, Faculty of Medicine, National and Kapodistrian University of Athens, Building 16, 1st Floor, 75 Mikras Asias Str., Goudi, 11527 Athens, Greece; (S.S.); (L.V.); (D.T.T.)
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Bellastella G, Carbone C, Scappaticcio L, Cirillo P, Troiani T, Morgillo F, Vietri MT, Della Corte CM, De Falco V, Napolitano S, Maiorino MI, De Bellis A, Esposito K. Hypothalamic-Pituitary Autoimmunity in Patients Treated with Anti-PD-1 and Anti-PD-L1 Antibodies. Cancers (Basel) 2021; 13:cancers13164036. [PMID: 34439190 PMCID: PMC8391584 DOI: 10.3390/cancers13164036] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/26/2021] [Accepted: 08/09/2021] [Indexed: 02/01/2023] Open
Abstract
Simple Summary The aim of this study is to search for APA and AHA and related pituitary dysfunction in patients treated with immunotherapy. APA and AHA could represent markers for early detection of patients at risk of developing pituitary deficiencies related to immune checkpoint inhibitors and undergoing closer follow-up. Furthermore, this study aims to evaluate the correlation between the presence of AHA and APA and the clinical response to checkpoint inhibitor therapy. However, further prospective studies will be needed to confirm our results. Abstract Background: Autoimmune hypophysitis is a frequent immune-related adverse event (irAE) in cancer patients treated with immunecheckpoint inhibitors. Studies seeking anti-pituitary (APA) and anti-hypothalamus (AHA) antibodies in patients treated with anti-PD-1 and anti-PD-L1 are scarce. The aim of this study is to search for APA and AHA and related pituitary dysfunction in patients treated with these agents. Methods:Cross-sectional and preliminary longitudinal studies were conducted at the Medical Oncology Unit and Endocrinology and Metabolic Diseases Unit of the University of Campania “Luigi Vanvitelli”. Fifty-four cancer patients on treatments with anti-PD-1 or anti-PD-L1 (Group 1) and 50 healthy controls were enrolled for a cross-sectional study; 13 cancer patients (Group 2) were enrolled for our preliminary longitudinal study. APA/AHA titers and changes in biochemical and hormonal profile were evaluated in Group 1; in Group 2, they were evaluated before and after nine weeks from the start of immunotherapy. Results: Patients of Group 1 showed a higher prevalence of APA and AHA than controls: 21 of them had APA, 16 had AHA, and 11 had both autoantibodies. In total, 7 of 13 patients in Group 2 became APA-positive and 3 became AHA-positive after nine weeks of immunotherapy, showing an increase in prolactin and a decrease in ACTH and IGF-1 levels compared with basal values. Conclusions:Anti-pituitary and anti-hypothalamus antibodies seem to play a pivotal role in hypothalamic–pituitary autoimmunity and secondary endocrine-related alterations evoked by anti-PD-1 and PD-L1 antibodies.
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Affiliation(s)
- Giuseppe Bellastella
- Unit of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (C.C.); (L.S.); (P.C.); (M.I.M.); (A.D.B.)
- Correspondence: or ; Tel.: +39-081-566-5289
| | - Carla Carbone
- Unit of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (C.C.); (L.S.); (P.C.); (M.I.M.); (A.D.B.)
| | - Lorenzo Scappaticcio
- Unit of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (C.C.); (L.S.); (P.C.); (M.I.M.); (A.D.B.)
| | - Paolo Cirillo
- Unit of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (C.C.); (L.S.); (P.C.); (M.I.M.); (A.D.B.)
| | - Teresa Troiani
- Medical Oncology, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (T.T.); (F.M.); (C.M.D.C.); (V.D.F.); (S.N.)
| | - Floriana Morgillo
- Medical Oncology, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (T.T.); (F.M.); (C.M.D.C.); (V.D.F.); (S.N.)
| | - Maria Teresa Vietri
- Unit of Clinical and Molecular Pathology, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
| | - Carminia Maria Della Corte
- Medical Oncology, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (T.T.); (F.M.); (C.M.D.C.); (V.D.F.); (S.N.)
| | - Vincenzo De Falco
- Medical Oncology, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (T.T.); (F.M.); (C.M.D.C.); (V.D.F.); (S.N.)
| | - Stefania Napolitano
- Medical Oncology, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (T.T.); (F.M.); (C.M.D.C.); (V.D.F.); (S.N.)
| | - Maria Ida Maiorino
- Unit of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (C.C.); (L.S.); (P.C.); (M.I.M.); (A.D.B.)
| | - Annamaria De Bellis
- Unit of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (C.C.); (L.S.); (P.C.); (M.I.M.); (A.D.B.)
| | - Katherine Esposito
- Diabetes Unit, Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
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Peiffert M, Cugnet-Anceau C, Dalle S, Chikh K, Assaad S, Disse E, Raverot G, Borson-Chazot F, Abeillon-du Payrat J. Graves' Disease during Immune Checkpoint Inhibitor Therapy (A Case Series and Literature Review). Cancers (Basel) 2021; 13:cancers13081944. [PMID: 33920721 PMCID: PMC8073133 DOI: 10.3390/cancers13081944] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/09/2021] [Accepted: 04/14/2021] [Indexed: 02/08/2023] Open
Abstract
Thyrotoxicosis is an adverse event associated with immune checkpoint inhibitors (ICPis) that occurs in 0.6 to 3.2% of treated patients, depending on ICPi class. Presentation usually consists of a biphasic thyroiditis with transient thyrotoxicosis and secondary hypothyroidism. ICPi-induced Graves' disease (GD), due to the stimulating activity of TSH-receptor autoantibodies (TRAb), is extremely rare. The aim of this retrospective study was to describe the characteristics and evolution of GD during ICPi therapy. Five among 243 patients followed for ICPi-induced thyrotoxicosis showed TRAb positivity (2% of the cohort). GD occurred quickly after initiation of ICPis; its course was typical for two patients, with prolonged requirement for antithyroid drug treatment (ATD). The three other patients experienced biphasic thyroiditis with secondary hypothyroidism requiring long-term substitution. Three other patients had a diagnosis of GD before starting ICPis; they evolved toward hypothyroidism with early cessation of ATD and long-term substitution treatment during ICPi treatment. None developed significant Graves' orbitopathy. ICPi treatment was not interrupted for thyroid dysfunction. In conclusion, GD is a rare, immune-related adverse event of ICPis with an unusual course and frequent evolution to biphasic thyroiditis. In the case of ICPi-induced thyrotoxicosis in the presence of TRAb, observing the spontaneous evolution and performing a scintigraphy are useful before starting ATD treatment. Pre-existing GD is not exacerbated by ICPis and tends to evolve towards hypothyroidism. ICPi treatment can be maintained with adequate biochemical surveillance.
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Affiliation(s)
- Mathilde Peiffert
- Faculté de Médecine, Université Lyon 1, 69008 Lyon, France; (S.D.); (K.C.); (E.D.); (G.R.); (F.B.-C.)
- Fédération d’Endocrinologie, Hôpital Louis Pradel, Groupement Hospitalier Est, Hospices Civils de Lyon, 69500 Bron, France
- Correspondence: (M.P.); (J.A.-d.P.); Tel.: +33-4-27-85-66-66 (J.A.-d.P.)
| | - Christine Cugnet-Anceau
- Service d’Endocrinologie-Diabète-Nutrition, Hôpital Lyon Sud, Hospices Civils de Lyon, 69310 Pierre-Bénite, France;
- ImmuCare, Institut de Cancérologie, Hospices Civils de Lyon, 69002 Lyon, France
| | - Stephane Dalle
- Faculté de Médecine, Université Lyon 1, 69008 Lyon, France; (S.D.); (K.C.); (E.D.); (G.R.); (F.B.-C.)
- ImmuCare, Institut de Cancérologie, Hospices Civils de Lyon, 69002 Lyon, France
- Service de Dermatologie, Hôpital Lyon Sud, Hospices Civils de Lyon, 69310 Pierre-Bénite, France
| | - Karim Chikh
- Faculté de Médecine, Université Lyon 1, 69008 Lyon, France; (S.D.); (K.C.); (E.D.); (G.R.); (F.B.-C.)
- Centre de Biologie Sud, Hôpital Lyon Sud, Hospices Civils de Lyon, 69310 Pierre-Bénite, France
| | - Souad Assaad
- Tox’imm, Centre Léon Bérard, 69008 Lyon, France;
- Service d’Hématologie et Médecine Interne, Centre Léon Berard, 69008 Lyon, France
| | - Emmanuel Disse
- Faculté de Médecine, Université Lyon 1, 69008 Lyon, France; (S.D.); (K.C.); (E.D.); (G.R.); (F.B.-C.)
- Service d’Endocrinologie-Diabète-Nutrition, Hôpital Lyon Sud, Hospices Civils de Lyon, 69310 Pierre-Bénite, France;
- INSERM U1060, INRA 1397, INSA Lyon, Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH RA), CarMeN Laboratory, 69310 Pierre-Bénite, France
| | - Gérald Raverot
- Faculté de Médecine, Université Lyon 1, 69008 Lyon, France; (S.D.); (K.C.); (E.D.); (G.R.); (F.B.-C.)
- Fédération d’Endocrinologie, Hôpital Louis Pradel, Groupement Hospitalier Est, Hospices Civils de Lyon, 69500 Bron, France
- INSERM U1052, CNRS, UMR5286, Cancer Research Center of Lyon, 69008 Lyon, France
| | - Françoise Borson-Chazot
- Faculté de Médecine, Université Lyon 1, 69008 Lyon, France; (S.D.); (K.C.); (E.D.); (G.R.); (F.B.-C.)
- Fédération d’Endocrinologie, Hôpital Louis Pradel, Groupement Hospitalier Est, Hospices Civils de Lyon, 69500 Bron, France
| | - Juliette Abeillon-du Payrat
- Fédération d’Endocrinologie, Hôpital Louis Pradel, Groupement Hospitalier Est, Hospices Civils de Lyon, 69500 Bron, France
- ImmuCare, Institut de Cancérologie, Hospices Civils de Lyon, 69002 Lyon, France
- Correspondence: (M.P.); (J.A.-d.P.); Tel.: +33-4-27-85-66-66 (J.A.-d.P.)
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Paschou SA, Stefanaki K, Psaltopoulou T, Liontos M, Koutsoukos K, Zagouri F, Lambrinoudaki I, Dimopoulos MA. How we treat endocrine complications of immune checkpoint inhibitors. ESMO Open 2021; 6:100011. [PMID: 33399077 PMCID: PMC7807832 DOI: 10.1016/j.esmoop.2020.100011] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 11/06/2020] [Accepted: 11/10/2020] [Indexed: 12/18/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) are antibodies that target certain immune checkpoints (ICs), such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD-1) or its ligand (PD-L1), and have emerged as a powerful new tool for oncologists. As these immune checkpoints are crucial for immunological self-tolerance, such therapies can trigger autoimmune adverse effects. Endocrine complications are among the most common, including hypophysitis, thyroid dysfunction, diabetes mellitus and primary adrenal insufficiency, while autoimmune polyendocrine syndrome type 2 (APS-2) may also present. The aim of this article is to critically appraise the literature and present (i) the biological role and function of the main ICs, (ii) the use of ICIs in the treatment of various cancer types, (iii) the endocrine complications of cancer immunotherapy with ICIs and (iv) practical recommendations for screening and management of patients with such endocrinopathies in everyday clinical practice.
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Affiliation(s)
- S A Paschou
- Division of Endocrinology, Diabetes and Metabolism, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - K Stefanaki
- Division of Endocrinology, Diabetes and Metabolism, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - T Psaltopoulou
- Division of Hematology and Oncology, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - M Liontos
- Division of Hematology and Oncology, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - K Koutsoukos
- Division of Hematology and Oncology, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - F Zagouri
- Division of Hematology and Oncology, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - I Lambrinoudaki
- Second Department of Obstetrics and Gynecology, Aretaieio Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - M-A Dimopoulos
- Division of Hematology and Oncology, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
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Muir CA, Menzies AM, Clifton-Bligh R, Tsang VHM. Thyroid Toxicity Following Immune Checkpoint Inhibitor Treatment in Advanced Cancer. Thyroid 2020; 30:1458-1469. [PMID: 32264785 DOI: 10.1089/thy.2020.0032] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Background: Inhibitory antibodies against cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) have antitumor efficacy and are now standard of care in the management of multiple cancer subtypes. However, the use is complicated by the development of autoimmunity, which can occur in multiple organ systems. Thyroiditis is the most common immune-related adverse event. Summary: Immune checkpoint inhibitor (ICI)-associated thyroiditis affects over 10% of treated patients. PD-1 inhibitors are associated with greater risk of thyroid dysfunction relative to CTLA-4 inhibitors, although the highest risk occurs with combined anti-CTLA-4 and anti-PD-1 treatment. Onset is typically rapid, within weeks to months and both hyperthyroidism and hypothyroidism can occur. The most frequent pattern of thyroid dysfunction is transient hyperthyroidism with evolution to hypothyroidism over four to six weeks. Most cases are asymptomatic and resolve without dedicated treatment. There is no sex or age predominance, and predictive risk factors have not been reliably identified. Thyroid autoantibodies are variably present and are not clearly related to the risk or progression of thyroid dysfunction following treatment with an ICI. Observational data suggest that development of ICI-associated thyroiditis may predict improved survival. Conclusions: ICI-associated thyroiditis is a distinct clinical entity. Mechanisms underlying etiology remain largely unknown. Awareness among health professionals is important to limit morbidity and avoid unnecessary periods of untreated hypothyroidism.
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Affiliation(s)
- Christopher A Muir
- Nothern Clinical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
- Cancer Genetics Laboratory, Kolling Institute of Medical Research, St. Leonards, Australia
| | - Alexander M Menzies
- Nothern Clinical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
- Melanoma Medical Oncology, Melanoma Institute Australia, Wollstonecraft, Australia
- Department of Medical Oncology and Royal North Shore Hospital, St. Leonards, Australia
| | - Roderick Clifton-Bligh
- Nothern Clinical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
- Cancer Genetics Laboratory, Kolling Institute of Medical Research, St. Leonards, Australia
- Department of Endocrinology, Royal North Shore Hospital, St. Leonards, Australia
| | - Venessa H M Tsang
- Nothern Clinical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
- Cancer Genetics Laboratory, Kolling Institute of Medical Research, St. Leonards, Australia
- Department of Endocrinology, Royal North Shore Hospital, St. Leonards, Australia
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Sakamoto K, Fukihara J, Morise M, Hashimoto N. Clinical burden of immune checkpoint inhibitor-induced pneumonitis. Respir Investig 2020; 58:305-319. [PMID: 32713811 DOI: 10.1016/j.resinv.2020.05.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 05/01/2020] [Accepted: 05/17/2020] [Indexed: 06/11/2023]
Abstract
Immune checkpoint inhibitors (ICIs) have been a breakthrough in medical oncology. However, many patients experience a novel type of adverse drug reaction that has a unique clinical presentation, called immune-related adverse events (irAEs). A breakdown of self-tolerance and an exaggerated autoimmune reaction by the host are assumed to be the underlying mechanisms. Therefore, special attention to the optimal diagnosis and management is required. Among the various effects of irAE, pneumonitis has been recognized as an important manifestation because of its high morbidity and mortality. As the application of ICIs is expanding to a wider variety of tumor types, as well as its use with cytotoxic agents and radiation, clinicians are highly likely to encounter this complication. In this review, we will summarize the current understanding of the underlying mechanisms, incidence, risk factors, optimal diagnostic workup, and management of ICI-related pneumonitis (IRP). We will also review fundamental information on drug-induced lung toxicity in the oncology setting. In addition, research perspectives focused on better risk stratification and management to avoid serious complications in the future are presented.
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Affiliation(s)
- Koji Sakamoto
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550. Japan.
| | - Jun Fukihara
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550. Japan.
| | - Masahiro Morise
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550. Japan.
| | - Naozumi Hashimoto
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550. Japan.
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Cooksley T, Girotra M, Ginex P, Gordon RA, Anderson R, Blidner A, Choi J, Dougan M, Glezerman I, Gupta D, Johnson D, Shannon VR, Suarez-Almazor M, Rapoport BL. Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of immune checkpoint inhibitor endocrinopathies and the role of advanced practice providers in the management of immune-mediated toxicities. Support Care Cancer 2020; 28:6175-6181. [DOI: 10.1007/s00520-020-05709-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 08/20/2020] [Indexed: 12/19/2022]
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Yamada H, Okajima F, Onda T, Fujimori S, Emoto N, Sugihara H. New-onset graves' disease after the initiation of nivolumab therapy for gastric cancer: a case report. BMC Endocr Disord 2020; 20:132. [PMID: 32847555 PMCID: PMC7449083 DOI: 10.1186/s12902-020-00613-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 08/20/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs) including thyroid dysfunction. There are only a few reports on Graves' disease induced by ICIs. We report a case of new-onset Graves' disease after the initiation of nivolumab therapy in a patient receiving gastric cancer treatment. CASE PRESENTATION The patient was a 66-year-old Japanese man, who was administered nivolumab (240 mg every 3 weeks) as a third-line therapy for stage IVb gastric cancer. His thyroid function was normal before the initiation of nivolumab therapy. However, he developed thyrotoxicosis before the third administration of nivolumab. Elevated, bilateral, and diffuse uptake of radioactive tracer was observed in the 99mTc-pertechnetate scintigraphy. Furthermore, the thyroid-stimulating hormone receptor antibody (TRAb) and thyroid-stimulating antibody (TSAb) test results, which were negative before the first administration of nivolumab, were positive after starting the therapy. The patient was diagnosed with Graves' disease, and the treatment with methimazole and potassium iodide restored thyroid function. CONCLUSIONS This is the first complete report of a case of new-onset Graves' disease after starting nivolumab therapy, confirmed by diffusely increased thyroid uptake in scintigraphy and the positive conversion of antibodies against thyroid-stimulating hormone receptor. It is important to perform thyroid scintigraphy and ultrasonography to accurately diagnose and treat ICI-induced thyrotoxicosis, because there are various cases in which Graves' disease is developed with negative and positive TRAb titres.
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Affiliation(s)
- Hiroshi Yamada
- Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan.
| | - Fumitaka Okajima
- Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Takeshi Onda
- Department of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, 1715, Kamagari, Inzai, Chiba, 270-1694, Japan
| | - Shunji Fujimori
- Department of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, 1715, Kamagari, Inzai, Chiba, 270-1694, Japan
| | - Naoya Emoto
- Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Hitoshi Sugihara
- Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
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Lotfinejad P, Kazemi T, Mokhtarzadeh A, Shanehbandi D, Jadidi Niaragh F, Safaei S, Asadi M, Baradaran B. PD-1/PD-L1 axis importance and tumor microenvironment immune cells. Life Sci 2020; 259:118297. [PMID: 32822718 DOI: 10.1016/j.lfs.2020.118297] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 08/10/2020] [Accepted: 08/15/2020] [Indexed: 12/23/2022]
Abstract
Triple-negative breast cancer (TNBC) is heterogeneous cancer with poor prognosis among the other breast tumors. Rapid recurrence and increased progression rate could be reasons for the poor prognosis of this type of breast cancer. Recently, because of the lack of specific targets in multiple cancer treatment, immune checkpoint blockade therapies with targeting PD-1/PD-L1 axis have displayed significant advances and improved survival. Among different types of breast cancers, TNBC is considered more immunogenic with high T-cell and other immune cells infiltration compared to other breast cancer subtypes. This immunogenic characteristic of TNBC is a beneficial marker in the immunotherapy of these tumors. Clinical studies with a focus on immune checkpoint therapy have demonstrated promising results in TNBC treatment. In this review, we summarize clinical trials with the immunotherapy-based treatment of different cancers and also discuss the interaction between infiltrating immune cells and breast tumor microenvironment. In addition, we focus on the signaling pathway that controls PD-L1 expression and continues with CAR T-cell therapy and siRNA as novel strategies and potential tools in targeted therapy.
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Affiliation(s)
- Parisa Lotfinejad
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tohid Kazemi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhad Jadidi Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sahar Safaei
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Milad Asadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran.
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Okura N, Asano M, Uchino J, Morimoto Y, Iwasaku M, Kaneko Y, Yamada T, Fukui M, Takayama K. Endocrinopathies Associated with Immune Checkpoint Inhibitor Cancer Treatment: A Review. J Clin Med 2020; 9:jcm9072033. [PMID: 32610470 PMCID: PMC7409155 DOI: 10.3390/jcm9072033] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 06/15/2020] [Accepted: 06/25/2020] [Indexed: 12/27/2022] Open
Abstract
Treatment with immune checkpoint inhibitors has shown efficacy against a variety of cancer types. The effects of nivolumab and pembrolizumab on lung cancer have been reported, and further therapeutic advances are ongoing. The side effects of immune checkpoint inhibitors are very different from those of conventional cytocidal anticancer drugs and molecular targeted drugs, and they involve various organs such as the digestive and respiratory organs, thyroid and pituitary glands, and skin. The generic term for such adverse events is immune-related adverse events (irAEs). They are relatively infrequent, and, if mild, treatment with immune checkpoint inhibitors can be continued with careful control. However, early detection and appropriate treatment are critical, as moderate-to-severe irAEs are associated with markedly reduced organ function and quality of life, with fatal consequences in some cases. Of these, endocrinopathies caused by immune checkpoint inhibitors are sometimes difficult to distinguish from nonspecific symptoms in patients with advanced cancer and may have serious outcomes when the diagnosis is delayed. Therefore, it is necessary to anticipate and appropriately address the onset of endocrinopathies during treatment with immune checkpoint inhibitors. Here, we present a review of endocrine disorders caused by immune checkpoint inhibitor treatment.
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Affiliation(s)
- Naoko Okura
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; (N.O.); (Y.M.); (M.I.); (Y.K.); (T.Y.); (K.T.)
| | - Mai Asano
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; (M.A.); (M.F.)
| | - Junji Uchino
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; (N.O.); (Y.M.); (M.I.); (Y.K.); (T.Y.); (K.T.)
- Correspondence: ; Tel.: +81-75-251-5513
| | - Yoshie Morimoto
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; (N.O.); (Y.M.); (M.I.); (Y.K.); (T.Y.); (K.T.)
| | - Masahiro Iwasaku
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; (N.O.); (Y.M.); (M.I.); (Y.K.); (T.Y.); (K.T.)
| | - Yoshiko Kaneko
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; (N.O.); (Y.M.); (M.I.); (Y.K.); (T.Y.); (K.T.)
| | - Tadaaki Yamada
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; (N.O.); (Y.M.); (M.I.); (Y.K.); (T.Y.); (K.T.)
| | - Michiaki Fukui
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; (M.A.); (M.F.)
| | - Koichi Takayama
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; (N.O.); (Y.M.); (M.I.); (Y.K.); (T.Y.); (K.T.)
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Deligiorgi MV, Panayiotidis MI, Trafalis DT. Endocrine adverse events related with immune checkpoint inhibitors: an update for clinicians. Immunotherapy 2020; 12:481-510. [PMID: 32345074 DOI: 10.2217/imt-2019-0132] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Designated as scientific breakthrough of current decade, immune checkpoint inhibitors attenuate the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1)/ligand 1 (PD-L1) pathways, depriving cancer cells of a key strategy of evasion from immunosurveillance. The reinvigoration of immune response translates into clinical success, inevitably entwined with a novel constellation of immune-related adverse events. The present review dissects the endocrine immune-related adverse events, emphasizing their unique profile featured by unpredictable onset, irreversibility, nonspecific symptoms, wide clinical spectrum and sophisticated diagnostic work-up. Guidelines advocate individualized decision-making process guided by clinicians' judgement. Future perspective should be governed by five principles - prevention, anticipation, detection, treatment, monitoring - aiming to gain the optimal profit diminishing immunotoxicity.
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Affiliation(s)
- Maria V Deligiorgi
- Department of Pharmacology - Clinical Pharmacology Unit, National & Kapodistrian University of Athens, Faculty of Medicine, Building 16, 1st Floor: 75 Mikras Asias, 11527-Goudi, Athens, Greece
| | - Mihalis I Panayiotidis
- Department of Applied Sciences, Group of Translational Biosciences, Faculty of Health & Life Sciences, Northumbria University, Ellison Building A516, Newcastle Upon Tyne, NE1 8ST, UK
| | - Dimitrios T Trafalis
- Department of Pharmacology - Clinical Pharmacology Unit, National & Kapodistrian University of Athens, Faculty of Medicine, Building 16, 1st Floor: 75 Mikras Asias, 11527-Goudi, Athens, Greece
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Weinmann SC, Pisetsky DS. Mechanisms of immune-related adverse events during the treatment of cancer with immune checkpoint inhibitors. Rheumatology (Oxford) 2020; 58:vii59-vii67. [PMID: 31816080 PMCID: PMC6900913 DOI: 10.1093/rheumatology/kez308] [Citation(s) in RCA: 150] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 05/31/2019] [Indexed: 12/14/2022] Open
Abstract
Immune checkpoint inhibitors are novel biologic agents to treat cancer by inhibiting the regulatory interactions that limit T cell cytotoxicity to tumours. Current agents target either CTLA-4 or the PD-1/PD-L1 axis. Because checkpoints may also regulate autoreactivity, immune checkpoint inhibitor therapy is complicated by side effects known as immune-related adverse events (irAEs). The aim of this article is to review the mechanisms of these events. irAEs can involve different tissues and include arthritis and other rheumatic manifestations. The frequency of irAEs is related to the checkpoint inhibited, with the combination of agents more toxic. Because of their severity, irAEs can limit therapy and require immunosuppressive treatment. The mechanisms leading to irAEs are likely similar to those promoting anti-tumour responses and involve expansion of the T cell repertoire; furthermore, immune checkpoint inhibitors can affect B cell responses and induce autoantibody production. Better understanding of the mechanisms of irAEs will be important to improve patient outcome as well as quality of life during treatment.
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Affiliation(s)
- Sophia C Weinmann
- Division of Rheumatology and Immunology, Duke University Medical Center, Durham, NC, USA
| | - David S Pisetsky
- Division of Rheumatology and Immunology, Duke University Medical Center, Durham, NC, USA.,Medical Research Service, VA Medical Center, Durham, NC, USA
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Sbardella E, Tenuta M, Sirgiovanni G, Gianfrilli D, Pozza C, Venneri MA, Cortesi E, Marchetti P, Lenzi A, Gelibter AJ, Isidori AM. Thyroid disorders in programmed death 1 inhibitor-treated patients: Is previous therapy with tyrosine kinase inhibitors a predisposing factor? Clin Endocrinol (Oxf) 2020; 92:258-265. [PMID: 31788837 DOI: 10.1111/cen.14135] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 11/07/2019] [Accepted: 11/29/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Programmed death 1 (PD-1) inhibitors are frequently associated with thyroid-related adverse events (TAEs), but many aspects remain unclear. This study aims to evaluate the incidence and characteristics of such events and to find any predictive factor for its development. METHODS We retrospectively analysed data from patients with advanced solid tumours (non-small-cell lung carcinoma, renal cell carcinoma, metastatic melanoma) treated with PD-1 inhibitors (nivolumab, pembrolizumab) in Oncology Unit B, Policlinico Umberto I of Rome, from June 2015 to December 2018. All patients underwent baseline thyroid function evaluations repeated monthly. RESULTS The cohort consisted of 126 patients (66.7% male, mean age 66.4 ± 9.7 years). One hundred and seven received nivolumab and 19 pembrolizumab. Twenty-three per cent of patients experienced TAEs (mainly CTCAE grade 1), with hypothyroidism in 15.1% (subclinical: 11.9%, overt: 3.2%) and hyperthyroidism in 8.0% (subclinical: 4.8%, overt: 3.2%). Median time to TAE onset was 8.7 ± 6.8 weeks (10.4 ± 7.6 weeks for hypothyroidism, 5.4 ± 3.0 weeks for hyperthyroidism). Most TAEs (89.7%) appeared within the first 3 months, none after 8 months. Most hypothyroid patients (63.2%) had previously been treated with a tyrosine kinase inhibitor (TKI). Logistic regression analysis showed that pretreatment with a TKI was a major predisposing factor for the development of hypothyroidism (OR 9.2, 95% CI: 1.4-59.9, P = .020). CONCLUSIONS TAEs are common during anti-PD-1 therapy and usually occur within the first 3 months of treatment. This is the first study evaluating the impact of previous oncologic therapies on TAEs, identifying TKI as a major risk factor for the development of hypothyroidism in patients treated with anti-PD-1.
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Affiliation(s)
- Emilia Sbardella
- Department of Experimental Medicine, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - Marta Tenuta
- Department of Experimental Medicine, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - Grazia Sirgiovanni
- Department of Radiological, Oncological and Pathological Sciences, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - Daniele Gianfrilli
- Department of Experimental Medicine, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - Carlotta Pozza
- Department of Experimental Medicine, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - Mary Anna Venneri
- Department of Experimental Medicine, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - Enrico Cortesi
- Department of Radiological, Oncological and Pathological Sciences, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - Paolo Marchetti
- Department of Radiological, Oncological and Pathological Sciences, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - Andrea Lenzi
- Department of Experimental Medicine, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - Alain J Gelibter
- Department of Radiological, Oncological and Pathological Sciences, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - Andrea M Isidori
- Department of Experimental Medicine, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
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Ellithi M, Elnair R, Chang GV, Abdallah MA. Toxicities of Immune Checkpoint Inhibitors: Itis-Ending Adverse Reactions and More. Cureus 2020; 12:e6935. [PMID: 32190487 PMCID: PMC7067353 DOI: 10.7759/cureus.6935] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 02/10/2020] [Indexed: 11/27/2022] Open
Abstract
Immune checkpoint inhibitors (ICI) have revolutionized the treatment of cancer worldwide. Not long ago, before the introduction of ICIs, many cancers incurred a grave prognosis on patients due to the lack of effective therapies. For instance, patients with malignant melanoma survive longer and experience a better quality of life than ever before due to agents such as nivolumab and ipilimumab. Nevertheless, toxicities associated with the use of ICIs have been increasingly recognized in clinical trials as well as oncology practice. The widespread usage of ICIs and the expected addition of newer ICIs to the arsenal of medications to fight cancer raise awareness of the potential toxicities of these medications. Once these toxicities develop, immunosuppression with or without withholding immunotherapy is the standard of care. Because the long-term adverse effects of these toxicities and the impact of stopping therapy on survival are not well characterized, a joint decision by both the oncologist and the patient should be carried out if stopping therapy is being considered. Nevertheless, long-term data is necessary to guide such decisions. In this article, we will discuss common ICI's immune-related adverse events with a simplified approach to recognizing and managing these events.
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Affiliation(s)
- Moataz Ellithi
- Internal Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, USA
| | - Radowan Elnair
- Hematology and Oncology, University of Nebraska, Omaha, USA
| | - Guy Vin Chang
- Internal Medicine, University of South Dakota, Sioux falls, USA
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Cugnet Anceau C, Abeillon J, Maillet D, Borson-Chazot F, Disse E. Les dysthyroïdies sous immunothérapie anti-cancéreuse. Bull Cancer 2020; 107:262-271. [DOI: 10.1016/j.bulcan.2019.10.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 10/03/2019] [Accepted: 10/17/2019] [Indexed: 10/25/2022]
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Agrawal L, Bacal A, Jain S, Singh V, Emanuele N, Emanuele M, Meah F. Immune checkpoint inhibitors and endocrine side effects, a narrative review. Postgrad Med 2020; 132:206-214. [PMID: 31876444 DOI: 10.1080/00325481.2019.1709344] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Immune checkpoint inhibitors (ICPIs) are novel drugs in the field of oncology however carry the risk of immune-related dermatologic, gastrointestinal, and endocrine side effects which can be fatal. These new innovative immunoregulatory drugs have intertwined the fields of oncology and endocrinology. CTLA-4 and PD-1 are co-inhibitory receptors on T cells that turn the T cell 'off' when binding to receptors on APCs. Tumor cells can also carry receptors for CTLA- and PD-1. By rendering T cells inactive, tumor cells can evade immune attack. Antibodies that bind to CTLA-4 and PD-1 lead to T cell activation and destruction of both tumor and normal host cells. ICPIs have been used in a variety of malignancies including melanoma, kidney cancer, and non-small cell lung cancer. A unique underrecognized side effect of the autoimmune response is hypophysitis leading to central adrenal insufficiency which can be fatal. Additional immune-related adverse events (irAEs) include hypothyroidism, hyperthyroidism, diabetes, and hypoparathyroidism.
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Affiliation(s)
- L Agrawal
- Department of Endocrinology, Edward Hines Junior VA Hospital, Hines, IL, USA
| | - A Bacal
- Department of Endocrinology, Loyola University Medical Center, Maywood, IL, USA
| | - S Jain
- Department of Endocrinology, Loyola University Medical Center, Maywood, IL, USA
| | - V Singh
- Department of Endocrinology, Loyola University Medical Center, Maywood, IL, USA
| | - N Emanuele
- Department of Endocrinology, Edward Hines Junior VA Hospital, Hines, IL, USA
| | - Ma Emanuele
- Department of Endocrinology, Loyola University Medical Center, Maywood, IL, USA
| | - F Meah
- Department of Endocrinology, Edward Hines Junior VA Hospital, Hines, IL, USA
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Elia G, Ferrari SM, Galdiero MR, Ragusa F, Paparo SR, Ruffilli I, Varricchi G, Fallahi P, Antonelli A. New insight in endocrine-related adverse events associated to immune checkpoint blockade. Best Pract Res Clin Endocrinol Metab 2020; 34:101370. [PMID: 31983543 DOI: 10.1016/j.beem.2019.101370] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Anticancer immunotherapy, in the form of immune checkpoint inhibition, is a paradigm shift that has transformed the care of patients with different types of solid and hematologic cancers. The most notable improvements have been seen in patients with melanoma, non-small-cell lung, bladder, renal, cervical, urotherial, and colorectal cancers, Merkel cell carcinoma, and Hodgkin lymphoma. Monoclonal antibodies (mAbs) targeting immune checkpoints (i.e., anti-CTLA: ipilimumab; anti-PD-1: nivolumab, pembrolizumab; anti-PD-L1: durvalumab, atezolizumab, avelumab) unleash the immune system against tumor cells targeting mainly T cells. Treatment with immune checkpoint inhibitors (ICIs) is associated with a variety of diverse and distinct immune-related adverse events (irAEs), reflecting the mechanistic underpinning of each target (i.e., CTLA-4, and PD-1/PD-L1 network). The most frequent endocrine irAEs associated with anti-PD-1 mAb treatment are thyroid dysfunctions, whereas hypophysitis is mostly linked to anti-CTLA-4 treatment. Type 1 diabetes mellitus and adrenalitis are rare irAEs. Combination therapy (anti-CTLA-4 plus anti-PD-1/PD-L1) can be associated with an increased risk and prevalence of endocrine irAEs. In this paper we discuss the pathophysiological and clinical aspects of irAEs with specific emphasis on endocrine irAEs associated with ICIs. With a growing number of patients treated with ICIs, a tight collaboration among oncologists, endocrinologists and immunologists appears necessary when the circumstances are more challenging and for better management of severe endocrine irAEs. Further investigations are urgently needed to better understand the mechanisms by which different ICIs can induce a variety of endocrine irAEs.
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Affiliation(s)
- Giusy Elia
- Department of Clinical and Experimental Medicine, University of Pisa, 56126, Pisa, Italy.
| | - Silvia Martina Ferrari
- Department of Clinical and Experimental Medicine, University of Pisa, 56126, Pisa, Italy.
| | - Maria Rosaria Galdiero
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy; WAO Center of Excellence, 80131, Naples, Italy; Institute of Experimental Endocrinology and Oncology "G. Salvatore" (IEOS), National Research Council (CNR), 80131, Naples, Italy.
| | - Francesca Ragusa
- Department of Clinical and Experimental Medicine, University of Pisa, 56126, Pisa, Italy.
| | - Sabrina Rosaria Paparo
- Department of Clinical and Experimental Medicine, University of Pisa, 56126, Pisa, Italy.
| | - Ilaria Ruffilli
- Department of Clinical and Experimental Medicine, University of Pisa, 56126, Pisa, Italy.
| | - Gilda Varricchi
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy; WAO Center of Excellence, 80131, Naples, Italy; Institute of Experimental Endocrinology and Oncology "G. Salvatore" (IEOS), National Research Council (CNR), 80131, Naples, Italy.
| | - Poupak Fallahi
- Department of Translational Research and of New Technologies in Medicine and Surgery, University of Pisa, 56126, Pisa, Italy.
| | - Alessandro Antonelli
- Department of Clinical and Experimental Medicine, University of Pisa, 56126, Pisa, Italy.
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Mazarico I, Capel I, Giménez-Palop O, Albert L, Berges I, Luchtenberg F, García Y, Fernández-Morales LA, De Pedro VJ, Caixàs A, Rigla M. Low frequency of positive antithyroid antibodies is observed in patients with thyroid dysfunction related to immune check point inhibitors. J Endocrinol Invest 2019; 42:1443-1450. [PMID: 31093955 DOI: 10.1007/s40618-019-01058-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 05/07/2019] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Immune checkpoint inhibitors (ICI), such as programmed death-1 inhibitors (anti-PD1), have become a cornerstone for the treatment of different advanced cancers. These antibodies act as modulators of immune checkpoint proteins. However, ICI can lead to the breaking of immune self-tolerance, inducing autoimmune side effects (irAEs), including endocrinopathies. One of the most frequent endocrine irAE of anti-PD1 is thyroid dysfunction, but the exact mechanism of this disease still remains unknown. MATERIALS AND METHODS We conducted a descriptive retrospective study, analyzing 11 patients who received at least one dose of anti-PD1 (nivolumab or pembrolizumab) and presented thyroid irAEs. Data were collected between September 2015 and May 2018 in our hospital. The aim was to analyze the clinically relevant features of thyroid irAEs and the frequency of antithyroid antibodies (ATA) positivity observed on them. RESULTS AND DISCUSSION 8 of the 11 patients were treated with nivolumab and the other three patients received pembrolizumab. Six patients presented silent thyroiditis with a thyrotoxicosis phase; three patients developed directly primary/subclinical hypothyroidism and two patients showed primary hyperthyroidism. Thyroid autoantibodies (anti-Thyroglobulin and anti-Thyroid Peroxidase) were assessed in all the 11 patients, and only in two of them (18%) a positive titer was displayed. Anti-TSH receptor antibodies (TRAbs) were examined in five patients, three with painless thyroiditis at the time of thyrotoxicosis and two with primary hyperthyroidism, and they all had undetectable levels. CONCLUSIONS In our sample of 11 Caucasian patients with thyroid dysfunction related with anti-PD1, we found low frequency of ATA positive titers, comparable to other recent reports in others ethnicities, which could suggest that silent thyroiditis due to pembrolizumab or nivolumab has a different pathogenesis from the classical autoimmune spontaneous thyroiditis. Further investigations are required to completely understand the immune mechanisms involved.
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Affiliation(s)
- I Mazarico
- Endocrinology and Nutrition Department, Parc Taulí University Hospital, Institut d'Investigació i Innovació ParcTaulí (I3PT), UAB, Parc Taulí 1, 08208, Sabadell, Barcelona, Spain.
| | - I Capel
- Endocrinology and Nutrition Department, Parc Taulí University Hospital, Institut d'Investigació i Innovació ParcTaulí (I3PT), UAB, Parc Taulí 1, 08208, Sabadell, Barcelona, Spain
| | - O Giménez-Palop
- Endocrinology and Nutrition Department, Parc Taulí University Hospital, Institut d'Investigació i Innovació ParcTaulí (I3PT), UAB, Parc Taulí 1, 08208, Sabadell, Barcelona, Spain
| | - L Albert
- Endocrinology and Nutrition Department, Parc Taulí University Hospital, Institut d'Investigació i Innovació ParcTaulí (I3PT), UAB, Parc Taulí 1, 08208, Sabadell, Barcelona, Spain
| | - I Berges
- Endocrinology and Nutrition Department, Parc Taulí University Hospital, Institut d'Investigació i Innovació ParcTaulí (I3PT), UAB, Parc Taulí 1, 08208, Sabadell, Barcelona, Spain
| | - F Luchtenberg
- Endocrinology and Nutrition Department, Parc Taulí University Hospital, Institut d'Investigació i Innovació ParcTaulí (I3PT), UAB, Parc Taulí 1, 08208, Sabadell, Barcelona, Spain
| | - Y García
- Oncology Department. Parc, Taulí University Hospital, Institut d'Investigació i Innovació ParcTaulí (I3PT), UAB, Sabadell, Spain
| | - L A Fernández-Morales
- Oncology Department. Parc, Taulí University Hospital, Institut d'Investigació i Innovació ParcTaulí (I3PT), UAB, Sabadell, Spain
| | - V J De Pedro
- Pharmacy Department. Parc, Taulí University Hospital, Institut d'Investigació i Innovació ParcTaulí (I3PT), UAB, Sabadell, Spain
| | - A Caixàs
- Endocrinology and Nutrition Department, Parc Taulí University Hospital, Institut d'Investigació i Innovació ParcTaulí (I3PT), UAB, Parc Taulí 1, 08208, Sabadell, Barcelona, Spain
| | - M Rigla
- Endocrinology and Nutrition Department, Parc Taulí University Hospital, Institut d'Investigació i Innovació ParcTaulí (I3PT), UAB, Parc Taulí 1, 08208, Sabadell, Barcelona, Spain
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Kassi E, Angelousi A, Asonitis N, Diamantopoulos P, Anastasopoulou A, Papaxoinis G, Kokkinos M, Giovanopoulos I, Kyriakakis G, Petychaki F, Savelli A, Benopoulou O, Gogas H. Endocrine-related adverse events associated with immune-checkpoint inhibitors in patients with melanoma. Cancer Med 2019; 8:6585-6594. [PMID: 31518074 PMCID: PMC6825974 DOI: 10.1002/cam4.2533] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 08/14/2019] [Accepted: 08/20/2019] [Indexed: 12/18/2022] Open
Abstract
Background Immune‐checkpoint inhibitors have been shown to improve survival in melanoma patients, but can also trigger immune‐related endocrinopathies, especially hypophysitis and thyroid dysfunction. Methods To assess the incidence and the spectrum of endocrinopathies in melanoma patients treated with immunotherapy a prospective observational study was conducted. Forty out of 339 patients, treated with immune‐checkpoint inhibitors, developed endocrinopathies. All patients had hormonal functional tests at screening (before the initiation of immunotherapy) and during follow‐up. Results The total incidence of endocrinopathies was 11.8%, 13.4% due to anti‐PD1/PDL1, 5% due to anti‐CTLA4, and 18.5% due to sequential and/or combination treatment. Twenty‐one patients (6.2%) presented with isolated anterior hypophysitis, eleven (3.2%) with primary thyroid dysfunction and eight (2.4%) with both abnormalities. The most frequent anterior pituitary hormone deficiency was central adrenal insufficiency, followed by central hypothyroidism and hypogonadotrophic hypogonadism. None of the patients with corticotroph axis failure recovered during follow‐up. Endocrinopathies occurred after a median of 22 weeks (range: 4‐156) from treatment initiation. Of note, sequential and/or combination therapy with anti‐CTLA4 and anti‐PD1/anti‐PDL1 led to an almost threefold incidence of hypophysitis compared to either monotherapy. Only one of 120 patients receiving anti‐CTLA4 monotherapy developed primary hypothyroidism. Conclusions Our cohort demonstrated an increased incidence of hypophysitis with anti‐PD1/anti‐PDL1 in contrast to the rarity of primary thyroid dysfunction with anti‐CTLA4 treatment. These results could be attributed to genetic/ethnic differences. Sequential treatment is, for the first time to our knowledge, reported to increase the risk of developing hypophysitis to a level as high as that of combination therapy.
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Affiliation(s)
- Eva Kassi
- First Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece.,Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Anna Angelousi
- First Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Nikolaos Asonitis
- First Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Diamantopoulos
- First Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Amalia Anastasopoulou
- First Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - George Papaxoinis
- First Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Michalis Kokkinos
- First Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Ilias Giovanopoulos
- First Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Georgios Kyriakakis
- First Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Fotini Petychaki
- First Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Akrivi Savelli
- First Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Olga Benopoulou
- First Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Helen Gogas
- First Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
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41
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Barroso-Sousa R, Barry WT, Garrido-Castro AC, Hodi FS, Min L, Krop IE, Tolaney SM. Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis. JAMA Oncol 2019; 4:173-182. [PMID: 28973656 DOI: 10.1001/jamaoncol.2017.3064] [Citation(s) in RCA: 738] [Impact Index Per Article: 123.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Importance If not promptly recognized, endocrine dysfunction can be life threatening. The incidence and risk of developing such adverse events (AEs) following the use of immune checkpoint inhibitor (ICI) regimens are unknown. Objective To compare the incidence and risk of endocrine AEs following treatment with US Food and Drug Administration-approved ICI regimens. Data Sources A PubMed search through July 18, 2016, using the following keywords was performed: "ipilimumab," "MDX-010," "nivolumab," "BMS-963558," "pembrolizumab," "MK-3475," "atezolizumab," "MPDL3280A," and "phase." Study Selection Thirty-eight randomized clinical trials evaluating the usage of these ICIs for treatment of advanced solid tumors were identified, resulting in a total of 7551 patients who were eligible for a meta-analysis. Regimens were categorized by class into monotherapy with a PD-1 (programmed cell death protein 1) inhibitor, a CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) inhibitor, or a PD-L1 (programmed cell death 1 ligand 1) inhibitor, and combination therapy with PD-1 plus CTLA-4 inhibitors. Data Extraction and Synthesis The data were extracted by 1 primary reviewer (R.B.-S.) and then independently reviewed by 2 secondary reviewers (W.T.B. and A.C.G.-C.) following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Inferences on the incidence of AEs were made using log-odds random effects models. Main Outcomes and Measures Incidence of all-grade hypothyroidism, hyperthyroidism, hypophysitis, primary adrenal insufficiency, and insulin-deficient diabetes. Results Overall, 38 randomized clinical trials comprising 7551 patients were included in this systematic review and meta-analysis. The incidence of both hypothyroidism and hyperthyroidism was highest in patients receiving combination therapy. Patients on the combination regimen were significantly more likely to experience hypothyroidism (odds ratio [OR], 3.81; 95% CI, 2.10-6.91, P < .001) and hyperthyroidism (OR, 4.27; 95% CI, 2.05-8.90; P = .001) than patients on ipilimumab. Compared with patients on ipilimumab, those on PD-1 inhibitors had a higher risk of developing hypothyroidism (OR, 1.89; 95% CI, 1.17-3.05; P = .03). The risk of hyperthyroidism, but not hypothyroidism, was significantly greater with PD-1 than with PD-L1 inhibitors (OR, 5.36; 95% CI, 2.04-14.08; P = .002). While patients who received PD-1 inhibitors were significantly less likely to experience hypophysitis than those receiving ipilimumab (OR, 0.29; 95% CI, 0.18-0.49; P < .001), those who received combination therapy were significantly more likely to develop it (OR, 2.2; 95% CI, 1.39-3.60; P = .001). For primary adrenal insufficiency and insulin-deficient diabetes no statistical inferences were made due to the smaller number of events. Conclusions and Relevance Our study provides more precise data on the incidence of endocrine dysfunctions among patients receiving ICI regimens. Patients on combination therapy are at increased risk of thyroid dysfunction and hypophysitis.
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Affiliation(s)
| | - William T Barry
- Department of Biostatistics and Computation Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Ana C Garrido-Castro
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - F Stephen Hodi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Le Min
- Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts
| | - Ian E Krop
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Sara M Tolaney
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
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42
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Martins Machado C, Almeida Santos L, Barroso A, Oliveira MJ. Nivolumab-induced hypothyroidism followed by isolated ACTH deficiency. BMJ Case Rep 2019; 12:12/8/e231236. [PMID: 31466960 DOI: 10.1136/bcr-2019-231236] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Cancer immunotherapy has been used in several malignancies with clinical benefit. Despite the clinical success, immune-related adverse events are frequent and endocrinopathies can be particularly severe. We report a 55-year-old male patient with stage IV pulmonary carcinoma treated with nivolumab who presented with thyroid dysfunction after the sixth administration of the drug. One year after thyroid dysfunction, the patient complained of severe fatigue, asthenia and weight loss. Laboratory testing showed low morning cortisol with undetected adrenocorticotropic hormone; other pituitary hormones were normal and MRI showed homogeneous enhancement of the pituitary gland and no space-occupying lesions. The diagnosis of nivolumab-induced hypophysitis was made and replacement treatment with hydrocortisone was started with clinical improvement. This case demonstrates that patients under immunotherapy are at risk for a large spectrum of endocrine dysfunctions that may worsen their prognosis. Close monitoring of these patients is warranted.
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Affiliation(s)
- Catarina Martins Machado
- Department of Endocrinology, Centro Hospitalar de Vila Nova de Gaia Espinho EPE, Vila Nova de Gaia, Portugal
| | - Lúcia Almeida Santos
- Department of Endocrinology, Centro Hospitalar de Vila Nova de Gaia Espinho EPE, Vila Nova de Gaia, Portugal
| | - Ana Barroso
- Department of Respiratory Medicine, Centro Hospitalar de Vila Nova de Gaia Espinho EPE, Vila Nova de Gaia, Portugal
| | - Maria João Oliveira
- Department of Endocrinology, Centro Hospitalar de Vila Nova de Gaia Espinho EPE, Vila Nova de Gaia, Portugal
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43
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Ruggeri RM, Campennì A, Giuffrida G, Trimboli P, Giovanella L, Trimarchi F, Cannavò S. Endocrine and metabolic adverse effects of immune checkpoint inhibitors: an overview (what endocrinologists should know). J Endocrinol Invest 2019; 42:745-756. [PMID: 30471004 DOI: 10.1007/s40618-018-0984-z] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Accepted: 11/15/2018] [Indexed: 12/26/2022]
Abstract
Immune checkpoint inhibitors (ICIs) are novel anticancer agents, recently introduced with the aim of boosting the immune response against tumors. ICIs are monoclonal autoantibodies that specifically target inhibitory receptors on T cells: cytotoxic T lymphocyte antigen 4 (CTLA4), programmed death 1 (PD-1) and its ligand (PD-1L). ICIs also generate peculiar dysimmune toxicities, called immune-related adverse events (irAEs), that can potentially affect any tissue, and some may be life-threatening if not promptly recognized. The endocrine and metabolic side effects of ICIs are reviewed here, with a particular focus on their clinical presentation and management. They are among the most frequent toxicities (around 10%) and include hypophysitis, thyroid disorders, adrenalitis, and diabetes mellitus. Treatment is based on the replacement of specific hormone deficits, accompanied by immunosuppression (with corticosteroids or other drugs), depending on irAEs grade, often without the need of ICI withdrawal, except in more severe forms. Prompt recognition of endocrine and metabolic irAEs and adequate treatment allow the patients to continue a therapy they are benefiting from. Endocrinologists, as an integral part of the multidisciplinary oncologic team, need to be familiar with the unique toxicity profile of these anticancer agents. Practical recommendations for their management are proposed.
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Affiliation(s)
- R M Ruggeri
- Unit of Endocrinology, Department of Clinical and Experimental Medicine, Building H, Floor 4, "G. Martino" University Hospital, University of Messina, 98125, Messina, Italy
| | - A Campennì
- Unit of Nuclear Medicine, Department of Biomedical and Dental Sciences and Morpho-Functional Imaging, University of Messina, Messina, Italy
| | - G Giuffrida
- Unit of Endocrinology, Department of Clinical and Experimental Medicine, Building H, Floor 4, "G. Martino" University Hospital, University of Messina, 98125, Messina, Italy.
| | - P Trimboli
- Nuclear Medicine, PET/CT Centre, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
| | - L Giovanella
- Nuclear Medicine, PET/CT Centre, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
| | - F Trimarchi
- Accademia Peloritana dei Pericolanti at the University of Messina, Messina, Italy
| | - S Cannavò
- Department of Human Pathology of Adulthood and Childhood "Gaetano Barresi", University of Messina, Messina, Italy
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Ma C, Hodi FS, Giobbie-Hurder A, Wang X, Zhou J, Zhang A, Zhou Y, Mao F, Angell TE, Andrews CP, Hu J, Barroso-Sousa R, Kaiser UB, Tolaney SM, Min L. The Impact of High-Dose Glucocorticoids on the Outcome of Immune-Checkpoint Inhibitor-Related Thyroid Disorders. Cancer Immunol Res 2019; 7:1214-1220. [PMID: 31088848 PMCID: PMC6606328 DOI: 10.1158/2326-6066.cir-18-0613] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 12/18/2018] [Accepted: 05/09/2019] [Indexed: 02/06/2023]
Abstract
Thyroid disorders have emerged as one of the most common immune-related adverse events (irAE), yet optimum management and biomarkers to predict vulnerable individuals remain to be explored. High-dose glucocorticoid (HDG) therapy is routinely recommended for irAEs. However, systematic analysis of the impact of glucocorticoid therapy on the outcome of immune-checkpoint inhibitor (ICI)-induced thyroid disorders is lacking. We analyzed 151 patients with or without ICI-related thyroid disorders. We divided the patients with ICI-related thyroid disorders into two subgroups: those with and without HDG treatment. Our results showed no significant differences between HDG and no HDG groups in terms of the median duration of thyrotoxicosis: 28 (range, 7-85) and 42 (range, 14-273) days, the median time to conversion from thyrotoxicosis to hypothyroidism: 39 days (range, 14-169) and 42 days (range, 14-315) days, the median time to onset of hypothyroidism: 63 (range, 21-190) and 63 (range, 14-489) days, and the median maintenance dose of levothyroxine: 1.5 (range, 0.4-2.3) μg/kg/day, and 1.3 (range, 0.3-2.5) μg/kg/day. The median pretreatment TSH was 2.3 (range, 0.3-5.2) mIU/L and 1.7 (range, 0.5-4.5) mIU/L in patients with and without ICI-related thyroid disorders, respectively. Baseline TSH was significantly higher in patients who developed ICI-related thyroid disorders (P = 0.05). Subgroup analysis revealed significantly higher baseline TSH in male but not in female patients with ICI-induced thyroid dysfunction. Our results show that HDG treatment did not improve the outcome of ICI-related thyroid disorders.
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Affiliation(s)
- Chanjuan Ma
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts
- Department of Endocrinology, Shanxi Provincial People's Hospital, Taiyuan, People's Republic of China
| | - F Stephen Hodi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Anita Giobbie-Hurder
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Xiaocheng Wang
- Department of Medical Record & Statistics, Shanxi Provincial People's Hospital, Taiyuan, People's Republic of China
| | - Jing Zhou
- Department of Endocrinology, Shanxi Provincial People's Hospital, Taiyuan, People's Republic of China
| | - Amy Zhang
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts
| | - Ying Zhou
- Department of Endocrinology and Metabolism, China-Japan Friendship Hospital, Beijing, People's Republic of China
| | - Fei Mao
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Trevor E Angell
- Division of Endocrinology, Diabetes and Metabolism, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Chelsea P Andrews
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Jiani Hu
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | | | - Ursula B Kaiser
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts
| | - Sara M Tolaney
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Le Min
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts.
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Nivolumab-induced Thyroid Dysfunctions in Patients with Previously Treated Non-small Cell Lung Cancer. Interdiscip Sci 2019; 11:287-291. [PMID: 31187431 DOI: 10.1007/s12539-019-00337-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Revised: 05/07/2019] [Accepted: 05/20/2019] [Indexed: 10/26/2022]
Abstract
BACKGROUND Nivolumab, a fully human IgG4 programmed cell death-1 checkpoint inhibitor, demonstrated its benefit of prolonged survival in advanced non-small cell lung cancer (NSCLC). However, nivolumab generated unique immune-related adverse events such as thyroid dysfunctions. Herein we assessed nivolumab-induced thyroid dysfunctions in patients with previously treated advanced NSCLC in our hospital. METHODS The medical records of 11 patients with advanced NSCLC who were initiated with nivolumab treatment between June 28, 2018, and January 15, 2019, in our hospital were reviewed. Serological tests of thyroid-stimulating hormone and free tetraiodothyronine were measured at baseline and every 8 weeks. RESULTS Three out of 11 patients developed new-onset hypothyroidism during the treatment, and two of three patients had transient hyperthyroidism first. Two patients were diagnosed with Grade 2 hypothyroidism and received levothyroxine therapy. The other one was Grade 1 hypothyroidism and asymptomatic. All these three patients continued nivolumab therapy. CONCLUSION Nivolumab-induced thyroid dysfunctions in advanced NSCLC were mostly mild and controlled. Thyroid function needs to be monitored for early prediction and appropriate managements of thyroid dysfunctions.
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46
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Sun X, Roudi R, Dai T, Chen S, Fan B, Li H, Zhou Y, Zhou M, Zhu B, Yin C, Li B, Li X. Immune-related adverse events associated with programmed cell death protein-1 and programmed cell death ligand 1 inhibitors for non-small cell lung cancer: a PRISMA systematic review and meta-analysis. BMC Cancer 2019; 19:558. [PMID: 31182061 PMCID: PMC6558759 DOI: 10.1186/s12885-019-5701-6] [Citation(s) in RCA: 111] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 05/10/2019] [Indexed: 12/15/2022] Open
Abstract
Background Programmed cell death protein-1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have remarkable clinical efficacy in the treatment of non-small cell lung cancer (NSCLC); however, the breakdown of immune escape causes a variety of immune-related adverse events (irAEs). With the increasing use of PD-1/PD-L1 inhibitors alone or in combination with other therapies, awareness and management of irAEs have become more important. We aimed to assess the incidence and nature of irAEs associated with PD-1 and PD-L1 inhibitors for NSCLC. Methods Articles from the MEDLINE, EMBASE, and Cochrane databases were searched through December 2017. The incidence of overall and organ-specific irAEs was investigated in all clinical trials with nivolumab, pembrolizumab, atezolimumab, durvalumab, and avelumab as single agents for treatment of NSCLC. We calculated the pooled incidence using R software with package Meta. Results Sixteen trials were included in the meta-analysis: 10 trials with PD-1 inhibitors (3734 patients) and 6 trials with PD-L1 inhibitors (2474 patients). The overall incidence of irAEs was 22% (95% confidence interval [CI], 17–28) for all grades and 4% (95% CI, 2–6) for high-grade irAEs. The frequency of irAEs varied based on drug type and organ, and patients treated with PD-1 inhibitors had an increased rate of any grade and high-grade irAEs compared with patients who received PD-L1 inhibitors. Organ-specific irAEs were most frequently observed in, in decreasing order, the endocrine system, skin, pulmonary tract, and gastrointestinal tract. The total number of patients whose death was attributed to irAEs was 14 (0.34%), and most (79%) of these patients died because of pneumonitis. The median time to the onset of irAEs after the initiation of treatment was 10 weeks (interquartile range, 6–19.5 weeks) and varied depending on the organ system involved. Conclusions The specificity of irAEs was closely associated with the mechanism of PD-1/PD-L1 antibodies involved in restarting anticancer immune attacks. Comprehensive understanding, timely detection, and effective management could improve the compliance of patients and guide the interruption of treatment. Electronic supplementary material The online version of this article (10.1186/s12885-019-5701-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xiaoying Sun
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.,Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Raheleh Roudi
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, 14496-14530, Iran
| | - Ting Dai
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.,Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Shangya Chen
- Department of Toxicology, Shandong Academy of Occupational Health and Occupational Medicine, Shandong Academy of Medical Science, Jinan, 250062, Shandong, China
| | - Bin Fan
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.,Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Hongjin Li
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.,Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yaqiong Zhou
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.,Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Min Zhou
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.,Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Bo Zhu
- Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Chengqian Yin
- Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Bin Li
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China. .,Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 201203, China. .,Department of Dermatology, Shaanxi Traditional Chinese Medicine Hospital, Xi'an, 710003, China.
| | - Xin Li
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China. .,Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 201203, China.
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Abstract
Immune checkpoint inhibitors act to restore T cell-mediated antitumor immunity. By this nature, these cancer immunotherapy drugs are associated with various immune-related adverse events such as thyroid dysfunction. We describe a case of thyrotoxicosis secondary to a programmed cell death 1 (PD-1) immune checkpoint inhibitor, pembrolizumab. A 30-year-old female was started on pembrolizumab immunotherapy for stage III small cell carcinoma of the ovary, hypercalcemic type. Thirteen days after her second cycle of therapy, she presented with symptoms consistent with thyrotoxicosis. A thyroiditis was diagnosed by thyroid function tests and ultrasonography. She was originally treated with prednisone and metoprolol for possible Grave's disease. Pertechnetate thyroid scan was more consistent with thyroiditis secondary to pembrolizumab. She underwent a total thyroidectomy 10 days after initial presentation for refractory thyrotoxicosis despite maximal medical therapy. Her symptoms resolved and thyroid function tests significantly improved. Pathology was consistent with severe thyroiditis. Immune microenvironment may play a role in the expression of programmed cell death protein 1 ligand 1 (PD-L1). Chronic inflammation surrounding tumor upregulates PD-L1 expression on tumor cells by the release of cytokines, which acts to inhibit tumor destruction. We suggest that our patient had an undetected chronic inflammation of the thyroid, specifically Hashimoto's thyroidits, which predisposed her to thyroid destruction when taking pembrolizumab. Understanding that an inflammatory environment impacts thyroid toxicity to PD-1 inhibitor therapy is novel and should be further studied.
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Affiliation(s)
- Brittney A Imblum
- Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, Six Founders Pavilion, Philadelphia, PA, 19104-4283, USA.
| | - Zubair W Baloch
- Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, Six Founders Pavilion, Philadelphia, PA, 19104-4283, USA
| | - Douglas Fraker
- Department of Surgery and Division of Endocrine & Oncologic Surgery, Hospital of the University of Pennsylvania, 3400 Spruce Street, Four Silverstein, Philadelphia, PA, 19104-4283, USA
| | - Virginia A LiVolsi
- Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, Six Founders Pavilion, Philadelphia, PA, 19104-4283, USA
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48
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Peiró I, Palmero R, Iglesias P, Díez JJ, Simó-Servat A, Marín JA, Jiménez L, Domingo-Domenech E, Mancho-Fora N, Nadal E, Villabona C. Thyroid dysfunction induced by nivolumab: searching for disease patterns and outcomes. Endocrine 2019; 64:605-613. [PMID: 30805887 DOI: 10.1007/s12020-019-01871-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 02/12/2019] [Indexed: 12/16/2022]
Abstract
PURPOSE Nivolumab is a monoclonal antibody that blocks the activation of programmed death-1 receptor, promoting T-cell activation against cancer cells. Thyroid dysfunction (TD) is a common immune-related adverse event (irAE) induced by nivolumab. We report the prevalence, patterns and outcomes of nivolumab-induced TD among cancer patients in our center. METHODS All patients treated with nivolumab during 2016 were included. We assessed thyroid function tests, thyroid autoimmunity, thyroid imaging, and clinical outcome during nivolumab therapy as well as overall survival (OS). RESULTS Seventy-three patients (55 with non-small-cell lung cancer [NSCLC], 9 with melanoma and 9 with Hodgkin lymphoma) were included. Median of follow up: 390.5 days. Seventeen patients (23.3%) developed TD during treatment. Thyrotoxicosis was reported in seven patients. Serum thyroid-stimulating hormone (TSH) nadir occurred after a median of 51 days (95% CI: 35-71). Thyroid antibodies were positive in three of the seven patients. Five of the seven hyperthyroid patients became hypothyroid later, and four of them required levothyroxine treatment. Primary hypothyroidism occurred in ten patients. Serum TSH peak occurred after a median of 110 days [95% CI: 85.2-197]. Thyroid autoimmunity was positive in one patient. In patients with NSCLC, TD was associated with better OS (HR = 0.4 [95% CI: 0.17-0.94]; p = 0.035). CONCLUSIONS TD induced by nivolumab is a common and heterogeneous irAE. Thyrotoxicosis develops earlier than hypothyroidism. A pattern consistent with a transient thyroiditis followed by hypothyroidism was observed in one-third of patients. Our results suggest that patients with NSCLC and nivolumab-induced TD might have better survival.
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Affiliation(s)
- Inmaculada Peiró
- Clinical Nutrition Unit, Institut Català d'Oncologia (ICO), L'Hospitalet de Llobregat, Avda Gran Via, 199-203, Barcelona, 08908, Spain.
- Unit of Nutrition and Cancer, Biomedical Research Institute of Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
| | - Ramón Palmero
- Department of Medical Oncology, Institut Català d'Oncologia (ICO), L'Hospitalet de Llobregat, Barcelona, Spain
- Clinical Research in Solid Tumors (CReST) Group, Oncobell, Biomedical Research Institute of Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Pedro Iglesias
- Department of Endocrinology, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain
| | - Juan José Díez
- Department of Endocrinology, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain
| | - Andreu Simó-Servat
- Department of Endocrinology, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Juan Antonio Marín
- Department of Medical Oncology, Institut Català d'Oncologia (ICO), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Laura Jiménez
- Department of Medical Oncology, Institut Català d'Oncologia (ICO), L'Hospitalet de Llobregat, Barcelona, Spain
- Clinical Research in Solid Tumors (CReST) Group, Oncobell, Biomedical Research Institute of Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Eva Domingo-Domenech
- Department of Hematology, Institut Català d'Oncologia (ICO), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Nuria Mancho-Fora
- Biostatistics Unit, Biomedical Research Institute of Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Ernest Nadal
- Department of Medical Oncology, Institut Català d'Oncologia (ICO), L'Hospitalet de Llobregat, Barcelona, Spain
- Clinical Research in Solid Tumors (CReST) Group, Oncobell, Biomedical Research Institute of Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Carlos Villabona
- Department of Endocrinology, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain
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49
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Jannin A, Penel N, Ladsous M, Vantyghem MC, Do Cao C. Tyrosine kinase inhibitors and immune checkpoint inhibitors-induced thyroid disorders. Crit Rev Oncol Hematol 2019; 141:23-35. [PMID: 31202955 DOI: 10.1016/j.critrevonc.2019.05.015] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 04/21/2019] [Accepted: 05/27/2019] [Indexed: 12/11/2022] Open
Abstract
Recently, tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICPIs) have emerged as new classes of anticancer therapies. Although generally considered less toxic than cytotoxic chemotherapy, these new drugs can cause significant unanticipated side effects including thyroid dysfunction. This review provides a literature assessment of thyroid dysfunctions induced by TKI and ICPIs. We intend to define for these two classes the frequency of thyroid involvement, the potential mechanisms that result in this toxicity, the clinical-biological impact and the therapeutic management. Detection of thyroid dysfunction requires monitoring of TSH, in combination with free T4 if needed and, depending on the clinical impact and the kinetics of biological abnormalities, starting symptomatic treatment of hyperthyroidism and/or correcting hypothyroidism.
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Affiliation(s)
- Arnaud Jannin
- Department of Endocrinology and Metabolism, CHU Lille, 59037 Lille, France.
| | - Nicolas Penel
- Medical Oncology Department, Oscar Lambret Cancer Centre, Lille, France; Medical Oncology Department, CHU Lille, 59037, Lille France.
| | - Miriam Ladsous
- Department of Endocrinology and Metabolism, CHU Lille, 59037 Lille, France.
| | - Marie Christine Vantyghem
- Department of Endocrinology and Metabolism, CHU Lille, 59037 Lille, France; UMR 1190 Translational Research in Diabetes INSERM, 59000 Lille, France.
| | - Christine Do Cao
- Department of Endocrinology and Metabolism, CHU Lille, 59037 Lille, France.
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50
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Ferrari SM, Fallahi P, Elia G, Ragusa F, Ruffilli I, Patrizio A, Galdiero MR, Baldini E, Ulisse S, Marone G, Antonelli A. Autoimmune Endocrine Dysfunctions Associated with Cancer Immunotherapies. Int J Mol Sci 2019; 20:ijms20102560. [PMID: 31137683 PMCID: PMC6566424 DOI: 10.3390/ijms20102560] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 05/20/2019] [Accepted: 05/23/2019] [Indexed: 02/07/2023] Open
Abstract
Immune checkpoint inhibitors block the checkpoint molecules. Different types of cancer immune checkpoint inhibitors have been approved recently: CTLA-4 monoclonal antibodies (as ipilimumab); anti-PD-1 monoclonal antibodies (as pembrolizumab and nivolumab); and anti-PD-L1 monoclonal antibodies (as atezolizumab, avelumab, and durmalumab). We collect recent published results about autoimmune endocrine dysfunctions associated with cancer antibody immunotherapies. These agents cause a raised immune response leading to immune-related adverse events (irAEs), varying from mild to fatal, based on the organ system and severity. Immune-related endocrine toxicities are usually irreversible in 50% of cases, and include hypophysitis, thyroid dysfunctions, type 1 diabetes mellitus, and adrenal insufficiency. Anti-PD-1-antibodies are more frequently associated with thyroid dysfunctions (including painless thyroiditis, hypothyroidism, thyrotoxicosis, or thyroid storm), while the most frequent irAE related to anti-CTLA-4-antibodies is hypophysitis. The combination of anti-CTLA-4 and anti-PD-1 antibodies is associated with a 30% chance of irAEs. Symptoms and clinical signs vary depending on the target organ. IrAEs are usually managed by an oncological therapist, but in more challenging circumstances (i.e., for new onset insulin–dependent diabetes, hypoadrenalism, gonadal hormones dysfunctions, or durable hypophysitis) an endocrinologist is needed.
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Affiliation(s)
- Silvia Martina Ferrari
- Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56126 Pisa, Italy.
| | - Poupak Fallahi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Savi 10, 56126 Pisa, Italy.
| | - Giusy Elia
- Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56126 Pisa, Italy.
| | - Francesca Ragusa
- Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56126 Pisa, Italy.
| | - Ilaria Ruffilli
- Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56126 Pisa, Italy.
| | - Armando Patrizio
- Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56126 Pisa, Italy.
| | - Maria Rosaria Galdiero
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131 Naples, Italy.
- WAO Center of Excellence, 80131 Naples, Italy.
| | - Enke Baldini
- Department of Experimental Medicine, 'Sapienza' University of Rome, 00161 Rome, Italy.
| | - Salvatore Ulisse
- Department of Experimental Medicine, 'Sapienza' University of Rome, 00161 Rome, Italy.
| | - Gianni Marone
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131 Naples, Italy.
- WAO Center of Excellence, 80131 Naples, Italy.
- Institute of Experimental Endocrinology and Oncology "Gaetano Salvatore" (IEOS), National Research Council (CNR), 80131 Naples, Italy.
| | - Alessandro Antonelli
- Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56126 Pisa, Italy.
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