- Credits - Section Writer: Dr. Om J Lakhani - Section Editor: Dr. Om J Lakhani - Video lecture : Dr. Alpesh Goyal - Q. What are the causes of hypothyroidism in cancer patients ? - • Drug induced - - Conventional anticancer agents - Targeted cancer therapy - Cancer immunotherapy - • Radiation to CNS or thyroid - • lodinated contrast use. - Q. True or false- those patients who develop hypothyroidism due to anti-cancer use are more likely to have better response to cancer treatment ? - Some studies have suggested this to be true - However this is controversial - Could be an elemental of bias - However may be potentially true for immunotherapy - Q. What are the various types of conventional anti-cancer drugs ? - Alkylating agents : Cisplatin, Carboplatin, Cyclophosphamide, Temozolomide - Antimetabolites: Methotrexate, Capecitabine, Azacitadine, 5-Flurouracil - Anthracyclines: Doxorubicin, Daunorubicin - Topoisomerase inhibitors: Irinotecan, Topotecan, Etoposide - Mitosis inhibitors: Paclitaxel, Docetaxel, Vincristine, Vinblastine - Miscellaneous: Asparaginase, Arsenic trioxide, ATRA, Mitotane - Q. Which of these drugs increase TBG levels ? - Mitotane - 5-FU - Asparginase - Q. What other type of thyroid dysfunction do you see with [[mitotane]] ? - Mitotane can produce [[Central hypothyroidism]] - Q. Which are the various forms of Targeted anti-cancer drugs ? - Tyrosine kinase inhibitors: Imatinib, Dasatinib, Nilotinib, Sunitinib, Sorafenib, Motesanib - Monocional antibodies: Bevacizumab, Rituximab, Panitumumab, Alemtuzumab - Proteasome inhibitors: Bortezomib, Carfilzomib - RXR agonist: Bexarotene - lodine based cancer therapy : 1131 MIBG therapy - Immunotoxins: Denileukin Difitox - mTOR inhibitors: Temsirolimus, Sirolimus - PARP inhibitors: Olaparib - CDK inhibitors: Ribeciclik, Dalhocielih - Q. Which of these produce hypothyroidism ? - All the tyrosine kinase inhibitors - Alemtuzumab - Bexerotene - I-131 MIBG - Q. Which are hormone based cancer therapies ? - Anti-androgens: Abiraterone, Bicalutamide, Cyproterone, Flutamide - Anti-estrogens and Als: Exemestane, Fulvestrant, Tamoxifen, Letrozole, Anastrozole - GnRH analogues: Goserelin, Histrelin, Leuprolide, Triptorelin - Peptide Hormones: Lanreotide, Octreotide, Pasireotide - Q. What is the impact of Tamoxifen on thyroid function ? - Tamoxifen would increase the TBG levels - Q. Which are the various immune check point inhibitors ? - Antibodies against CTL4 - Ipilimumab - Tremelimumab - Antibodies against PD-1 - **Pembrolizumab** (**Keytruda**) · - Nivolumab (**Opdivo**) · - Cemiplimab (Libtayo) - Antibodies against PD-L1 - **durvalumab** - atezolizumab - avelumab - Q. How do tyrosine kinase inhibitors produce thyroid dysfunction ? - By two methods - 1. Increasing the requirement of levothyroxine in patients who are athyreotic - This is especially true with Imatinib and the dose of LT4 must be doubled in such patients when initiated on imatinib - Typically almost always occurs within 2 weeks of starting the drug - The enhanced thyroid hormone metabolism attributed to increased Type 3 deiodination. - 2. New onset of thyroid dysfunction - This is seen with Sunitinib and Sorafenib - TKI → inhibits VEGF → ischemic thyroiditis → thyroid dysfunction - This effect is often delayed and occurs about 4-94 weeks after starting the drug - Q. Bexrotene is used in what patients ? - It is mainly used in patients with Cutaneous T cell lymphoma - It is a RXR agonist - Q. What type of hypothyroidism is seen with Bexarotene ? - Mainly central hypothyroidism - It is very rapid and occurs within hours - It reduces TSH-beta gene transcription - It can also suppress thyrotropes - Q. What is Alemtuzumab ? - Classification: Alemtuzumab is a humanized monoclonal antibody. - Target: It is directed against CD52, a protein present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes are derived. - Usage in Therapy: - It is used in the treatment of chronic lymphocytic leukemia (CLL) and multiple sclerosis (MS). - In CLL, it is used for B-cell chronic lymphocytic leukemia, particularly for patients who have been treated with alkylating agents and have failed fludarabine therapy. - In MS, it's administered to reduce relapses in relapsing-remitting multiple sclerosis. - Mechanism of Action: - Induces lysis of lymphocytes through antibody-dependent cell-mediated cytotoxicity and complement fixation. - Leads to profound lymphopenia, thus modulating the immune responses. - Administration: It is typically administered intravenously. - Q. What kind of thyroid dyfunction is produced by Alemtuzumab? - It produces [[Graves' disease]] - This is mainly because of IRIS or immune reconstitution - It is mainly seen in Multiple sclerosis patients given this drug - Typically occurs after 6-31 months after giving the therapy - Q. How is iodine given before MIBG scan ? - Lugol's iodine, 5-6 drops, 3-5 times/day, beginning 1 d before and till 6 d after therapeutic/diagnostic MIBG - Q. What type of autoimmune diseases are seen with Cancer immunotherapy or [[Immune checkpoint inhibitors]] therapy ? - Mainly those induced by T-cells - It mainly leads to T-cell activation and destruction of Cancer cells -  - Q. What are the various thyroid disorders seen with [[Immune checkpoint inhibitors]] ? - Central hypothyroidism due to [[hypophysitis]] - Primary hypothyroidism - Painless thyroiditis - Transient thyrotoxicosis - Graves disease - Euthyroid orbitopathy - Q. Of the various immune check point inhibitors, what are the differential actions on various endocrine organs ? - [[CTLA-4 inhibitor]] - [[Ipilimumab]] - more involvement of Pituitary^^ - Pituitary gland expresses. CTLA-4 - hence more pituitary involvement - Generaly occurs about 9 weeks after initiation of therapy - [[PD1 inhibitor]] - [[Nivolomumab]] or [[Pembrolizumab]] - more involvement of Adrenal and Thyroid #ClinicalPearl - It can also cause [[Type 1 Diabetes]] - Both type 1 and hypophysitits can coexist in the same patient - Q. How common is central hypothyroidism with [[Ipilimumab]] ? - Almost 100% - This drug is common in metastatic melanoma - Pituitary enlargement is almost commonly seen which resolves on discontinuation of the drug - Q. What kind of thyroid dysfunction is seen with [[interferon alpha]] ? - Autoimmune thyroiditis- mainly hypothyroidism- rarely even Graves' disease - Q. Summarize the thyroid dysfunction seen with various anti-cancer drugs -  - Q. How should you monitor patients on [[Immune checkpoint inhibitors]] ? - TSH, free T4, 8 am cortisol before x and before each cycle - Consider baseline MRI pituitary - Keep a close watch for mass effects, hyponatremia - Low threshold for hormonal evaluation and MR imaging Video lecture- by Dr. Alpesh Goyal <iframe width="560" height="315" src="https://www.youtube.com/embed/hGP_EGwhHDw" title="YouTube video player" frameborder="0" allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture; web-share" allowfullscreen></iframe> Reference: 1. Bhattacharya S, Goyal A, Kaur P, Singh R, Kalra S. Anticancer drug-induced thyroid dysfunction. European Endocrinology. 2020 Apr;16(1):32.