{"id":51672,"date":"2023-09-30T11:48:44","date_gmt":"2023-09-30T11:48:44","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=51672"},"modified":"2023-10-07T08:33:21","modified_gmt":"2023-10-07T08:33:21","slug":"tyrosine-kinase-inhibitors-and-thyroid-toxicity","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol16no3\/tyrosine-kinase-inhibitors-and-thyroid-toxicity\/","title":{"rendered":"Tyrosine Kinase Inhibitors and Thyroid Toxicity"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

In recent years, the widespread use of tyrosine kinase\ninhibitors (TKIs) in oncology, either in combination with chemotherapy or\nradiotherapy or as a single agent, has led to a growing interest in the effects\ndetermined by these drugs on the endocrine system, on thyroid function.\nDysregulation of tyrosine kinase receptor activity is a crucial event that\ndetermines the ‘escape’ of the tumour cell from the regulation of physiological\ngrowth mechanisms, leading to tumor genesis. The receptors ‘targeted’ by TKIs\nare implicated in cell survival, proliferation, invasiveness, and tumour\nangiogenesis. The tolerability profile of each molecule is variable and in\ncomparison, to conventional cytotoxic agents, TKIs are associated with a lower\ndegree of toxicity. Several tyrosine kinase inhibitor drugs have been approved\nand are used in therapy 1,2<\/sup>.  As\na result, the use of these drugs has increased and new side effects associated\nwith them have been highlighted. TKIs induce thyroid dysfunction and manifest\nin various forms such as hypothyroidism, thyroiditis, and hyperthyroidism. The\nmost common is hypothyroidism, which can be diagnosed or remains at subclinical\nlevels 3-5<\/sup>.  Sunitinib is\nparticularly associated with these side effects that are related to thyroid\nfunction. Retrospective studies indicate that with sunitinib use there is a\n53-85% risk of hypothyroidism while prospective data report an incidence of\nhypothyroidism of 36-71%. Other TKIs such as sorafenib, imatinib, and\nvandetanib induce thyroid dysfunction, though to a lesser extent than sunitinib\n6-8<\/sup>.<\/p>\n\n\n\n

TKIs and thyroid dysfunction<\/strong><\/p>\n\n\n\n

The main drugs believed to cause thyroid dysfunction\nare described and their incidences are analysed.<\/p>\n\n\n\n

Sunitinib<\/strong><\/p>\n\n\n\n

The use of sunitinib has been associated with the\nhighest risk of developing hypothyroidism 9<\/sup>. This drug is an orally\nadministered TKI and has multitarget activity involving the platelet-derived\ngrowth factor receptor (PDGFR), vascular endothelial growth factor receptor\n(VEGFR), kit, and RET (Table 1)[10,11].<\/p>\n\n\n\n

Table 1: Examples of TKIs and their targets<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n
\n

Target<\/strong><\/p>\n<\/td>\n

\n

Drug<\/strong><\/p>\n<\/td>\n

\n

Approved indications<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

BCR-ABL<\/p>\n<\/td>\n

\n

Imatinib<\/p>\n

Dasatinib<\/p>\n

Nilotinib<\/p>\n<\/td>\n

\n

Chronic myeloid leukaemia<\/p>\n

Philadelphia chromosome positive acute lymphoid leukaemia<\/p>\n<\/td>\n<\/tr>\n

\n

KIT<\/p>\n<\/td>\n

\n

Imatinib<\/p>\n

Sunitinib<\/p>\n<\/td>\n

\n

Gastrointestinal stromal tumour<\/p>\n<\/td>\n<\/tr>\n

\n

PDGFR \u03b1\/\u03b2<\/p>\n<\/td>\n

\n

Imatinib<\/p>\n<\/td>\n

\n

Chronic myelomonocyticleukaemia (with TEL-PDGFR\u03b2 fusion)<\/p>\n

Hypereosinophilic syndrome (with PDGFR\u03b2 fusion)<\/p>\n

Dermatofibrosarcoma protuberans<\/p>\n<\/td>\n<\/tr>\n

\n

HER 2<\/p>\n<\/td>\n

\n

Lapatinib<\/p>\n<\/td>\n

\n

Her2+ breast cancer<\/p>\n<\/td>\n<\/tr>\n

\n

EGFR<\/p>\n<\/td>\n

\n

Gefitinib<\/p>\n<\/td>\n

\n

Lung adenocarcinoma (with EGFR mutation)<\/p>\n<\/td>\n<\/tr>\n

\n

VEGFR<\/p>\n<\/td>\n

\n

Sorafenib<\/p>\n

Sunitinib<\/p>\n<\/td>\n

\n

Kidney cancer<\/p>\n

Hepatocellular carcinoma (sorafenib only)<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Sunitinib treatment resulted in thyroid dysfunction\nafter two cases experienced symptoms such as marked asthenia, confusion,\ndecreased cold\/heat tolerance, palpitations, decreased heat tolerance, and neck\npain after sunitinib treatment. Both patients had subnormal serum\nthyroid-stimulating hormone (TSH) levels and received thyroid hormone\nreplacement therapy, which resulted in resolution of symptoms and physiologic\nlevels of TSH 12,13<\/sup>. <\/p>\n\n\n\n

These clinical observations prompted prospective\nstudies to identify possible associations between sunitinib and the development\nof thyroid dysfunction. Thus, data from 42 imatinib-resistant GIST\ngastrointestinal stromal tumour patients who had been treated with for at least\nthree cycles of sunitinib were analysed. These patients had normal serum TSH\nlevels and were not taking thyroid medications or drugs that may cause thyroid\ndysfunction. The data collected showed abnormal serum TSH concentrations in 26\npatients (62%); persistent primary hypothyroidism was registered in 15 patients\n(36%); 4 patients (10%) developed isolated TSH suppression; in 7 patients (17%)\na transient TSH increase was observed; biochemical data showed no signs of\nautoimmune thyroid disease in any patient 12<\/sup>. <\/p>\n\n\n\n

There are many other studies showing a close\nassociation between sunitinib treatment and thyroid dysfunction. The\nconclusions to be drawn from these are: a) The longer the sunitinib treatment,\nthe higher the risk of hypothyroidism. b) After discontinuing sunitinib, serum\nTSH levels return to normal over approximately 60 days 6<\/sup>. The\naverage time to develop thyroid dysfunction is about 4 weeks. Patients who did\nnot develop hypothyroidism in the first cycle did not develop hypothyroidism in\nthe more advanced stages of treatment. 14,15<\/sup>.<\/p>\n\n\n\n

Sorafenib<\/strong><\/p>\n\n\n\n

Sorafenib is an orally administered TKI with\ninhibitory activity on several kinases such as BRAF, VEGFR, RET 16,17<\/sup>.\nBecause of the increased risk of thyroid dysfunction in patients receiving\nsunitinib, several studies have been conducted to investigate the association\nof other TKIs with this type of dysfunction 18,19<\/sup>. <\/p>\n\n\n\n

These include a retrospective study evaluating thyroid\nfunction testing in patients receiving sorafenib for metastatic renal cell\ncarcinoma (RCC). Results showed that of the 39 patients, 8 (21%) developed\nhypothyroidism and 7 hypothyroidism and hyperthyroidism. Clinical events due to\nthyroid dysfunction requiring thyroid hormone replacement therapy occurred in\nonly 2 subjects 20<\/sup>. Another study involved 38 patients, with\nmetastatic RCC treated with sorafenib 400 mg administered twice daily, in whom\nthyroid function was monitored over time. Thyroid hormones were assessed before\nstarting treatment and on the first day of each treatment cycle. Of the 38\npatients, 23 had normal baseline thyroid function and 15 had thyroid\ndysfunction. The results showed that among the 23 patients with normal basal\nthyroid hormones, high serum TSH was present in 7 patients (30%), and low serum\nTSH in 1 patient (5%). No additional treatment had to be initiated. Of the 15\npatients with basal thyroid insufficiency, two patients, whose initial\ncondition was subclinical hypothyroidism (elevated serum TSH but normal T3 and\nT4), subsequently showed clinical signs of hypothiroidism. Thyroid hormone\ntherapy had to be initiated in these patients 6, 21-23<\/sup>.<\/p>\n\n\n\n

Imatinib<\/strong><\/p>\n\n\n\n

Imatinib is an oral TKI that activates with RET,\nBCR-ABL, PDGFR, c-Fms, and c-Kit. In a study of imatinib treatment for advanced\nmedullary thyroid cancer (MTC) in 15 patients, 10 of whom had undergone total\nthyroidectomy and were receiving hormone replacement therapy, 9 patients\ndeveloped hypothyroidism (the 10th patient had unmonitored thyroid function).\nStudies have shown that a mean 210% (range 150-350%) increase in hormone\nreplacement therapy is required to normalize TSH levels immediately after\nstarting treatment. Normal function was maintained in patients with intact\nthyroid 24, 25<\/sup>.<\/p>\n\n\n\n

Other studies have reported similar results,\nsuggesting that the effect of imatinib on thyroid function is relevant only to\npatients who have undergone total thyroidectomy, as it appears that the action\nof imatinib does not occur in the thyroid itself  6,26<\/sup>. For further confirmation, a\nstudy with imatinib in patients with chronic myeloid leukemia and normal\nthyroid function reported no cases of thyroid changes 27<\/sup>.<\/p>\n\n\n\n

Nilotinib<\/strong><\/p>\n\n\n\n

Nilotinib has received clinical approval for the\ntreatment of Philadelphia-positive chronic myeloid leukemia form (Ph-positive\nCML).  It belongs to the second generation\nof TKIs, designed on the structural analogy with imatinib but provided with\nenhanced efficacy on BCR-ABL inhibitory power 6,28-30<\/sup>.<\/p>\n\n\n\n

A retrospective study evaluated the effect of nilotinib on thyroid function in Ph-positive CML patients. Of the 55 patients, 6 (11%) were taking thyroid medication prior to initiating nilotinib therapy, and 18 (33%) had previously been treated with interferon. The results showed that: 12 patients (22%) developed hypothyroidism (6 subclinical, 6 clinical); 18 subjects (33%) developed hyperthyroidism (10 subclinical, 8 clinical). In most patients treated with thyroid hormone replacement therapy prior to initiating nilotinib, it is not necessary to change the dose of thyroid hormone used, despite the risk of developing thyroid hormone abnormalities has been reported in patients previously treated with interferon: however, endpoint data not statistically significant. Four patients had thyroiditis (3 had antithyroid antibodies) and 1 patient had hyperthyroidism before hypothyroidism. In 3 of these patients, spontaneous resolution of hypothyroidism was observed while hormone replacement therapy was required in one patient. Therefore, it can be concluded that nilotinib-induced thyroid dysfunction rarely requires clinical pharmacological treatment 31<\/sup>. <\/p>\n\n\n\n

Vandetanib<\/strong><\/p>\n\n\n\n

Vandetanib is administered orally and has targeted\nactivity at EGFR, VEGFR, and RET.<\/p>\n\n\n\n

In a study with vandetanib administered at a dose of\n100 mg\/day in subjects with advanced hereditary medullary thyroid carcinoma who\nhad previously undergone total thyroidectomy and all were on hormone\nreplacement therapy, there was a mean 5.1-fold increase in serum TSH, but no\ncases of symptomatic hypothyroidism 32\u201334<\/sup>.<\/p>\n\n\n\n

Mechanisms responsible for the induction of\nhypothyroidism<\/strong><\/p>\n\n\n\n

Understanding the mechanism leading to hypothyroidism\nis a burning problem for scientists, they are conducting many different studies\nto answer this question. At present, there are no conclusive data, but various\nhypotheses have been proposed that need to be confirmed. Since this side effect\nwas mainly observed with sunitinib use, many studies have focused on this TKI.<\/p>\n\n\n\n

For sunitinib, multiple mechanisms appear to be\ninvolved: <\/p>\n\n\n\n

Sunitinib appears to have a direct cytotoxic effect on thyroid cells, possibly by inhibiting the activity of VEGFR and\/or PDGFR in thyroid follicular cells whose activity is only partially regulated by TSH 6,35,36.<\/sup> Experiments in rats reported that administration of VEGF inhibitors induced capillary depletion in various organs, including the thyroid gland where the greatest regression (68%) was observed. . Other interesting data show that TSH can be increased up to 19 times than the control value, while free T4 is unchanged. It should be noted that after treatment with VEGF inhibitors, capillary remodeling occurs in thyroid tissue 37<\/sup>.<\/p>\n\n\n\n

It appears that sunitinib leads to altered thyroid activity by the inhibitory action of the thyroid peroxidase (TPO) by blocking thyroid hormone synthesis. As the thyroid has reserves of thyroid hormones, this could explain the latency period between the start of sunitinib therapy and the development of hypothyroidism. The ability of sunitinib to inhibit TPO activity has been evaluated in vitro<\/em> but not in vivo<\/em> 38,39<\/sup>. <\/p>\n\n\n\n

Sunitinib can block the absorption of iodine and thereby cause transient hypothyroidism. The most widely accepted mechanism for this effect proposes that sunitinib interacts with the iodine-sodium synchronizer (NIS), whose TSH regulation occurs via cAMP, unaffected by the drug. However, Sunitib does not seem to affect NIS 6<\/sup>. <\/p>\n\n\n\n

Finally, sunitinib does not appear to induce autoimmune thyroid disease, as may occur with interferon-\u03b1 and interleukin-based therapies 6<\/sup>. As for sorafenib, it also inhibits VEGFR and PDGFR, thereby weakening the capillaries of thyroid tissue, but unlike sunitinib, it appears to interact with TSH-mediated regulation, because TSH is involved in RAF, which is a target of sorafenib. However, the potential effects of sunitinib on normal thyroid function have not been thoroughly investigated, nor can sorafenib have less of a thyroid effect than sunitinib 6,40<\/sup>. <\/p>\n\n\n\n

Discussion<\/strong><\/p>\n\n\n\n

Over the past 50 years, cancer treatment has evolved\nfrom the use of a highly toxic drug such as nitrogen mustard (classic\ncytotoxic, acting on all cells and having an extremely limited margin of\nselectivity) until recent years when certain drugs have been introduced to have\nhormonal regulatory effects on tumor growth or the cell cycle control mechanism\nunderlying malignancies 41-44<\/sup>. These new drugs belong to targeted\nmolecular therapy that disrupt specific cell life signaling pathways and are\nmore tolerable than traditional cancer drugs (Figure 1)45,46<\/sup>. <\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 1: Summary of the TKI effects<\/strong><\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Molecularly targeted therapeutic drugs designed to act\non specific cellular targets that interfere with cell growth; this leads to a\ndecrease in nonspecific toxicity. Molecular targeted therapy indeed exhibits\nlower toxicity than traditional therapies, but this should not be\nunderestimated, as it can affect different areas of the body such as the\ncardiovascular, skin, lungs, liver, kidneys, thyroid, gastrointestinal tract\nand nerves 47 -50<\/sup>. Side effects are usually of low intensity and are\ntherefore more easily tolerated by patients; however, there may be degrees of\ntoxicity that must be addressed by discontinuation of therapy or other\npharmacological strategies. A distinction can also be made between targeted and\nuntargeted side effects. Targeted toxicity is due to the primary\npharmacological action of the drug (thus related to the drug’s mechanism of\naction) while off-target toxicity is due to a secondary pharmacological effect\nof the drug (which is not related to the drug’s mechanism of action)3<\/sup>.<\/p>\n\n\n\n

The most common endocrine disturbance associated with\nTKI use is hypothyroidism, which may develop ex-novo or, if pre-existing,\nrequires an adjustment in the thyroxine dose. Although TKI-induced\nhypothyroidism is only a manageable side effect, some results suggest a\npotential prognostic role in cancer treatment efficacy. For example, in a study\nwith sunitinib or sorafenib in patients with metastatic CRC, the clinical picture\nof hypothyroidism was found in 21 out of 66 patients (38.1%) and was associated\nwith a better chance of survival (16.0 \u00b1 0.8 months versus 6.0\u00b10.8 months,\np=0.032)51<\/sup>. An explanation for the association between\nhypothyroidism and increased chances of survival after TKI treatment may be due\nto the inhibitory effect of hypothyroidism on tumor growth. The proposed\nmechanism suggests that thyroid hormone may stimulate the growth of certain\ntypes of tumors by acting directly or indirectly by regulating the expression\nof certain growth factors 6<\/sup>. Clinical data show how hypothyroidism\ncan inhibit tumor growth: in breast cancer patients, hypothyroidism is\nfavorably associated with a lower risk of tumor development, less aggressive\ntumor, and advanced age 6,52<\/sup>.<\/p>\n\n\n\n

Since data have suggested that the presence of\nhypothyroidism due to TKIs is associated with improved treatment efficacy,\ntreatment of hypothyroidism may lead to worsening clinical outcomes 53-57<\/sup>.\nIndeed, thyroid hormone replacement therapy may be permitted in patients with\ncancer who are active or in remission. However, elevated serum VEGF values\n\u200b\u200bhave been identified in most hypothyroid patients receiving hormone\nreplacement therapy 58\u201362<\/sup>. It should be noted that some studies have\nfailed to show a life expectancy benefit related to the development of\nhypothyroidism 6,63-65<\/sup>.<\/p>\n\n\n\n

There are currently no recommendations for monitoring thyroid activity during treatment with TKIs and the interval for periodic measurement of TSH levels has not been determined. There are various suggestions, such as measuring thyroid function on the first day of each treatment cycle. However, it is certainly necessary to monitor thyroid function even after the end of TKI therapy to check its recovery 66-74<\/sup>. A reasonable approach is to monitor thyroid function, both before and for 2-4 weeks after the end of treatment. If elevated TSH values \u200b\u200bare found shortly after stopping treatment, hypothyroidism is likely to persist and should be treated with thyroxine, as it may worsen in subsequent cycles of treatment. However, at present, further evaluation of the progression of thyroid function in TKI-treated patients is still needed to determine appropriate therapeutic measures 73-76<\/sup>.<\/p>\n\n\n\n

Conclusions<\/strong><\/p>\n\n\n\n

The use of molecularly targeted drugs in therapy has\nresulted in improvements in the fight against cancer, as the therapeutic effect\nis more selective and the incidence of adverse events and toxicity is smaller\nthan in the past. Furthermore, these effects are usually dose dependent and\nreversible. However, early symptoms of toxicity due to molecularly targeted\ntherapies are often unrecognized by patients and not reported to oncologists.\nThese first symptoms can develop into situations that are very dangerous and\nrisky for the patient’s health, and in some (rare) cases even lead to the death\nof the patient.<\/p>\n\n\n\n

Therefore, patients should be monitored by the\ntreating physician and properly informed about possible toxic effects so that\nthey can be treated consciously and can be reported to the physician during the\nclinical examination.<\/p>\n\n\n\n

Acknowledgments<\/strong><\/p>\n\n\n\n

The authors thank\n\u201cFondazione per l\u2019Oncologia Pediatrica ONLUS\u201d for their dedicated patient care\nand scientific support.<\/p>\n\n\n\n

Conflict of Interest<\/strong><\/p>\n\n\n\n

The authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.<\/p>\n\n\n\n

Funding Sources<\/strong><\/p>\n\n\n\n

The authors received no specific funding for this work. <\/p>\n\n\n\n

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