**3.2. Thalidomide and lenalidomide**

Thalidomide and lenalidomide are immunomodulatory drugs with antineoplastic activity [63,64]. These agents enhance T-cell stimulation and proliferation, induce endogenous cytokine release, and increase number and function of natural killer cells, thus enhancing

immune-mediated destruction of tumor cells. They also inhibit proliferation and induce apoptosis of tumor cells and exert antiangiogenic activity [63,64].

Thyroid Function Abnormalities in Patients Receiving Anticancer Agents 317

insufficiency [84]. The prevalence of autoimmune hypophysitis varies among different studies (0%–17%) [85], being 3-5% in larger studies. Similarly to classical autoimmune hypophysitis, secondary hypothyroidism has been reported in patients who develop

Direct damage to the thyroid induced by these agents presents two clinical common forms: hyperthyroidism in Graves' disease and thyroid destruction with hypothyroidism in Hashimoto's thyroiditis. Since these conditions are classically included in autoimmune thyroid diseases phenotype and previous studies suggested that *CTLA-4* is a candidate gene conferring susceptibility to thyroid autoimmunity [86], an autoimmune pathogenesis has also been suggested for thyropathies induced by anti-CTLA4-mAbs (anti-CTLA4-IT). The incidence of these conditions varies from 0 to 4% among the different trials. In two studies [87,88], tremelimumab (15 mg/Kg body weight) was associated with thyreopathy (hyper- /hypothyroidism, autoimmune-thyroiditis, or Graves' disease) in 4% of cases. In studies on ipilimumab, the reported incidence of anti-CTLA4-IT was apparently lower, namely 0-2%, being mild hypothyroidism the most frequent thyroid side-effect. Recently, Hodi et al. in a large phase III trial, reported for the first time an improvement in overall survival obtained by ipilimumab in pretreated patients affected by metastatic melanoma [89]. The treatment was associated with thyroid disorders or abnormal thyroid function tests in approximately 2% of patients. In a randomized phase II study on a cohort of 115 patients affected by metastatic melanoma, evaluating the potential protective effect of budesonide on IRAEs induced by ipilimumab, hypothyroidism was diagnosed in 5.3% of patients who received ipilimumab with placebo (3 out of 57 patients; with severe hypothyroidism in one of them, 1.8%), compared with no cases in the group of patients treated with budesonide as well. These data suggest a potential protective effect of budesonide in terms of reduced incidence of ipilimimab-related thyroiditis,

but this hypothesis needs to be confirmed in specifically designed clinical trials [90].

not infrequently associated with autoimmune thyroiditis [92].

hormone supplementation [93].

In a phase I study [91] evaluating the combination of ipilimumab (10 mg/Kg every 3 weeks for 4 cycles, than every 3 months) with bevacizumab (7.5 mg/kg - Cohort 1; 15 mg/kg cohort 2 every 3 weeks) in a group of 21 patients affected by unresectable stage III or stage IV melanoma, thyroiditis was diagnosed in 4 (19%) patients. No cases of endocrine-IRAEs were reported in a trial on 36 patients who received both ipilimumab (0.1-3 mg/kg; 24 patients received the higher dose) and interleukin-2 (720,000 IU/kg every 8 hours) which is

The onset of anti-CTLA4-IT appears rather earlier than other IRAEs, occurring after 2-4 infusions. In most cases the anti-CTLA4-ITs have a subclinical course or may be transient. Alternatively, this condition may be characterized either by hypothyroidism with increased serum TSH concentrations, normal free-T4, and presence of anti-TPO antibodies, less frequently anti-TG antibodies or evolve in permanent hypothyroidism, requiring thyroid

Sporadic cases of Graves' ophthalmopathy associated with ipilimumab therapy in euthyroid patients have been reported [82,94]. In these cases the effective treatment was to administer a high dose of glucocorticoids in the acute phase, rapidly tapered down and continue with

hypophysitis induced by anti-CTLA-4 monoclonal antibodies.

Thalidomide and lenalidomide are approved for the treatment of multiple myeloma. Lenalidomide has also been approved for 5q myelodysplastic syndrome. Both agents are under evaluation for the treatment of several solid tumors, including thyroid cancer [65-67] and for a range of autoimmune diseases [68].

Hypothyroidism has been associated to treatment with these drugs with varying grades and frequency [68-71]. In a recent study on patients affected by multiple myeloma and treated with thalidomide [69], subclinical hypothyroidism was reported in 20% of participants, and 7% showed overt hypothyroidism, mostly occurring 1–6 months after initiating treatment [69].

Lenalidomide is more potent and showed a more favorable toxicity profile compared to thalidomide [72,73]. Hypothyroidism due to lenalidomide has been reported in 5%–10% of patients [74,75]. Thyroid abnormalities were found in 10 out of 170 patients who received lenalidomide for various hematological cancers. After a median of 5 months of therapy the patients reported both hypothyroidism and thyrotoxicosis. However, many of them had been exposed to prior radiation or thalidomide [76].

Many mechanisms have been suggested for the hypothyroidism induced by these drugs [69], including inhibition of thyroid hormone secretion [77] or a reduction of iodine uptake into follicular cells [78]. Most probably, since thalidomide and lenalidomide exert an antiangiogenic activity, compromise the blood flow to the thyroid may explain thyroid toxicity [69]. In some patients, TSH suppression has been documented before the development of hypothyroidism, suggesting ischemic thyroiditis [69]. Alternatively, a thyrotoxicosis triggered by an immune-mediated destructive thyroiditis may be hypothesized. This condition may be induced by deregulation of cytokine levels or through direct effects on T-lymphocytes [69]. A direct toxic effect on thyroid cells is also possible, but this has not been evaluated. TSH measurement before treatment and then every 2–3 months during treatment is recommended [1,79].
