Sunitinib-induced Hypothyroidism Research Articles

Tyrosine Kinase Inhibitors and Thyroid Toxicity

Some multithyrosine kinase inhibitors have been reported to cause changes in thyroid function. For the management of sunitinib-induced hypothyroidism, an evaluation of thyroid hormone and antibody profile is recommended before starting treatment with tyrosine kinase inhibitors. Patients with pre-existing thyroid dysfunction should undergo dose adjustment of L-thyroxine during treatment with tyrosine kinase inhibitors. Thyroid dysfunction is not a reason to discontinue or reduce the dosage of sunitinib. Their occurrence appears to correlate with increased antitumour efficacy of the inhibitor. There are currently no guidelines for monitoring thyroid activity during treatment with TKIs, and the time interval at which TSH should be periodically measured has not yet been determined. A reasonable approach is to monitor thyroid function, both before and during 2-4 weeks after the end of therapy. A comprehensive analysis of adverse events associated with the use of these inhibitors could help clinical monitoring of patients along with the adoption of appropriate management approaches.

Sunitinib-Induced Hypothyroidism and Survival in Pancreatic Neuroendocrine Tumors

AbstractSunitinib has been approved for the treatment of pancreatic neuroendocrine tumors, renal-cell carcinoma, and gastrointestinal stromal tumors. The elevation of thyroid-stimulating hormone serum levels is a common side effect. Studies suggest a correlation between sunitinib-induced hypothyroidism and treatment outcome in patients with renal-cell carcinoma and gastrointestinal stromal tumors. This study assessed whether sunitinib-induced hypothyroidism is a predictive marker of the objective response rate, progression-free survival, and overall survival in pancreatic neuroendocrine tumor patients. Twenty-nine patients treated with sunitinib for advanced pancreatic neuroendocrine tumors were included. The incidence of sunitinib-induced hypothyroidism was 33%. The median progression-free survival of patients who developed hypothyroidism was 16 months (95% confidence interval: 6.2–25.8 months) as compared with six months among euthyroid patients (95% confidence interval: 0.1–12.2 months) (p=0.02). The median overall survival was 77 months (95% confidence interval: 31.4–122.6 months) in hypothyroid patients but 12 months (95% confidence interval: 5.9–18.1 months) in subjects with euthyroidism (p=0.001). The median overall survival from the time of initial diagnosis ranged from 247 months in patients with hypothyroidism to 65 months in euthyroid subjects (p=0.015). Elevated thyroid-stimulating hormone levels are a prognostic biomarker of improved outcomes of sunitinib therapy in pancreatic neuroendocrine tumor patients.

\u0399mpact of sunitinib-induced hypothyroidism on survival of patients with metastatic renal cancer

BackgroundSunitinib plays an important role in managing the metastatic renal cell cancer (mRCC). Sunitinib-induced hypothyroidism is a common side-effect of the drug. There have been attempts to link hypothyroidism with a better clinical outcome in sunitinib-treated (mRCC) patients. Our aim was to relate the impact of hypothyroidism to the survival of these patients.MethodsWe have evaluated 70 patients with mRCC that received sunitinib as a first line treatment. Thyroid-stimulating hormone (TSH) was measured at baseline, after 15 days of treatment (day-15) and at the end of the second cycle (day-75).Biomarker data and correlations with response were analysed with Microsoft Excel. Comparison results from Student’s t-test with a p less than 0.05 were considered statistically significant. Kaplan-Meyer and log-rank tests were performed using GraphPad Prism 5 for Windows.ResultsRegarding the response to treatment, a progression-free survival (PFS) of 9.47 months and an overall survival (OS) of 22.03 months were demonstrated. Our data are consistent with published data by other authors.On day-15 from the beginning of the treatment an important number of patients exhibited a TSH elevation. On day-15 42.86% had a TSH over the upper normal limit and 50.0% at the end of the second cycle (day-75).TSH increased earlier in patients that exhibited an objective response (× 3.33 times the baseline values on day-15) than patients that exhibited disease stabilisation (× 2.18) or disease progression (× 1.59). Early increases in TSH were associated with a longer PFS (11.92 vs. 8.82 months, p = 0.0476) and a longer OS (3.10 vs. 1.08 years, p = 0.0011).ConclusionsEarly TSH-increase is associated with a clinical benefit. The patients that showed at least a twofold increase of their baseline TSH, responded to therapy by stabilisation or by regression of disease.This is the only study to our knowledge which shows that early increases - 2 weeks from starting the treatment - in TSH levels have a prognostic value. Both PFS and OS of the patients who demonstrated a higher than a twofold rise were significantly longer than the PFS and the OS of the patients that presented a lower or no TSH-increase.

P113 - Does sunitinib-induced hypothyroidism correlate with better outcomes in metastatic renal cell carcinoma?

P113 - Does sunitinib-induced hypothyroidism correlate with better outcomes in metastatic renal cell carcinoma?

Role of Sunitinib-Induced Hypothyroidism in Oncological Patients

Role of Sunitinib-Induced Hypothyroidism in Oncological Patients

Sunitinib-induced hypothyroidism predicts progression-free survival in metastatic renal cell carcinoma patients

Sunitinib is a tyrosine kinase inhibitor (TKI) used in treatment of metastatic renal cell carcinoma (mRCC), gastrointestinal stromal tumors and pancreatic neuroendocrine tumors. One of the most common side effects related to sunitinib is hypothyroidism. Recent trials suggest correlation between the incidence of hypothyroidism and treatment outcome in patients treated with TKI. This study evaluates whether development of hypothyroidism is a predictive marker of progression-free survival (PFS) in patients with mRCC treated with sunitinib. Twenty-seven patients diagnosed with clear cell mRCC, after nephrectomy and in ‘good’ or ‘intermediate’ MSKCC risk prognostic group, were included in the study. All patients received sunitinib as a first-line treatment on a standard schedule (initial dose 50 mg/day, 4 weeks on, 2 weeks off). The thyroid-stimulating hormone serum levels were obtained at the baseline and every 12 weeks of treatment. In statistic analyses, we used Kaplan–Meier method for assessment of progression-free survival; for comparison of survival, we used log-rank test. In our study, the incidence of hypothyroidism was 44%. The patients who had developed hypothyroidism had better median PFS to patients with normal thyroid function 28,3 months [95% (CI) 20.4–36.2 months] versus 9.8 months (6.4–13.1 months). In survival analysis, we perceive that thyroid dysfunction is a predictive factor of a progression-free survival (PFS). In the unified group of patients, the development of hypothyroidism during treatment with sunitinib is a positive marker for PFS. During that treatment, thyroid function should be evaluated regularly.

Is sunitinib-induced hypothyroidism a predictive clinical marker for better response in metastatic renal cell carcinoma patients?

Background: The main goal of this study was to examine whether the occurrence of hypothyroidism during sunitinib therapy in patients with metastatic renal cell carcinoma (mRCC) is associated with a better outcome.Methods: The study enrolled 81 patients with pathologically proven mRCC who were treated with sunitinib between March 2008 and June 2013.Thyroid function evaluation comprised (free-thyroxine) FT4 and thyroid-stimulating hormone (TSH) before treatment and at day 1 of each 6-week cycle. Survival analysis was performed using the Kaplan–Meier method, and the differences among the groups were determined using the log-rank test.Results: Hypothyroidism occurred in 30 (37%) of 81 patients within a median 3 months (range 1–18) of treatment initiation. There was a statistically significant correlation between the occurrence of hypothyroidism during treatment and the rate of objective remission (ORR) (hypothyroid patients vs euthyroid patients: 46.7 vs 13.7%, respectively; P = 0.001). Median progression-free survival (PFS) was 10 (95% CI 6.13–13.8) months in the euthyroid patients, and 17 (95% CI 9.33–24.6) months in the hypothyroid patients (P = 0.001). The median overall survival (OS) was 39 (95% CI 25.4–52.5) months in the hypothyroid patients and 20 (95% CI 14.7–25.2) months in the euthyroid patients (P = 0.019).Conclusions: The occurrence of hypothyroidism during treatment in patients was significantly associated with longer PFS, OS and better ORR in the current study.

Pleural and pericardial effusions combined with ascites in a patient with severe sunitinib-induced hypothyroidism

To best of our knowledge, this is the first reported case of pericardial and pleural effusions combined with ascites, precipitated with severe sunitinib-induced hypothyroidism. A 58-year-old man presented in our emergency department due to dyspnoea and dry cough. Sixteen months earlier, the patient underwent left nephrectomy due to metastatic renal cell adenocarcinoma (RCC), and therapy with sunitinib was initiated postoperatively. Thyroid function was not assessed during the therapy. On admission, all laboratory findings were within normal range. Computed tomography of the chest detected voluminous bilateral pleural effusions and mild pericardial effusion, and echocardiography revealed pericardial effusion. Thoracocentesis was carried out three times, and cytological examination showed no signs of malignant cells. After assessment of the thyroid function, neglected hypothyroidism was registered. Substitution therapy with levothyroxine was initiated, and thyroid function normalised 2 weeks later. Few days after the last thoracocentesis, his condition suddenly got worse. Thoracocentesis was repeated, and microbiological analysis of the exudate came positive for Klebsiella pneumoniae and Streptococcus pneumoniae. Despite the implemented therapeutic measures, his clinical condition progressively deteriorated. The patient died 27 days after the admission, hospital-acquired pneumonia was identified as the cause of death. Our case emphasises the necessity of careful monitoring and management of side-effects in patients who receive sunitinib. Hypothyroidism is a known cause of pleural, pericardial and abdominal effusions, as reported in several case reports. Timely initiation of substitution levothyroxine therapy can decrease unnecessary pauses in the therapy with sunitinib, as well as prevent development of severe symptoms.

Is sunitinib-induced hypothyroidism a predictive clinical marker for better response in metastatic renal cell carcinoma patients?

e15624 Background: The main goal of this study was to examine whether the occurrence of hypothyroidism during sunitinib therapy in patients with metastatic renal cell carcinoma (mRCC) is associated...

P135 The effect of sunitinib-induced hypothyroidism in the outcome of mRCC patients

P135 The effect of sunitinib-induced hypothyroidism in the outcome of mRCC patients

Risks associated with sunitinib use and monitoring to improve patient outcomes

Risks associated with sunitinib use and monitoring to improve patient outcomes

Severe hypothyroidism presenting as myxedema coma in the postoperative period in a patient taking sunitinib: case report and review of literature

The case of a 62-year-old Caucasian woman who underwent urgent hip hemiarthroplasty for repair of a pathological fracture is reported. The patient's medical history was significant for renal cell carcinoma, cerebellar metastases, and sunitinib-induced hypothyroidism. Her intraoperative course was complicated by profound hypothermia, bradycardia, augmentation of neuromuscular blockade, delayed emergence, failure of postoperative extubation, and need for mechanical ventilation. The intensive care course was significant for hypothermia requiring forced-air warming, treatment with intravenous thyroxine (T4), and hemodynamic supportive care.

Extreme hypothyroidism associated with sunitinib treatment for metastatic renal cancer

Although thyroid abnormalities are reported with the use of tyrosine kinase inhibitors, patients rarely require replacement therapy. The initial multicentre studies of sunitinib for metastatic renal cancer did not report hypothyroidism in fatigued patients, and thyroid tests were not routinely monitored. More recent studies, however, suggest that up to 70% of patients develop thyroid test abnormalities during treatment with sunitinib. Despite these concerns, the clinical relevance of sunitinib-induced hypothyroidism is uncertain since thyroid gland recovery is the norm in most patients. We report a case of a patient with metastatic papillary renal cell cancer on combination anti-angiogenic therapy with sunitinib, who developed unusually high thyroid stimulating hormone levels and severe symptoms despite receiving L-thyroxine. Our case also illustrates the complexity of managing sunitinib-associated thyroid dysfunction, which may be accompanied by transient thyroiditis, hyperthyroidism, and profound hypothyroidism.

Does Sunitinib-Induced Hypothyroidism Play a Role in the Activity of Sunitinib in Metastatic Renal Cell Carcinoma?

Background: The objective of this study was to evaluate if hypothyroidism developing during sunitib therapy in patients with metastatic renal cell carcinoma (mRCC) is associated with a better outcome. Methods: Thirty-one consecutive patients with clear cell mRCC were retrospectively analyzed. Thyroid function was assessed prior to therapy, every 6 weeks during the first 6 months and every 2–4 months thereafter. Hypothyroidism was considered present if thyroid-stimulating hormone (TSH) exceeded the upper normal limit (UNL) with normal triiodothyronine (T3) and thyroxine (T4). Results: Hypothyroidism occurred in 16 patients (52%) within 3 months (range 0.7–22.9) of treatment initiation. Thyroid replacement corrected TSH below the UNL in 10 patients (63%). The distribution according to Motzer prognostic criteria revealed good prognosis in 16 patients (52%), intermediate in 9 (29%) and poor in 6 (19%). The hypothyroid patients tended to have longer progression-free survival (PFS; median 12.2 vs. 9.4 months; p = 0.234) and longer survival (median 22.4 vs. 13.9 months; p = 0.234) than the euthyroid patients. Clinical benefits were similar in both groups. Conclusions: Hypothyroidism that develops in mRCC patients treated with sunitinib is associated with a trend toward prolonged PFS and survival, with a similar clinical benefit rate.

Association of hypothyroidism with improved outcomes in first-line treatment of renal cell carcinoma with sunitinib.

466 Background: Sunitinib, a multitarget tyrosine-kinase inhibitor, has become a standard of care for first-line low and intermediate risk metastatic renal cell carcinoma (mRCC). Sunitinib-induced hypothyroidism and hypertension have been correlated with better outcomes in those patients. Methods: Fifty patients with mRCC, treated in the first-line with sunitinib, were retrospective analyzed at one brazilian institution, for overall survival (OS), progression free survival (PFS), overall response rate (ORR) and toxicity. We evaluated clinical and laboratory parameters, such as hypothyroidism (TSH level > 5,5 mIU/L) and hypertension, to identify prognostic factors. Results: The median age of patients was 58 years (range: 37-73 years), 82% were male, 54% were ECOG 0 or 1, and 76% were classified in low or intermediate risk. Nefrectomy was performed in 96% of cases. Lung and bone were the most common sites of metastases. The incidence of hypothyroidism and hypertension during treatment were 40% and 34%, respectively. ORR for the entire population was 40% and it was statistically superior in patients that developed hypothyroidism during treatment (90% vs. 20%; p<0,0001). Median survival and PFS were 21.7 months (10.65-17.70 months, 95% CI) and 14.2 months (15.77-27.58 months, 95% CI), respectively. In univariate analysis, ECOG (p<0,0001), MSKCC criteria (p<0,0001), hypothyroidism (p<00001) and hypertension (p=0,001) were associated with OS. In multivariate analysis, ECOG (p<0,0001), MSKCC criteria (p<0,0001) and hypothyroidism (p<00001) were independent prognostic factors for OS. The most common severe adverse events (G3-4) were asthenia (14%), diarrhoea (6%), neutropenia (14%), thrombocytopenia (10%), hand-foot syndrome (6%) and hypertension (8%). Conclusions: Efficacy in survival and toxicity profile of sunitinib in first-line treatment of mRCC in patients out of clinical trials were comparable to prior studies. Hypothyroidism, MSKCC criteria and ECOG were independent prognostic factors for survival.

Sunitinib-Induced Hypothyroidism Is due to Induction of Type 3 Deiodinase Activity and Thyroidal Capillary Regression

Sunitinib-Induced Hypothyroidism Is due to Induction of Type 3 Deiodinase Activity and Thyroidal Capillary Regression

A Case of Sunitinib-Induced Destructive Thyroiditis

Sunitinib is a multi-targeted tyrosine-kinase inhibitor used for gastrointestinal stromal tumors and renal cell carcinoma (RCC). Sev-eral recent studies have reported sunitinib-induced hypothyroidism and thyroid dysfunction; however, the underlying mechanisms are not clear. Here, we report a patient with metastatic RCC, who developed destructive thyroidtis due to sunitinib treatment. The course followed in this case may be useful in understanding the clinical course of sunitinib-induced thyroiditis. (

Sunitinib-Induced Hypothyroidism Is due to Induction of Type 3 Deiodinase Activity and Thyroidal Capillary Regression

Anticancer treatment with the tyrosine kinase inhibitor sunitinib causes thyroid dysfunction. Our objective was to investigate the time course and underlying mechanisms of sunitinib-induced thyroid dysfunction. Thyroid function tests of 83 patients on sunitinib were collected retrospectively for their total treatment duration between January 2006 and November 2009 and prospectively in 15 patients on sunitinib for 10 wk. Additionally, thyroid function and histology were assessed in rats on sunitinib (8 d; n = 10) and after sunitinib withdrawal (11 d; n = 7) and compared with controls (n = 7). Patients were seen at a university outpatient oncology clinic. Patients and Animals: Patients with metastatic renal cell carcinoma or gastrointestinal stromal tumors participated in the clinical study and Wistar Kyoto rats were used in the rat study. Sunitinib was taken according to a 4 wk "on," 2 wk "off" treatment regimen. Blood samples for measurement of thyroid function were collected at baseline and at wk 4 and 10. In rats, blood, liver, and thyroid were collected to assess thyroid hormones, deiodinase activity, and thyroid histology. TSH and free T(4) levels, deiodinase activity, and thyroid histology were assessed. Forty-two percent of patients in the retrospective study developed elevated TSH levels. Prospective analysis showed increased TSH levels within 10 wk of treatment, accompanied by a decreased T(3)/rT(3) ratio. In rats, serum T(4) and T(3) decreased, hepatic type 3 deiodinase activity increased, and thyroid histology showed marked capillary regression, which all but thyroid hormones reversed after sunitinib withdrawal. Sunitinib induces hypothyroidism due to alterations in T(4)/T(3) metabolism as well as thyroid capillary regression.

Sunitinib-induced severe hypothyroidism with cardiac compromise

Tyrosine kinase inhibitors (TKI) are an increasingly used class of anti-cancer agent. Sunitinib (sutent(®), Pfizer™, New York) is standard first-line therapy for patients with metastatic renal cancer. It is associated with a number of toxicities, including thyroid dysfunction. We present a case of sunitinib-induced severe hypothyroidism resulting in cardiac compromise. The case highlights the importance of interval thyroid function monitoring for patients on drugs, such as sunitinib and other TKIs.

The impact of sunitinib-induced hypothyroidism on progression-free survival of metastatic renal cancer patients: A prospective single-center study

BackgroundSeveral studies have reported unexpected rates of hypothyroidism in patients treated with sunitinib. The biochemical basis of this impairment is unknown. A relationship between hypothyroidism and improved outcome has been suggested in some cancer patients. Here we describe the incidence of newly onset hypothyroidism and its relationship with progression-free survival in metastatic renal cell carcinoma patients undergoing sunitinib treatment at our institution. Patients and methodsBetween July 2007 and June 2009, 22 patients received a first line sunitinib for metastatic renal cell carcinoma. Thyroid function tests were prospectively evaluated as routine laboratory assessment in every patient, at baseline and on the first and last day of every ON and OFF sunitinib period. ResultsThe median duration of treatment was 39.5 weeks. During sunitinib therapy, 13 patients (59.1%) showed at least one elevated TSH level. No reductions of TSH below normal ranges were observed. L-thyroxine replacement therapy was required in 2 patients. Based on thyroid function, median progression-free survival was 8.55 months for hypothyroid compared with 7.03 months for euthyroid patients (P < 0.05). ConclusionPatients administered sunitinib have an high incidence of hypothyroidism. The improved outcome of hypothyroid patients suggests an important relationship between sunitinib and this uncommon side effect.